|
1
|
Merle-Nguyen L, Ando-Grard O, Bourgon C, St Albin A, Jacquelin J, Klonjkowski B, Le Poder S, Meunier N. Early corticosteroid treatment enhances recovery from SARS-CoV-2 induced loss of smell in hamster. Brain Behav Immun 2024; 118:78-89. [PMID: 38367845 DOI: 10.1016/j.bbi.2024.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 02/03/2024] [Accepted: 02/14/2024] [Indexed: 02/19/2024] Open
Abstract
Among the numerous long COVID symptoms, olfactory dysfunction persists in ∼10 % of patients suffering from SARS-CoV-2 induced anosmia. Among the few potential therapies, corticoid treatment has been used for its anti-inflammatory effect with mixed success in patients. In this study, we explored its impact using hamster as an animal model. SARS-CoV-2 infected hamsters lose their smell abilities and this loss is correlated with damage of the olfactory epithelium and persistent presence of innate immunity cells. We started a dexamethasone treatment 2 days post infection, when olfaction was already impacted, until 11 days post infection when it started to recover. We observed an improvement of olfactory capacities in the animals treated with corticoid compared to those treated with vehicle. This recovery was not related to differences in the remaining damage to the olfactory epithelium, which was similar in both groups. This improvement was however correlated with a reduced inflammation in the olfactory epithelium with a local increase of the mature olfactory neuron population. Surprisingly, at 11 days post infection, we observed an increased and disorganized presence of immature olfactory neurons, especially in persistent inflammatory zones of the epithelium. This unusual population of immature olfactory neurons coincided with a strong increase of olfactory epithelium proliferation in both groups. Our results indicate that persistent inflammation of the olfactory epithelium following SARS-CoV-2 infection may alter the extent and speed of regeneration of the olfactory neuron population, and that corticoid treatment is effective to limit inflammation and improve olfaction recovery following SARS-CoV-2 infection.
Collapse
Affiliation(s)
- Laetitia Merle-Nguyen
- Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay, Jouy-en-Josas, France
| | - Ophélie Ando-Grard
- Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay, Jouy-en-Josas, France
| | - Clara Bourgon
- Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay, Jouy-en-Josas, France
| | - Audrey St Albin
- Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay, Jouy-en-Josas, France
| | - Juliette Jacquelin
- Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay, Jouy-en-Josas, France
| | - Bernard Klonjkowski
- UMR 1161 Virologie, INRAE-ENVA-ANSES, École Nationale Vétérinaire d'Alfort, Maisons-Alfort, 94704 Paris, France
| | - Sophie Le Poder
- UMR 1161 Virologie, INRAE-ENVA-ANSES, École Nationale Vétérinaire d'Alfort, Maisons-Alfort, 94704 Paris, France
| | - Nicolas Meunier
- Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay, Jouy-en-Josas, France.
| |
Collapse
|
|
2
|
Jang SS, Pak KS, Strom A, Gomez L, Kim K, Doherty TA, DeConde AS, Ryan AF, Yan CH. Pro-inflammatory markers associated with COVID-19-related persistent olfactory dysfunction. Int Forum Allergy Rhinol 2024; 14:786-793. [PMID: 37676246 PMCID: PMC10918027 DOI: 10.1002/alr.23264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 08/24/2023] [Accepted: 08/25/2023] [Indexed: 09/08/2023]
Abstract
INTRODUCTION While localized inflammation has been implicated in the pathophysiology of acute coronavirus disease of 2019 (COVID-19) olfactory dysfunction (OD), persistent COVID-19 OD remains poorly understood with limited therapeutics. Our prospective study evaluated olfactory cleft (OC) biomarkers as predictors of persistent OD in mucus sampling. METHODS COVID-19 subjects with persistent OD >3 months confirmed by psychophysical olfaction tests were compared to COVID-19 subjects with no OD and those with no prior infection. OC mucus samples were evaluated for 13 anti-viral and inflammatory biomarkers. Cohorts were compared using analysis of variance (ANOVA) and Mann-Whitney tests with multi-comparison adjustment. Viral RNA was assessed through RT-PCR using the COVID-19 N2 primer. RESULTS Thirty-five samples were collected (20 COVID persistent OD, 8 COVID no OD, and 7 non-COVID no OD). Significant differences in IFN-λ1 (p = 0.007) and IFN-γ (p = 0.006) expression in OC mucus were found across all three groups, with the highest cytokine concentrations corresponding to COVID OD. IFN-α2 levels were elevated in COVID OD versus no OD (p = 0.026). Mean IFN-γ levels were the highest in COVID OD, but there were higher levels found in COVID no OD compared to non-COVID no OD (p = 0.008). No difference was seen in IL6. No N2 gene expression was detected in all cohorts. CONCLUSION IFN pathway cytokines were found elevated in the olfactory microenvironment of COVID-19 persistent OD compared to those with no OD and no prior history of COVID-19 infection.
Collapse
Affiliation(s)
- Sophie S Jang
- Department of Otolaryngology, Head and Neck Surgery, University of California San Diego, La Jolla, California, USA
| | - Kwang S Pak
- Department of Otolaryngology, Head and Neck Surgery, University of California San Diego, La Jolla, California, USA
| | - Allyssa Strom
- Division of Rheumatology, Allergy & Immunology, University of California San Diego, La Jolla, California, USA
| | - Leslie Gomez
- Department of Otolaryngology, Head and Neck Surgery, University of California San Diego, La Jolla, California, USA
| | - Kyubo Kim
- Department of Otolaryngology, Head and Neck Surgery, University of California San Diego, La Jolla, California, USA
| | - Taylor A Doherty
- Division of Rheumatology, Allergy & Immunology, University of California San Diego, La Jolla, California, USA
| | - Adam S DeConde
- Department of Otolaryngology, Head and Neck Surgery, University of California San Diego, La Jolla, California, USA
| | - Allen F Ryan
- Department of Otolaryngology, Head and Neck Surgery, University of California San Diego, La Jolla, California, USA
| | - Carol H Yan
- Department of Otolaryngology, Head and Neck Surgery, University of California San Diego, La Jolla, California, USA
| |
Collapse
|
|
3
|
Ramirez-Gil LS, Ley-Tomas JJ, Hernaiz-Leonardo JC, Alobid I, Mullol J, Ceballos-Cantu JC. Effects of Endoscopic Sinus Surgery on Olfactory Function. Curr Allergy Asthma Rep 2023; 23:715-731. [PMID: 38038879 DOI: 10.1007/s11882-023-01115-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2023] [Indexed: 12/02/2023]
Abstract
PURPOSE OF REVIEW To review the effects of endoscopic sinus surgery and endonasal approaches to the skull base on olfaction. RECENT FINDINGS Advancements in endonasal endoscopic approaches to the sinuses and skull base allow for direct treatment of a variety of sinonasal and skull base diseases. However, these extended approaches will often require manipulation of normal anatomical structures and the olfactory neuroepithelium. Depending on the planned procedure and extent of disease, the prognosis of olfactory perception can vary significantly among patients. Endoscopic sinonasal surgical procedures may impact olfaction. Optimizing olfactory function requires proper surgical techniques, gentle handling of tissue, and perioperative care. Surgeons must discuss objectives and manage patient expectations. Routine olfactory assessment is crucial in surgical work-up and follow-up. Preserving anatomical structures while addressing the obstruction of the olfactory cleft helps to prevent decreased olfactory threshold. However, smell identification and discrimination do not always correlate with sinonasal anatomy.
Collapse
Affiliation(s)
- L Stefano Ramirez-Gil
- Department of Otolaryngology-Head and Neck Surgery, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Vasco de Quiroga 15 Tlalpan, CDMX 14080, Mexico
| | - J J Ley-Tomas
- Department of Otolaryngology-Head and Neck Surgery, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, CDMX, Mexico
| | - J C Hernaiz-Leonardo
- Department of Otolaryngology - Head and Neck Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Isam Alobid
- Rhinology and Skull Base Unit, Department of Otorhinolaryngology, Hospital Clinic. Barcelona, Barcelona, Catalonia, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Catalonia, Spain
- Universitat de Barcelona., Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Joaquim Mullol
- Rhinology and Skull Base Unit, Department of Otorhinolaryngology, Hospital Clinic. Barcelona, Barcelona, Catalonia, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Catalonia, Spain
- Universitat de Barcelona., Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - J C Ceballos-Cantu
- Department of Otolaryngology-Head and Neck Surgery, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Vasco de Quiroga 15 Tlalpan, CDMX 14080, Mexico.
| |
Collapse
|
|
4
|
Li P, Wang N, Kai L, Si J, Wang Z. Chronic intranasal corticosteroid treatment induces degeneration of olfactory sensory neurons in normal and allergic rhinitis mice. Int Forum Allergy Rhinol 2023; 13:1889-1905. [PMID: 36800514 DOI: 10.1002/alr.23142] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 01/31/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023]
Abstract
BACKGROUND Nasal eosinophilic inflammation is the therapeutic target for olfactory dysfunction in allergic rhinitis (AR). Intranasal corticosteroids are commonly considered to offer targetable benefit given their immunosuppressive property. However, experimental evidence suggests that continuous corticosteroid exposure may directly cause olfactory damage by disrupting the turnover of olfactory sensory neurons (OSNs). This potentially deleterious effect of corticosteroids calls into question their long-term topical use for treating olfactory loss related to AR. The aim of this study was to assess the impacts of chronic intranasal corticosteroid treatment on olfactory function and OSN population in mice under normal and pathological conditions. METHODS BALB/c mice were intranasally treated with fluticasone propionate (FP, 0.3 mg/kg) for up to 8 weeks. Additional mice were used to establish an ovalbumin-induced mouse model of AR, followed by nasal challenge with ovalbumin for 8 weeks in the presence or absence of intranasal FP treatment. The authors examined olfactory function, OSN existence, neuronal turnover, and nasal inflammation using behavioral test, histological analyses, Western blotting, and enzyme-linked immunosorbent assay. RESULTS Intranasal treatment with FP for 8 weeks (FP-wk8) reduced odor sensitivity in normal mice. This reduction was concomitant with loss of OSNs and the axons projecting to the olfactory bulb, primarily resulting from increased neuronal apoptosis. In FP-wk8 AR mice, intranasal FP treatment attenuated olfactory impairment and eosinophilic inflammation but failed to reconstitute OSN population and axonal projections. CONCLUSION These results suggest that chronic intranasal corticosteroid treatment contributes to OSN degeneration that may reduce the therapeutic effectiveness for AR-related olfactory loss.
Collapse
Affiliation(s)
- Pu Li
- Department of Otolaryngology-Head and Neck Surgery, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Na Wang
- Department of Otolaryngology-Head and Neck Surgery, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Luo Kai
- Department of Otolaryngology-Head and Neck Surgery, Peking University Shougang Hospital, Beijing, China
| | - Jinyuan Si
- Department of Otolaryngology-Head and Neck Surgery, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Zhenlin Wang
- Department of Otolaryngology-Head and Neck Surgery, Xuanwu Hospital Capital Medical University, Beijing, China
| |
Collapse
|
|
5
|
Cheng N, Wang Y, Gu Z. Understanding the role of NLRP3-mediated pyroptosis in allergic rhinitis: A review. Biomed Pharmacother 2023; 165:115203. [PMID: 37481928 DOI: 10.1016/j.biopha.2023.115203] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/12/2023] [Accepted: 07/18/2023] [Indexed: 07/25/2023] Open
Abstract
Allergic rhinitis (AR) is a chronic, inflammatory disease of the nasal mucosa, caused by the immunoglobulin E-mediated immune response. The annual incidence rate of AR is on the rise, exerting a significant impact on individuals' physical and mental wellbeing. The treatment effect in some patients is still not ideal, as the pathogenesis of AR is complex and diverse. Recent studies have shown that NLRP3 inflammasome-mediated pyroptosis is widely involved in the occurrence and development of AR through various pathways. This article reviews the mechanism of pyroptosis and its research progress in the field of AR, and puts forward possible therapeutic targets to offer innovative approaches for its management.
Collapse
Affiliation(s)
- Nuo Cheng
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China
| | - Yunxiu Wang
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
| | - Zhaowei Gu
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
| |
Collapse
|
|
6
|
Verma AK, Zheng J, Meyerholz DK, Perlman S. SARS-CoV-2 infection of sustentacular cells disrupts olfactory signaling pathways. JCI Insight 2022; 7:e160277. [PMID: 36378534 PMCID: PMC9869979 DOI: 10.1172/jci.insight.160277] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Loss of olfactory function has been commonly reported in SARS-CoV-2 infections. Recovery from anosmia is not well understood. Previous studies showed that sustentacular cells, and occasionally olfactory sensory neurons (OSNs) in the olfactory epithelium (OE), are infected in SARS-CoV-2-infected patients and experimental animals. Here, we show that SARS-CoV-2 infection of sustentacular cells induces inflammation characterized by infiltration of myeloid cells to the olfactory epithelium and variably increased expression of proinflammatory cytokines. We observed widespread damage to, and loss of cilia on, OSNs, accompanied by downregulation of olfactory receptors and signal transduction molecules involved in olfaction. A consequence of OSN dysfunction was a reduction in the number of neurons in the olfactory bulb expressing tyrosine hydroxylase, consistent with reduced synaptic input. Resolution of the infection, inflammation, and olfactory dysfunction occurred over 3-4 weeks following infection in most but not all animals. We also observed similar patterns of OE infection and anosmia/hyposmia in mice infected with other human coronaviruses such as SARS-CoV and MERS-CoV. Together, these results define the downstream effects of sustentacular cell infection and provide insight into olfactory dysfunction in COVID-19-associated anosmia.
Collapse
Affiliation(s)
| | - Jian Zheng
- Department of Microbiology and Immunology and
| | | | | |
Collapse
|
|
7
|
LaFever BJ, Imamura F. Effects of nasal inflammation on the olfactory bulb. J Neuroinflammation 2022; 19:294. [PMID: 36494744 PMCID: PMC9733073 DOI: 10.1186/s12974-022-02657-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
Sinonasal diseases, such as rhinosinusitis, affect up to 12% of individuals each year which constitutes these diseases as some of the most common medical conditions in the world. Exposure to environmental pathogens and toxicants via the nasal cavity can result in a severe inflammatory state commonly observed in these conditions. It is well understood that the epithelial and neuronal cells lining the olfactory mucosa, including olfactory sensory neurons (OSNs), are significantly damaged in these diseases. Prolonged inflammation of the nasal cavity may also lead to hyposmia or anosmia. Although various environmental agents induce inflammation in different ways via distinct cellular and molecular interactions, nasal inflammation has similar consequences on the structure and homeostatic function of the olfactory bulb (OB) which is the first relay center for olfactory information in the brain. Atrophy of the OB occurs via thinning of the superficial OB layers including the olfactory nerve layer, glomerular layer, and superficial external plexiform layer. Intrabulbar circuits of the OB which include connectivity between OB projection neurons, OSNs, and interneurons become significantly dysregulated in which synaptic pruning and dendritic retraction take place. Furthermore, glial cells and other immune cells become hyperactivated and induce a state of inflammation in the OB which results in upregulated cytokine production. Moreover, many of these features of nasal inflammation are present in the case of SARS-CoV-2 infection. This review summarizes the impact of nasal inflammation on the morphological and physiological features of the rodent OB.
Collapse
Affiliation(s)
- Brandon J. LaFever
- grid.240473.60000 0004 0543 9901Department of Pharmacology, Penn State College of Medicine, 500 University Dr., Hershey, PA 17033 USA
| | - Fumiaki Imamura
- grid.240473.60000 0004 0543 9901Department of Pharmacology, Penn State College of Medicine, 500 University Dr., Hershey, PA 17033 USA
| |
Collapse
|
|
8
|
Hernandez AK, Juratli L, Haehner A, Hsieh JW, Landis BN, Hummel T. Assessment of olfactory fluctuations in a clinical context. Eur Arch Otorhinolaryngol 2022; 279:5685-5690. [PMID: 35661914 PMCID: PMC9649505 DOI: 10.1007/s00405-022-07462-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/18/2022] [Indexed: 01/04/2023]
Abstract
PURPOSE The aim of the study was to investigate whether olfactory fluctuations (OF) are pronounced in patients with sinonasal olfactory dysfunction (OD). METHODS The retrospective investigation included patients aged 18 years or older, who consulted a tertiary referral center for olfactory loss. Patients with normal smell function were excluded. Patients answered a structured questionnaire about their olfactory symptoms, with specific questions related to the presence of OF and its average frequency, amplitude, duration, time since most recent OF, and associated symptoms of self-reported OF. Patients also underwent clinical evaluation including a structured medical history and physical examination including nasal endoscopy. In addition, we assessed orthonasal olfactory function using Sniffin' Sticks, and gustatory function using "taste sprays". RESULTS Participants included 131 men and 205 women (n = 336), aged 18 to 86 years (mean 50, SD 16). Patient-reported fluctuations occurred most frequently in sinonasal (38%), idiopathic (29%), and postviral (29%) OD. Amplitude of OF was highest in postviral OD (p = 0.009). Average frequency, duration, and the time since the most recent fluctuation were not significantly different between groups (all p's > 0.42). Odor discrimination (p = 0.002) and identification (p = 0.017) scores were higher among those individuals with OF. CONCLUSION Amplitude of OF may help distinguish postviral from other causes of OD, especially in patients presenting with equivocal symptoms of sinonasal disease.
Collapse
Affiliation(s)
- Anna Kristina Hernandez
- Smell and Taste Clinic, Department of Otorhinolaryngology, Technische Universität Dresden, Haus 5, Fetscherstrasse 74, 01307, Dresden, Germany.
| | - Lena Juratli
- Smell and Taste Clinic, Department of Otorhinolaryngology, Technische Universität Dresden, Haus 5, Fetscherstrasse 74, 01307, Dresden, Germany
- University of Michigan Medical School, Ann Arbor, MI, USA
| | - Antje Haehner
- Smell and Taste Clinic, Department of Otorhinolaryngology, Technische Universität Dresden, Haus 5, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Julien W Hsieh
- Rhinology-Olfactology Unit, Department of Otorhinolaryngology, University of Geneva, Geneva, Switzerland
| | - Basile N Landis
- Rhinology-Olfactology Unit, Department of Otorhinolaryngology, University of Geneva, Geneva, Switzerland
| | - Thomas Hummel
- Smell and Taste Clinic, Department of Otorhinolaryngology, Technische Universität Dresden, Haus 5, Fetscherstrasse 74, 01307, Dresden, Germany
| |
Collapse
|
|
9
|
Mechin V, Asproni P, Bienboire-Frosini C, Cozzi A, Chabaud C, Arroub S, Mainau E, Nagnan-Le Meillour P, Pageat P. Inflammation interferes with chemoreception in pigs by altering the neuronal layout of the vomeronasal sensory epithelium. Front Vet Sci 2022; 9:936838. [PMID: 36172609 PMCID: PMC9510685 DOI: 10.3389/fvets.2022.936838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/18/2022] [Indexed: 11/22/2022] Open
Abstract
Chemical communication is widely used by animals to exchange information in their environment, through the emission and detection of semiochemicals to maintain social organization and hierarchical rules in groups. The vomeronasal organ (VNO) is one of the main detectors of these messages, and its inflammation has been linked to behavioral changes because it potentially prevents molecule detection and, consequently, the translation of the signal into action. Our previous study highlighted the link between the intensity of vomeronasal sensory epithelium (VNSE) inflammation, probably induced by farm contaminant exposure, and intraspecific aggression in pigs. The aim of this study was to evaluate the cellular and molecular changes that occur during vomeronasalitis in 76 vomeronasal sensorial epithelia from 38 intensive-farmed pigs. Histology was used to evaluate the condition of each VNO and classify inflammation as healthy, weak, moderate, or strong. These data were compared to the thickness of the sensorial epithelium and the number of type 1 vomeronasal receptor cells using anti-Gαi2 protein immunohistochemistry (IHC) and analysis. The presence of odorant-binding proteins (OBPs) in the areas surrounding the VNO was also analyzed by IHC and compared to inflammation intensity since its role as a molecule transporter to sensory neurons has been well-established. Of the 76 samples, 13 (17%) were healthy, 31 (41%) presented with weak inflammation, and 32 (42%) presented with moderate inflammation. No severe inflammation was observed. Epithelial thickness and the number of Gαi2+ cells were inversely correlated with inflammation intensity (Kruskal–Wallis and ANOVA tests, p < 0.0001), while OBP expression in areas around the VNO was increased in inflamed VNO (Kruskal–Wallis test, p = 0.0094), regardless of intensity. This study showed that inflammation was associated with a reduction in the thickness of the sensory epithelium and Gαi2+ cell number, suggesting that this condition can induce different degrees of neuronal loss. This finding could explain how vomeronasalitis may prevent the correct functioning of chemical communication, leading to social conflict with a potential negative impact on welfare, which is one of the most important challenges in pig farming.
Collapse
Affiliation(s)
- Violaine Mechin
- Tissue Biology and Chemical Communication Department, IRSEA, Institute of Research in Semiochemistry and Applied Ethology, Apt, France
- *Correspondence: Violaine Mechin
| | - Pietro Asproni
- Tissue Biology and Chemical Communication Department, IRSEA, Institute of Research in Semiochemistry and Applied Ethology, Apt, France
| | - Cécile Bienboire-Frosini
- Molecular Biology and Chemical Communication Department, IRSEA, Institute of Research in Semiochemistry and Applied Ethology, Apt, France
| | - Alessandro Cozzi
- Research and Education Board, IRSEA, Institute of Research in Semiochemistry and Applied Ethology, Apt, France
| | - Camille Chabaud
- Molecular Biology and Chemical Communication Department, IRSEA, Institute of Research in Semiochemistry and Applied Ethology, Apt, France
| | - Sana Arroub
- Statistics and Data Management Service, IRSEA, Institute of Research in Semiochemistry and Applied Ethology, Apt, France
| | - Eva Mainau
- Department of Animal and Food Science, School of Veterinary Science, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Patrick Pageat
- Research and Education Board, IRSEA, Institute of Research in Semiochemistry and Applied Ethology, Apt, France
| |
Collapse
|
|
10
|
Chemosensory Functions in Patients with Inflammatory Bowel Disease and Their Association with Clinical Disease Activity. Nutrients 2022; 14:nu14173543. [PMID: 36079801 PMCID: PMC9460206 DOI: 10.3390/nu14173543] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/17/2022] [Accepted: 08/25/2022] [Indexed: 12/29/2022] Open
Abstract
Purpose: Decreased olfactory and gustatory functions are present in various systemic autoimmune diseases. However, little is known about the chemosensory functions of patients with inflammatory bowel disease (IBD). The present study aimed to investigate olfactory and gustatory functions in patients with IBD and their correlation with clinical disease activity. Methods: A total of 103 patients with IBD were included (52 men, 51 women, mean age 40.3 ± 1.2 years) in the present study. Chemosensory functions were assessed utilizing the “Sniffin’ Sticks” olfactory function test and “taste sprays” gustatory function test. The clinical disease activity of patients was graded as remission, mild, and moderate−severe. In addition, inflammatory markers (fecal calprotectin, C-reactive protein and blood leucocyte count) were recorded. Results: In total, 70% of IBD patients were normosmic, 30% were hyposmic, and none of them was functionally anosmic; 6% of the patients showed signs of hypogeusia. Patients with moderate−severe IBD reached a higher olfactory threshold score compared with patients with remission (p = 0.011) and mild IBD (p < 0.001). The BMI of IBD patients was inversely correlated with their olfactory threshold (r = −0.25, p = 0.010). Olfactory and gustatory function in IBD patients did not correlate with duration of disease, blood leucocyte count, CRP level, or fecal calprotectin level. However, patients’ olfactory function significantly increased after 4 months of TNF-α inhibitor treatment (p = 0.038). Conclusions: IBD patients are more likely to present with hyposmia. Olfactory thresholds were mainly affected. They were significantly associated with clinical disease activity and BMI. As shown in a subgroup, treatment with TNF-α inhibitors appeared to improve olfactory function.
Collapse
|
|
11
|
Olonisakin TF, Moore JA, Barel S, Uribe B, Parker DM, Bowers EMR, Nouraie SM, Wenzel SE, Lee SE. Fractional Exhaled Nitric Oxide as a Marker of Mucosal Inflammation in Chronic Rhinosinusitis. Am J Rhinol Allergy 2022; 36:465-472. [PMID: 35238663 DOI: 10.1177/19458924221080260] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Fractional exhaled nitric oxide (FeNO) is a cost-effective, noninvasive point-of-care test that has proven valuable in identifying patients with lower airway inflammation and predicting the likelihood of responsiveness to inhaled corticosteroid therapy in asthma. The utility of FeNO in upper airway disease, specifically in CRS, remains to be determined. OBJECTIVE The goal of this study was to test whether FeNO could serve as a noninvasive marker of sinonasal mucosal inflammation in CRS patients. METHODS FeNO was obtained using a nitric oxide analyzer (NIOX VERO) as well as nasal mucus, the 22-item Sinonasal Outcome Test (SNOT-22), University of Pennsylvania Smell Identification Test (UPSIT), and Lund-Kennedy endoscopic scores concurrently in 112 CRS patients. Nasal mucus was analyzed for cytokine expression using solid-phase sandwich ELISA. Linear regression with Spearman correlation coefficient was used to determine strength of relationship between variables. RESULTS CRS patients showed elevated FeNO levels with asthma (47.12 ± 5.21 ppb) or without asthma (43.24 ± 9.810 ppb). Elevated FeNO levels correlated with sinonasal mucosal inflammation, as determined by increased levels of CCL26 and TNFα in nasal mucus obtained from CRS patients. Furthermore, elevated FeNO levels selectively correlated with worsened SNOT-22 nasal symptoms (P = 0.03) and Lund-Kennedy endoscopic scores (P = 0.007), but did not correlate with UPSIT scores. CONCLUSIONS FeNO levels correlated with increased sinonasal mucosal inflammation and symptom severity in CRS regardless of asthma status. FeNO measurements may serve as a quick and noninvasive marker in evaluating CRS patients.
Collapse
Affiliation(s)
| | - John A Moore
- Department of Otolaryngology - Head & Neck Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Stephanie Barel
- School of Medicine, Lake Erie College of Osteopathic Medicine (LECOM), Erie, Pennsylvania, USA
| | - Bliss Uribe
- School of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
| | | | - Eve M R Bowers
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | | | - Sally E Wenzel
- Department of Environmental & Occupational Health
- University of Pittsburgh Asthma and Environmental Lung Health Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Stella E Lee
- Division of Otolaryngology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| |
Collapse
|
|
12
|
Clark IA. Chronic cerebral aspects of long COVID, post-stroke syndromes and similar states share their pathogenesis and perispinal etanercept treatment logic. Pharmacol Res Perspect 2022; 10:e00926. [PMID: 35174650 PMCID: PMC8850677 DOI: 10.1002/prp2.926] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/11/2022] [Accepted: 01/17/2022] [Indexed: 12/15/2022] Open
Abstract
The chronic neurological aspects of traumatic brain injury, post-stroke syndromes, long COVID-19, persistent Lyme disease, and influenza encephalopathy having close pathophysiological parallels that warrant being investigated in an integrated manner. A mechanism, common to all, for this persistence of the range of symptoms common to these conditions is described. While TNF maintains cerebral homeostasis, its excessive production through either pathogen-associated molecular patterns or damage-associated molecular patterns activity associates with the persistence of the symptoms common across both infectious and non-infectious conditions. The case is made that this shared chronicity arises from a positive feedback loop causing the persistence of the activation of microglia by the TNF that these cells generate. Lowering this excess TNF is the logical way to reducing this persistent, TNF-maintained, microglial activation. While too large to negotiate the blood-brain barrier effectively, the specific anti-TNF biological, etanercept, shows promise when administered by the perispinal route, which allows it to bypass this obstruction.
Collapse
Affiliation(s)
- Ian Albert Clark
- Research School of BiologyAustralian National UniversityCanberraACTAustralia
| |
Collapse
|
|
13
|
Lin YT, Yeh TH. Studies on Clinical Features, Mechanisms, and Management of Olfactory Dysfunction Secondary to Chronic Rhinosinusitis. FRONTIERS IN ALLERGY 2022; 3:835151. [PMID: 35386650 PMCID: PMC8974686 DOI: 10.3389/falgy.2022.835151] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/01/2022] [Indexed: 12/14/2022] Open
Abstract
Chronic rhinosinusitis (CRS) is one of the most common causes of inflammation of the olfactory system, warranting investigation of the link between chronic inflammation and the loss of olfactory function. Type 2 inflammation is closely related to the clinical features and disease mechanisms of olfactory dysfunction secondary to CRS. Patients with eosinophilic CRS, aspirin-exacerbated respiratory disease, and central compartment atopic disease report increased olfactory dysfunction. Increased levels of interleukin-(IL-)2, IL-5, IL-6, IL-10, and IL-13 in the mucus from the olfactory slit have been reported to be associated with reduced olfactory test scores. The influence of several cytokines and signaling transduction pathways, including tumor necrosis factor-α, nuclear factor-κB, and c-Jun N-terminal kinases, on olfactory signal processing and neurogenesis has been demonstrated. Corticosteroids are the mainstay treatment for olfactory dysfunction secondary to CRS. Successful olfaction recovery was recently demonstrated in clinical trials of biotherapeutics, including omalizumab and dupilumab, although the treatment effect may diminish gradually after stopping the use of the medications. Future studies are required to relate the complex mechanisms underlying chronic inflammation in CRS to dysfunction of the olfactory system.
Collapse
Affiliation(s)
- Yi-Tsen Lin
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan
| | - Te-Huei Yeh
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan
- College of Medicine, National Taiwan University, Taipei, Taiwan
- *Correspondence: Te-Huei Yeh
| |
Collapse
|
|
14
|
Chelette BM, Loeven AM, Gatlin DN, Landi Conde DR, Huffstetler CM, Qi M, Fadool DA. Consumption of dietary fat causes loss of olfactory sensory neurons and associated circuitry that is not mitigated by voluntary exercise in mice. J Physiol 2021; 600:1473-1495. [PMID: 34807463 PMCID: PMC10102708 DOI: 10.1113/jp282112] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Excess nutrition causes loss of olfactory sensory neurons (OSNs) and reduces odour discrimination and odour perception in mice. To separate diet-induced obesity from the consumption of dietary fat, we designed pair-feeding experiments whereby mice were maintained on isocaloric diets for 5 months, which prevented increased fat storage. To test our hypothesis that adiposity was not a prerequisite for loss of OSNs and bulbar projections, we used male and female mice with an odorant receptor-linked genetic reporter (M72tauLacZ; Olfr160) to visualize neural circuitry changes resulting from elevated fat in the diet. Simultaneously we monitored glucose clearance (diagnostic for prediabetes), body fat deposition, ingestive behaviours, select inflammatory markers and energy metabolism. Axonal projections to defined olfactory glomeruli were visualized in whole-mount brains, and the number of OSNs was manually counted across whole olfactory epithelia. After being pair fed a moderately high-fat (MHF) diet, mice of both sexes had body weight, adipose deposits, energy expenditure, respiratory exchange ratios and locomotor activity that were unchanged from control-fed mice. Despite this, they were still found to lose OSNs and associated bulbar projections. Even with unchanged adipocyte storage, pair-fed animals had an elevation in TNF cytokines and an intermediate ability for glucose clearance. Albeit improving health metrics, access to voluntary running while consuming an ad libitum fatty diet still precipitated a loss of OSNs and associated axonal projections for male mice. Our results support that long-term macronutrient imbalance can drive anatomical loss in the olfactory system regardless of total energy expenditure. KEY POINTS: Obesity can disrupt the structure and function of organ systems, including the olfactory system that is important for food selection and satiety. We designed dietary treatments in mice such that mice received fat, but the total calories provided were the same as in control diets so that they would not gain weight or increase adipose tissue. Mice that were not obese but consumed isocaloric fatty diets still lost olfactory neuronal circuits, had fewer numbers of olfactory neurons, had an elevation in inflammatory signals and had an intermediate ability to clear glucose (prediabetes). Mice were allowed access to running wheels while consuming fatty diets, yet still lost olfactory structures. We conclude that a long-term imbalance in nutrition that favours fat in the diet disrupts the olfactory system of mice in the absence of obesity.
Collapse
Affiliation(s)
- Brandon M Chelette
- Department of Biological Science, Florida State University, Tallahassee, FL, USA.,Programs in Neuroscience, Florida State University, Tallahassee, FL, USA
| | - Ashley M Loeven
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Destinee N Gatlin
- Department of Biological Science, Florida State University, Tallahassee, FL, USA.,Programs in Neuroscience, Florida State University, Tallahassee, FL, USA
| | - Daniel R Landi Conde
- Department of Biological Science, Florida State University, Tallahassee, FL, USA.,Programs in Neuroscience, Florida State University, Tallahassee, FL, USA
| | - Carley M Huffstetler
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Meizhu Qi
- Department of Biological Science, Florida State University, Tallahassee, FL, USA.,Programs in Neuroscience, Florida State University, Tallahassee, FL, USA
| | - Debra Ann Fadool
- Department of Biological Science, Florida State University, Tallahassee, FL, USA.,Programs in Neuroscience, Florida State University, Tallahassee, FL, USA.,Molecular Biophysics, Florida State University, Tallahassee, FL, USA
| |
Collapse
|
|
15
|
Porta-Etessam J, Núñez-Gil IJ, González García N, Fernandez-Perez C, Viana-Llamas MC, Eid CM, Romero R, Molina M, Uribarri A, Becerra-Muñoz VM, Aguado MG, Huang J, Rondano E, Cerrato E, Alfonso E, Mejía AFC, Marin F, Roubin SR, Pepe M, Feltes G, Maté P, Cortese B, Buzón L, Mendez JJ, Estrada V. COVID-19 anosmia and gustatory symptoms as a prognosis factor: a subanalysis of the HOPE COVID-19 (Health Outcome Predictive Evaluation for COVID-19) registry. Infection 2021; 49:677-684. [PMID: 33646505 PMCID: PMC7917537 DOI: 10.1007/s15010-021-01587-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/08/2021] [Indexed: 12/13/2022]
Abstract
Olfactory and gustatory dysfunctions (OGD) are a frequent symptom of coronavirus disease 2019 (COVID-19). It has been proposed that the neuroinvasive potential of the novel SARS-CoV-2 could be due to olfactory bulb invasion, conversely studies suggest it could be a good prognostic factor. The aim of the current study was to investigate the prognosis value of OGD in COVID-19. These symptoms were recorded on admission from a cohort study of 5868 patients with confirmed or highly suspected COVID-19 infection included in the multicenter international HOPE Registry (NCT04334291). There was statistical relation in multivariate analysis for OGD in gender, more frequent in female 12.41% vs 8.67% in male, related to age, more frequent under 65 years, presence of hypertension, dyslipidemia, diabetes, smoke, renal insufficiency, lung, heart, cancer and neurological disease. We did not find statistical differences in pregnant (p = 0.505), patient suffering cognitive (p = 0.484), liver (p = 0.1) or immune disease (p = 0.32). There was inverse relation (protective) between OGD and prone positioning (0.005) and death (< 0.0001), but no with ICU (0.165) or mechanical ventilation (0.292). On univariable logistic regression, OGD was found to be inversely related to death in COVID-19 patients. The odds ratio was 0.26 (0.15-0.44) (p < 0.001) and Z was - 5.05. The presence of anosmia is fundamental in the diagnosis of SARS.CoV-2 infection, but also could be important in classifying patients and in therapeutic decisions. Even more knowing that it is an early symptom of the disease. Knowing that other situations as being Afro-American or Latino-American, hypertension, renal insufficiency, or increase of C-reactive protein (CRP) imply a worse prognosis we can make a clinical score to estimate the vital prognosis of the patient. The exact pathogenesis of SARS-CoV-2 that causes olfactory and gustative disorders remains unknown but seems related to the prognosis. This point is fundamental, insomuch as could be a plausible way to find a treatment.
Collapse
Affiliation(s)
- Jesús Porta-Etessam
- Hospital Clínico San Carlos, Madrid, Spain.
- Universidad Complutense de Madrid, Madrid, Spain.
- Neurology Department. C/Profesor Martín Lagos S/N, 28049, Madrid, Spain.
| | | | - Nuria González García
- Hospital Clínico San Carlos, Madrid, Spain
- Neurology Department. C/Profesor Martín Lagos S/N, 28049, Madrid, Spain
| | | | | | - Charbel Maroun Eid
- Hospital Universitario La Paz. Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain
| | | | - María Molina
- Hospital Universitario Severo Ochoa, Leganés, Spain
| | - Aitor Uribarri
- Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | | | | | - Jia Huang
- The Second Affiliated Hospital of Southern, University of Science and Technology Shenzhen, Shenzhen, China
| | | | - Enrico Cerrato
- San Luigi Gonzaga University Hospital, Orbassano and Rivoli Infermi Hospital, Rivoli, Turin, Italy
| | - Emilio Alfonso
- Institute of Cardiology and Cardiovascular Surgery, Havana, Cuba
| | | | | | | | - Martino Pepe
- Azienda Ospedaliero-Universitaria Consorziale Policlinico Di Bari, Bari, Italy
| | | | - Paloma Maté
- Hospital Universitario Infanta Sofia, San Sebastian de Los Reyes, Madrid, Spain
| | | | - Luis Buzón
- Hospital Universitario de Burgos, Burgos, Spain
| | | | | |
Collapse
|
|
16
|
Lee JC, Nallani R, Cass L, Bhalla V, Chiu AG, Villwock JA. A Systematic Review of the Neuropathologic Findings of Post-Viral Olfactory Dysfunction: Implications and Novel Insight for the COVID-19 Pandemic. Am J Rhinol Allergy 2021; 35:323-333. [PMID: 32915650 PMCID: PMC10404900 DOI: 10.1177/1945892420957853] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Post-viral olfactory dysfunction is a common cause of both short- and long-term smell alteration. The coronavirus pandemic further highlights the importance of post-viral olfactory dysfunction. Currently, a comprehensive review of the neural mechanism underpinning post-viral olfactory dysfunction is lacking. OBJECTIVES To synthesize the existing primary literature related to olfactory dysfunction secondary to viral infection, detail the underlying pathophysiological mechanisms, highlight relevance for the current COVID-19 pandemic, and identify high impact areas of future research. METHODS PubMed and Embase were searched to identify studies reporting primary scientific data on post-viral olfactory dysfunction. Results were supplemented by manual searches. Studies were categorized into animal and human studies for final analysis and summary. RESULTS A total of 38 animal studies and 7 human studies met inclusion criteria and were analyzed. There was significant variability in study design, experimental model, and outcome measured. Viral effects on the olfactory system varies significantly based on viral substrain but generally include damage or alteration in components of the olfactory epithelium and/or the olfactory bulb. CONCLUSIONS The mechanism of post-viral olfactory dysfunction is highly complex, virus-dependent, and involves a combination of insults at multiple levels of the olfactory pathway. This will have important implications for future diagnostic and therapeutic developments for patients infected with COVID-19.
Collapse
Affiliation(s)
- Jason C. Lee
- Department of Otolaryngology—Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas
| | - Rohit Nallani
- Department of Otolaryngology—Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas
| | - Lauren Cass
- Department of Otolaryngology—Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas
| | - Vidur Bhalla
- Saint Luke’s Hospital of Kansas City, Kansas City, Missouri
| | - Alexander G. Chiu
- Department of Otolaryngology—Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas
| | - Jennifer A. Villwock
- Department of Otolaryngology—Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas
| |
Collapse
|
|
17
|
Pendolino AL, Kaura A, Navaratnam AV, Pendolino M, Bianchi G, Unadkat S, Ottaviano G, Randhawa PS, Andrews PJ. Olfactory dysfunction in antineutrophil cytoplasmic antibody-associated vasculitides: A review of the literature. World J Methodol 2021; 11:15-22. [PMID: 33777721 PMCID: PMC7970017 DOI: 10.5662/wjm.v11.i2.15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/02/2021] [Accepted: 02/21/2021] [Indexed: 02/06/2023] Open
Abstract
Olfactory dysfunction (OD) has been described in patients with antineutrophil cytoplasmic antibody-associated vasculitides (AAV), but the underlying mechanisms are not completely understood. The causes of altered smell function can generally be divided into conductive, sensorineural or others. To date no specific treatment is available for AAV-related OD and the efficacy of currently available options has not been explored. The aim of this review is to provide an overview of the causes that may lead to OD in patients with AAV. Current available treatments for OD and possible options in patients with AAV presenting with smell impairment are also mentioned.
Collapse
Affiliation(s)
- Alfonso Luca Pendolino
- Department of Ear, Nose and Throat, Royal National ENT and Eastman Dental Hospitals, London WC1E 6DG, United Kingdom
- Ear Institute, University College London, London WC1X 8EE, United Kingdom
| | - Anika Kaura
- Department of Ear, Nose and Throat, Royal National ENT and Eastman Dental Hospitals, London WC1E 6DG, United Kingdom
- Ear Institute, University College London, London WC1X 8EE, United Kingdom
| | - Annakan V Navaratnam
- Department of Ear, Nose and Throat, Royal National ENT and Eastman Dental Hospitals, London WC1E 6DG, United Kingdom
| | - Monica Pendolino
- Division of Rheumatology, Department of Locomotor System, ASL 3, Genoa 16121, Italy
| | - Gerolamo Bianchi
- Division of Rheumatology, Department of Locomotor System, ASL 3, Genoa 16121, Italy
| | - Samit Unadkat
- Department of Ear, Nose and Throat, Royal National ENT and Eastman Dental Hospitals, London WC1E 6DG, United Kingdom
| | - Giancarlo Ottaviano
- Department of Neurosciences DNS, Otolaryngology Section, University of Padua, Padua 35128, Italy
| | - Premjit S Randhawa
- Department of Ear, Nose and Throat, Royal National ENT and Eastman Dental Hospitals, London WC1E 6DG, United Kingdom
| | - Peter J Andrews
- Department of Ear, Nose and Throat, Royal National ENT and Eastman Dental Hospitals, London WC1E 6DG, United Kingdom
- Ear Institute, University College London, London WC1X 8EE, United Kingdom
| |
Collapse
|
|
18
|
Sollai G, Melis M, Mastinu M, Paduano D, Chicco F, Magri S, Usai P, Hummel T, Barbarossa IT, Crnjar R. Olfactory Function in Patients with Inflammatory Bowel Disease (IBD) Is Associated with Their Body Mass Index and Polymorphism in the Odor Binding-Protein (OBPIIa) Gene. Nutrients 2021; 13:nu13020703. [PMID: 33671721 PMCID: PMC7926749 DOI: 10.3390/nu13020703] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/09/2021] [Accepted: 02/19/2021] [Indexed: 02/06/2023] Open
Abstract
Smell strongly contributes to food choice and intake, influencing energy balance and body weight; its reduction or loss has been related to malnutrition problems. Some patients with inflammatory bowel disease (IBD), mainly Crohn’s disease (CD) and ulcerative colitis (UC), are underweight, while others are overweight. Some studies suggest that changes in eating habits could be linked to specific disorders of the olfactory functions. We assessed the olfactory performance in 199 subjects (healthy control (HC) n = 99, IBD n = 100), based on the olfactory Threshold, Discrimination and Identification score (TDI score), measured with the “Sniffin’ Sticks” test. Subjects were genotyped for the rs2590498 polymorphism of the OBPIIa gene. IBD patients showed both a slightly, but significantly, lower olfactory function and a higher BMI compared to HC subjects. Threshold (in both population) and Discrimination (in IBD patients) olfactory score were affected by the OBPIIa genotype. BMI was influenced by both health status and OBPIIa genotype. A lower olfactory function may delay the satiety sensation and thus increase meal duration and body weight in IBD patients. However, the AA genotype of the OBPIIa seems to “protect” IBD patients from more severe olfactory dysfunction.
Collapse
Affiliation(s)
- Giorgia Sollai
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
- Correspondence: ; Tel.: +39-070-6754160
| | - Melania Melis
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
| | - Mariano Mastinu
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
| | - Danilo Paduano
- Department of Medical Sciences and Public Health, University of Cagliari, Presidio Policlinico of Monserrato, 09042 Cagliari, Italy; (D.P.); (F.C.); (S.M.); (P.U.)
| | - Fabio Chicco
- Department of Medical Sciences and Public Health, University of Cagliari, Presidio Policlinico of Monserrato, 09042 Cagliari, Italy; (D.P.); (F.C.); (S.M.); (P.U.)
| | - Salvatore Magri
- Department of Medical Sciences and Public Health, University of Cagliari, Presidio Policlinico of Monserrato, 09042 Cagliari, Italy; (D.P.); (F.C.); (S.M.); (P.U.)
| | - Paolo Usai
- Department of Medical Sciences and Public Health, University of Cagliari, Presidio Policlinico of Monserrato, 09042 Cagliari, Italy; (D.P.); (F.C.); (S.M.); (P.U.)
| | - Thomas Hummel
- Smell and Taste Clinic, Department of Otorhinolaryngology, TU Dresden, 01067 Dresden, Germany;
| | - Iole Tomassini Barbarossa
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
| | - Roberto Crnjar
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
| |
Collapse
|
|
19
|
Meunier N, Briand L, Jacquin-Piques A, Brondel L, Pénicaud L. COVID 19-Induced Smell and Taste Impairments: Putative Impact on Physiology. Front Physiol 2021; 11:625110. [PMID: 33574768 PMCID: PMC7870487 DOI: 10.3389/fphys.2020.625110] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/31/2020] [Indexed: 12/18/2022] Open
Abstract
Smell and taste impairments are recognized as common symptoms in COVID 19 patients even in an asymptomatic phase. Indeed, depending on the country, in up to 85-90% of cases anosmia and dysgeusia are reported. We will review briefly the main mechanisms involved in the physiology of olfaction and taste focusing on receptors and transduction as well as the main neuroanatomical pathways. Then we will examine the current evidences, even if still fragmented and unsystematic, explaining the disturbances and mode of action of the virus at the level of the nasal and oral cavities. We will focus on its impact on the peripheral and central nervous system. Finally, considering the role of smell and taste in numerous physiological functions, especially in ingestive behavior, we will discuss the consequences on the physiology of the patients as well as management regarding food intake.
Collapse
Affiliation(s)
- Nicolas Meunier
- Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France
| | - Loïc Briand
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS UMR6265, INRAE UMR 1324, Université de Bourgogne Franche Comté, Dijon, France
| | - Agnès Jacquin-Piques
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS UMR6265, INRAE UMR 1324, Université de Bourgogne Franche Comté, Dijon, France
- Department of Clinical Neurophysiology, University Hospital, Dijon, France
| | - Laurent Brondel
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS UMR6265, INRAE UMR 1324, Université de Bourgogne Franche Comté, Dijon, France
| | - Luc Pénicaud
- STROMALab, Université de Toulouse, CNRS ERL 5311, Inserm U1031, Université Paul Sabatier (UPS), Toulouse, France
| |
Collapse
|
|
20
|
Fragiel M, Miró Ò, Llorens P, Jiménez S, Piñera P, Burillo G, Martín A, Martín-Sánchez FJ, García-Lamberechts EJ, Jacob J, Alquézar-Arbé A, Juárez R, Jiménez B, Del Rio R, Mateo Roca M, García AH, López Laguna N, Lopez Diez MP, Pedraza García J, Fernández de Simón Almela A, Lopez Diaz JJ, Eiroa Hernández P, Ruiz de Lobera N, Porta-Etessam J, Fernández Pérez C, Calvo E, González Del Castillo J. Incidence, clinical, risk factors and outcomes of Guillain-Barré in Covid-19. Ann Neurol 2020; 89:598-603. [PMID: 33295021 DOI: 10.1002/ana.25987] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 12/02/2020] [Accepted: 12/02/2020] [Indexed: 12/14/2022]
Abstract
We diagnosed 11 Guillain-Barré syndrome (GBS) cases among 71,904 COVID patients attended at 61 Spanish emergency departments (EDs) during the 2-month pandemic peak. The relative frequency of GBS among ED patients was higher in COVID (0.15‰) than non-COVID (0.02‰) patients (odds ratio [OR] = 6.30, 95% confidence interval [CI] = 3.18-12.5), as was the standardized incidence (9.44 and 0.69 cases/100,000 inhabitant-years, respectively, OR = 13.5, 95% CI = 9.87-18.4). Regarding clinical characteristics, olfactory-gustatory disorders were more frequent in COVID-GBS than non-COVID-GBS (OR = 27.59, 95% CI = 1.296-587) and COVID-non-GBS (OR = 7.875, 95% CI = 1.587-39.09) patients. Although COVID-GBS patients were more frequently admitted to intensive care, mortality was not increased versus control groups. Our results suggest SARS-CoV-2 could be another viral infection causing GBS. ANN NEUROL 2021;89:598-603.
Collapse
Affiliation(s)
- Marcos Fragiel
- Emergency Department, San Carlos Clinical Hospital, Instituto de Investigación Sanitaria San Carlos (San Carlos Health Research Institute), Complutense University, Madrid, Spain
| | - Òscar Miró
- Emergency Department, Clinical Hospital, Instituto de Investigaciones Biomédicas August Pi i Sunyer (August Pi i Sunyer Institute for Biomedical Research), University of Barcelona, Barcelona, Spain
| | - Pere Llorens
- Emergency Department, Alicante General Hospital, Miguel Hernández University, Alicante, Spain
| | - Sònia Jiménez
- Emergency Department, Clinical Hospital, Instituto de Investigaciones Biomédicas August Pi i Sunyer (August Pi i Sunyer Institute for Biomedical Research), University of Barcelona, Barcelona, Spain
| | - Pascual Piñera
- Emergency Department, Reina Sofía Hospital, Murcia, Spain
| | - Guillermo Burillo
- Emergency Department, University Hospital of the Canary Islands, Tenerife, Spain
| | - Alfonso Martín
- Emergency Department, Severo Ochoa Hospital, Leganés, Madrid, Spain
| | - Francisco J Martín-Sánchez
- Emergency Department, San Carlos Clinical Hospital, Instituto de Investigación Sanitaria San Carlos (San Carlos Health Research Institute), Complutense University, Madrid, Spain
| | - Eric J García-Lamberechts
- Emergency Department, San Carlos Clinical Hospital, Instituto de Investigación Sanitaria San Carlos (San Carlos Health Research Institute), Complutense University, Madrid, Spain
| | - Javier Jacob
- Emergency Department, Bellvitge University Hospital, Barcelona, Spain
| | - Aitor Alquézar-Arbé
- Emergency Department, Hospital of the Holy Cross and Saint Paul, Barcelona, Spain
| | - Ricardo Juárez
- Emergency Department, Our Lady Prado Hospital of Talavera de la Reina, Toledo, Spain
| | - Blas Jiménez
- Emergency Department, Vinalopó de Elche University Hospital, Alicante, Spain
| | - Rigoberto Del Rio
- Emergency Department, University Hospital of Torrevieja de Alicante, Alicante, Spain
| | - Miriam Mateo Roca
- Emergency Department, Hospital of the Holy Cross and Saint Paul, Barcelona, Spain
| | - Arturo H García
- Emergency Department, Sacred Family Clinic, Barcelona, Spain
| | | | | | | | | | - Juan J Lopez Diaz
- Emergency Department, Lucus Augusti Lugo University Hospital, Lugo, Spain
| | | | | | | | | | - Elpidio Calvo
- Internal Medicine Department, San Carlos Clinical Hospital, Instituto de Investigación Sanitaria San Carlos (San Carlos Health Research Institute), Complutense University, Madrid, Spain
| | - Juan González Del Castillo
- Emergency Department, San Carlos Clinical Hospital, Instituto de Investigación Sanitaria San Carlos (San Carlos Health Research Institute), Complutense University, Madrid, Spain
| | | |
Collapse
|
|
21
|
Iannuzzi L, Salzo AE, Angarano G, Palmieri VO, Portincasa P, Saracino A, Gelardi M, Dibattista M, Quaranta N. Gaining Back What Is Lost: Recovering the Sense of Smell in Mild to Moderate Patients After COVID-19. Chem Senses 2020; 45:875-881. [PMID: 33033827 PMCID: PMC7665358 DOI: 10.1093/chemse/bjaa066] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The purpose of our cohort study was to quantify olfactory deficits in Coronavirus disease 2019 (COVID-19) patients using Sniffin' Sticks and a pre-post design to evaluate olfactory recovery. Thirty adult patients with laboratory-confirmed mild to moderate forms of COVID-19 underwent a quantitative olfactory test performed with the Sniffin' Sticks test (SST; Burghardt, Wedel, Germany), considering olfactory threshold (T), odor discrimination (D), and odor identification (I). Results were presented as a composite TDI score (range 1-48) that used to define functional anosmia (TDI ≤ 16.5), hyposmia (16.5 < TDI < 30.5), or functionally normal ability to smell (TDI ≥ 30.5). Patients also self-evaluated their olfactory function by rating their ability to smell on a visual analogue scale (Visual Analog Scale rating) and answering a validated Italian questionnaire (Hyposmia Rating Scale). Patients were tested during hospitalization and about 2 months after symptoms onset. During the hospitalization, the overall TDI score indicated that our cohort had impairments in their olfactory ability (10% was diagnosed with anosmia and more than 50% were hyposmic). Almost all patients showed a significant improvement at around 1 month following the first test and for all the parts of the SST except for odor identification. None of the subjects at 1 month was still diagnosed with anosmia. We also quantified the improvement in the TDI score based on initial diagnosis. Anosmic subjects showed a greater improvement than hyposmic and normosmic subjects. In conclusion, within a month time window and 2 months after symptoms' onset, in our cohort of patients we observed a substantial improvement in the olfactory abilities.
Collapse
Affiliation(s)
- Lucia Iannuzzi
- ENT Clinic, Department of Biomedical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
| | - Anna Eugenia Salzo
- ENT Clinic, Department of Biomedical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
| | - Gioacchino Angarano
- Clinic of Infectious Diseases, Department of Biomedical sciences and Human Oncology, University of Bari, Bari, Italy
| | - Vincenzo Ostilio Palmieri
- Clinica Medica “A. Murri,” Department of Biomedical sciences and Human Oncology, University of Bari, Bari, Italy
| | - Piero Portincasa
- Clinica Medica “A. Murri,” Department of Biomedical sciences and Human Oncology, University of Bari, Bari, Italy
| | - Annalisa Saracino
- Clinic of Infectious Diseases, Department of Biomedical sciences and Human Oncology, University of Bari, Bari, Italy
| | | | - Michele Dibattista
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari A. Moro, Bari, Italy
| | - Nicola Quaranta
- ENT Clinic, Department of Biomedical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
| |
Collapse
|
|
22
|
Lietzau G, Nyström T, Wang Z, Darsalia V, Patrone C. Western Diet Accelerates the Impairment of Odor-Related Learning and Olfactory Memory in the Mouse. ACS Chem Neurosci 2020; 11:3590-3602. [PMID: 33054173 PMCID: PMC7645872 DOI: 10.1021/acschemneuro.0c00466] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Olfactory dysfunction could be an early indicator of cognitive decline in type 2 diabetes (T2D). However, whether obesity affects olfaction in people with T2D is unclear. This question needs to be addressed, because most people with T2D are obese. Importantly, whether different contributing factors leading to obesity (e.g., different components of diet or gain in weight) affect specific olfactory functions and underlying mechanisms is unknown. We examined whether two T2D-inducing obesogenic diets, one containing a high proportion of fat (HFD) and one with moderate fat and high sugar (Western diet, WD), affect odor detection/discrimination, odor-related learning, and olfactory memory in the mouse. We also investigated whether the diets impair adult neurogenesis, GABAergic interneurons, and neuroblasts in the olfactory system. Here, we further assessed olfactory cortex volume and cFos expression-based neuronal activity. The WD-fed mice showed declined odor-related learning and olfactory memory already after 3 months of diet intake (p = 0.046), although both diets induced similar hyperglycemia and weight gain compared to those of standard diet-fed mice (p = 0.0001 and p < 0.0001, respectively) at this time point. Eight months of HFD and WD diminished odor detection (p = 0.016 and p = 0.045, respectively), odor-related learning (p = 0.015 and p = 0.049, respectively), and olfactory memory. We observed no changes in the investigated cellular mechanisms. We show that the early deterioration of olfactory parameters related to learning and memory is associated with a high content of sugar in the diet rather than with hyperglycemia or weight gain. This finding could be exploited for understanding, and potentially preventing, cognitive decline/dementia in people with T2D. The mechanisms behind this finding remain to be elucidated.
Collapse
Affiliation(s)
- Grazyna Lietzau
- Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm 118-83, Sweden
- Department of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk 80-210, Poland
| | - Thomas Nyström
- Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm 118-83, Sweden
| | - Zhida Wang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Vladimer Darsalia
- Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm 118-83, Sweden
| | - Cesare Patrone
- Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm 118-83, Sweden
| |
Collapse
|
|
23
|
Niu H, Wang Q, Zhao W, Liu J, Wang D, Muhammad B, Liu X, Quan N, Zhang H, Zhang F, Wang Y, Li H, Yang R. IL-1β/IL-1R1 signaling induced by intranasal lipopolysaccharide infusion regulates alpha-Synuclein pathology in the olfactory bulb, substantia nigra and striatum. Brain Pathol 2020; 30:1102-1118. [PMID: 32678959 PMCID: PMC7754320 DOI: 10.1111/bpa.12886] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Olfactory dysfunction is one of the early symptoms seen in Parkinson's disease (PD). However, the mechanisms underlying olfactory pathology that impacts PD disease progression and post-mortem appearance of alpha-Synuclein (α-Syn) inclusions in and beyond olfactory bulb in PD remain unclear. It has been suggested that environmental toxins inhaled through the nose can induce inflammation in the olfactory bulb (OB), where Lewy body (LB) is the first to be found, and then, spread to related brain regions. We hypothesize that OB inflammation triggers local α-Syn pathology and promotes its spreading to cause PD. In this study, we evaluated this hypothesis by intranasal infusion of lipopolysaccharides (LPS) to induce OB inflammation in mice and examined cytokines expression and PD-like pathology. We found intranasal LPS-induced microglia activation, inflammatory cytokine expression and α-Syn overexpression and aggregation in the OB via interleukin-1β (IL-1β)/IL-1 receptor type I (IL-1R1) dependent signaling. In addition, an aberrant form of α-Syn, the phosphorylated serine 129 α-Syn (pS129 α-Syn), was found in the OB, substantia nigra (SN) and striatum 6 weeks after the LPS treatment. Moreover, 6 weeks after the LPS treatment, mice showed reduced SN tyrosine hydroxylase, decreased striatal dopaminergic metabolites and PD-like behaviors. These changes were blunted in IL-1R1 deficient mice. Further studies found the LPS treatment inhibited IL-1R1-dependent autophagy in the OB. These results suggest that IL-1β/IL-1R1 signaling in OB play a vital role in the induction and propagation of aberrant α-Syn, which may ultimately trigger PD pathology.
Collapse
Affiliation(s)
- Haichen Niu
- Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical University, Xuzhou, 221004, China.,Department of Genetics, Xuzhou Medical University, Xuzhou, 221004, China
| | - Qian Wang
- Graduate School, Xuzhou Medical University, Xuzhou, 221004, China.,Department of Geriatric Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China
| | - Weiguang Zhao
- Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical University, Xuzhou, 221004, China.,Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, 221004, China
| | - Jianxin Liu
- Department of human anatomy, Xuzhou Medical University, Xuzhou, 221004, China
| | - Deguang Wang
- Department of human anatomy, Xuzhou Medical University, Xuzhou, 221004, China
| | - Bilal Muhammad
- Graduate School, Xuzhou Medical University, Xuzhou, 221004, China.,Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China
| | - Xiaoyu Liu
- Department of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, FL, 33458, USA
| | - Ning Quan
- Department of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, FL, 33458, USA
| | - Haoyu Zhang
- School of Marine Sciences, Nanjing University of Information Science and Technology, Nanjing, 210044, China
| | - Fang Zhang
- Laboratory of Morphology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Yong Wang
- Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Haiying Li
- Jiangsu Key Laboratory of Brain Disease and Bioinformation, Xuzhou Medical University, Xuzhou, 221004, China.,Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Rongli Yang
- Department of Geriatric Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China.,Department of Geriatrics, Xuzhou Medical University, Xuzhou, 221004, China
| |
Collapse
|
|
24
|
Darnell EP, Wroblewski KE, Pagel KL, Kern DW, McClintock MK, Pinto JM. IL-1Rahigh-IL-4low-IL-13low: A Novel Plasma Cytokine Signature Associated with Olfactory Dysfunction in Older US Adults. Chem Senses 2020; 45:407-414. [PMID: 32369568 PMCID: PMC7320218 DOI: 10.1093/chemse/bjaa029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Inflammation has been implicated in physical frailty, but its role in sensory impairment is unclear. Given that olfactory impairment predicts dementia and mortality, determining the role of the immune system in olfactory dysfunction would provide insights mechanisms of neurosensory decline. We analyzed data from the National Social Life, Health and Aging Project, a representative sample of home-dwelling older US adults. Plasma levels of 18 cytokines were measured using standard protocols (Luminex xMAP). Olfactory function was assessed with validated tools (n-butanol sensitivity and odor identification, each via Sniffin' Sticks). We tested the association between cytokine profiles and olfactory function using multivariate ordinal logistic regression, adjusting for age, gender, race/ethnicity, education level, cognitive function, smoking status, and comorbidity. Older adults with the IL-1Rahigh-IL-4low-IL-13low cytokine profile had worse n-butanol odor sensitivity (odds ratio [OR] = 1.61, 95% confidence interval [CI] 1.19-2.17) and worse odor identification (OR = 1.42, 95% CI 1.11-1.80). Proinflammatory, Th1, or Th2 cytokine profiles were not associated with olfactory function. Moreover, accounting for physical frailty did not alter the main findings. In conclusion, we identified a plasma cytokine signature-IL-1Rahigh-IL-4low-IL-13low-that is associated with olfactory dysfunction in older US adults. These data implicate systemic inflammation in age-related olfactory dysfunction and support a role for immune mechanisms in this process, a concept that warrants additional scrutiny.
Collapse
Affiliation(s)
- Eli P Darnell
- Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA
| | - Kristen E Wroblewski
- Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA
| | - Kristina L Pagel
- Department of Comparative Human Development, The University of Chicago, Chicago, IL, USA
- Center on Demography and Aging, The University of Chicago, Chicago, IL, USA
- Institute for Mind and Biology, The University of Chicago, Chicago, IL, USA
| | - David W Kern
- Department of Comparative Human Development, The University of Chicago, Chicago, IL, USA
| | - Martha K McClintock
- Department of Comparative Human Development, The University of Chicago, Chicago, IL, USA
- Center on Demography and Aging, The University of Chicago, Chicago, IL, USA
- Institute for Mind and Biology, The University of Chicago, Chicago, IL, USA
| | - Jayant M Pinto
- Center on Demography and Aging, The University of Chicago, Chicago, IL, USA
- Section of Otolaryngology—Head and Neck Surgery, Department of Surgery, The University of Chicago, Chicago, IL, USA
| |
Collapse
|
|
25
|
Yoo F, Soler ZM, Mulligan JK, Storck KA, Lamira JM, Pasquini WN, Hill JB, Noonan TE, Washington BJ, Schlosser RJ. Olfactory cleft mucus proteins associated with olfactory dysfunction in a cohort without chronic rhinosinusitis. Int Forum Allergy Rhinol 2019; 9:1151-1158. [PMID: 31442006 DOI: 10.1002/alr.22391] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/24/2019] [Accepted: 07/04/2019] [Indexed: 01/28/2023]
Abstract
BACKGROUND Olfactory dysfunction (OD) is a common problem, affecting up to 20% of the general population. Previous studies identified olfactory cleft mucus proteins associated with OD in chronic rhinosinusitis (CRS) but not in a healthy population. In this study we aimed to identify olfactory cleft mucus proteins associated with olfaction in individuals without sinus disease. METHODS Subjects free of sinus disease completed medical history questionnaires that collected data regarding demographics, comorbidities, and past exposures. Olfactory testing was performed using Sniffin' Sticks, evaluating threshold, discrimination, and identification. Olfactory cleft mucus (OC) and, in select cases, inferior turbinate mucus (IT) were collected with Leukosorb paper and assays performed for 17 proteins, including growth factors, cytokines/chemokines, cell-cycle regulators, and odorant-binding protein (OBP). RESULTS Fifty-six subjects were enrolled in the study, with an average age of 47.8 (standard deviation [SD], 17.6) years, including 33 females (58.9%). The average threshold/discrimination/identification (TDI) score was 30.3 (SD, 6.4). In localization studies, OBP concentrations were significantly higher in OC than IT mucus (p = 0.006). Cyclin-dependent kinase inhibitor 2A (CDKN2A/p16INK4a), basic fibroblast growth factor (bFGF), chemokine ligand 2 (CCL2/MCP-1), granulocyte macrophage colony-stimulating factor (GM-CSF), and chemokine ligand 20 (CCL20/MIP-3a) all inversely correlated with overall TDI (all rho ≥ -0.479, p ≤ 0.004). Stem cell factor (SCF) correlated positively with overall TDI (rho = 0.510, p = 0.002). CONCLUSION Placement of Leukosorb paper is relatively site-specific for olfactory proteins and it is feasible to collect a variety of olfactory cleft proteins that correlate with olfactory function. Further study is required to determine mechanisms of OD in non-CRS subjects.
Collapse
Affiliation(s)
- Frederick Yoo
- Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
| | - Zachary M Soler
- Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
| | - Jennifer K Mulligan
- Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
| | - Kristina A Storck
- Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
| | - Jensine M Lamira
- Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
| | - Whitney N Pasquini
- Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
| | - Jonathan B Hill
- Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
| | - Tegan E Noonan
- University of South Carolina School of Medicine, Columbia, SC
| | | | - Rodney J Schlosser
- Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC.,Department of Surgery, Ralph H. Johnson VA Medical Center, Charleston, SC
| |
Collapse
|
|
26
|
Kim DK, Choi SA, Eun KM, Kim SK, Kim DW, Phi JH. Tumour necrosis factor alpha and interleukin-5 inhibit olfactory regeneration via apoptosis of olfactory sphere cells in mice models of allergic rhinitis. Clin Exp Allergy 2019; 49:1139-1149. [PMID: 30980570 DOI: 10.1111/cea.13401] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 04/02/2019] [Accepted: 04/03/2019] [Indexed: 01/15/2023]
Abstract
BACKGROUND Olfactory dysfunction is frequently experienced by patients with allergic rhinitis. It is thought to result from structural and functional changes occurring in the olfactory mucosa caused by inflammation. However, the current understanding of the pathophysiology of olfactory dysfunction in allergic rhinitis remains unclear. OBJECTIVE To investigate the mechanism by which the olfactory neural cells are damaged in allergic rhinitis. METHODS Olfactory sphere cells (OSCs) were established after dissociation and serial cultures of cells from the mouse olfactory mucosa. Viability and proliferation of OSCs were compared between control and allergic rhinitis mice models, and olfactory stem cell markers were analysed in vivo. To elucidate which cytokines have an inhibitory effect on OSCs, viability and apoptotic markers of OSCs were investigated. RESULTS Olfactory sphere cells were successfully isolated from the olfactory mucosa of mice, and these cells expressed markers of neural stem cells. To investigate the neural differentiation, we performed the immunocytochemical staining and found significantly elevated expressions of Tuji1, GFAP and O4 on OSCs. On the comparison of the characteristics of OSCs between control and allergic rhinitis model, we detected significantly fewer neurospheres, reduced clonogenic capacity and decreased expression of olfactory neural stem cell markers in allergic rhinitis model. When OSCs were treated with several major allergic cytokines were treated on OSCs, only TNF-α showed an inhibitory effect on OSCs. Interestingly, IL-5 had an inhibitory effect on the viability of OSCs in combination with TNF-α, whereas IL-5 alone does not have an effect. Moreover, TNF-α combined with IL-5 significantly increased the apoptotic expression, compared with TNF-α or IL-5 alone. Additionally, allergic rhinitis mice models showed the increased apoptotic expression. CONCLUSION AND CLINICAL RELEVANCE Allergic rhinitis mice models showed lower expression of OSCs, and TNF-α combined with IL-5 had an apoptotic effect on OSCs. Therefore, these cytokines may be therapeutic targets for olfactory dysfunction in patients with allergic rhinitis.
Collapse
Affiliation(s)
- Dong-Kyu Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital and Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, South Korea
| | - Seung Ah Choi
- Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyoung Mi Eun
- Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung-Ki Kim
- Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Dae Woo Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
| | - Ji Hoon Phi
- Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, South Korea
| |
Collapse
|
|
27
|
Yan CH, Overdevest JB, Patel ZM. Therapeutic use of steroids in non-chronic rhinosinusitis olfactory dysfunction: a systematic evidence-based review with recommendations. Int Forum Allergy Rhinol 2018; 9:165-176. [DOI: 10.1002/alr.22240] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 10/12/2018] [Indexed: 12/29/2022]
Affiliation(s)
- Carol H. Yan
- Department of Otolaryngology-Head and Neck Surgery; Stanford University; Stanford CA
| | | | - Zara M. Patel
- Department of Otolaryngology-Head and Neck Surgery; Stanford University; Stanford CA
| |
Collapse
|
|
28
|
Seo Y, Kim HS, Kang KS. Microglial involvement in the development of olfactory dysfunction. J Vet Sci 2018; 19:319-330. [PMID: 29032655 PMCID: PMC5974513 DOI: 10.4142/jvs.2018.19.3.319] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 09/20/2017] [Accepted: 10/07/2017] [Indexed: 12/20/2022] Open
Abstract
Olfactory impairment is the most common clinical manifestation among the elderly, and its prevalence increases sharply with age. Notably, growing evidence has shown that olfactory dysfunction is the first sign of neurodegeneration, indicating the importance of olfactory assessment as an early marker in the diagnosis of neurological disorders. In this review, we describe the nature of olfactory dysfunction and the advantage of using animal models in olfaction study, and we include a brief introduction to olfactory behavior tests widely used in this field. The contribution of microglia in the neurodegenerative processes including olfactory impairment is then discussed to provide a comprehensive description of the physiopathological role of interactions between neurons and microglia within the olfactory system.
Collapse
Affiliation(s)
- Yoojin Seo
- Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan 49241, Korea
| | - Hyung-Sik Kim
- Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan 49241, Korea
| | - Kyung-Sun Kang
- Adult Stem Cell Research Center, Seoul National University, Seoul 08826, Korea.,Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| |
Collapse
|
|
29
|
Victores AJ, Chen M, Smith A, Lane AP. Olfactory loss in chronic rhinosinusitis is associated with neuronal activation of c-Jun N-terminal kinase. Int Forum Allergy Rhinol 2017; 8:415-420. [PMID: 29193850 DOI: 10.1002/alr.22053] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 10/22/2017] [Accepted: 11/07/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND Olfactory inflammation in chronic rhinosinusitis (CRS) is associated with cytokines that may result in the death of olfactory sensory neurons. The principal signaling molecules involved in the apoptotic pathway are c-Jun N-terminal kinases (JNK). Although the JNK pathway has emerged as a key player in programmed cell death in neuroinflammation, its specific role in CRS-associated olfactory loss has not been thoroughly investigated. METHODS JNK activation was studied in human tissue samples from 9 control and 11 CRS patients by immunohistochemical staining for phosphorylated c-Jun. A mouse model of inducible olfactory cytokine expression was used to experimentally control inflammation and assess JNK activation over time. RESULTS In patients with CRS, activation of c-Jun is significantly increased relative to non-CRS control subjects, and there is an associated loss of sensory neurons. In the olfactory inflammation mouse model, prolonged induction of inflammation results in elevation of c-Jun expression and neuronal apoptosis. CONCLUSION Activation of neuronal JNK is a feature of chronic olfactory inflammation that is associated with neuronal apoptosis. Given that inhibition of JNK activity is neuroprotective in other settings, antagonism of this pathway may have therapeutic potential in the management of inflammatory olfactory loss or other disorders linked to olfactory neuronal apoptosis.
Collapse
Affiliation(s)
- Andrew J Victores
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Mengfei Chen
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Amy Smith
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Andrew P Lane
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| |
Collapse
|
|
30
|
Hauser LJ, Chandra RK, Li P, Turner JH. Role of tissue eosinophils in chronic rhinosinusitis-associated olfactory loss. Int Forum Allergy Rhinol 2017; 7:957-962. [PMID: 28742240 DOI: 10.1002/alr.21994] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 06/05/2017] [Accepted: 06/28/2017] [Indexed: 01/05/2023]
Abstract
BACKGROUND Olfactory dysfunction is 1 of the hallmark symptoms of chronic rhinosinusitis (CRS). Eosinophilic inflammation has been implicated as a potential causative factor. However, prior studies have been limited by retrospective study designs, concomitant use of systemic corticosteroids, and other confounding factors. METHODS CRS and healthy non-CRS control subjects undergoing endoscopic sinus or skull-base surgery were prospectively enrolled and completed olfactory testing utilizing the 40-item Smell Identification Test (SIT) immediately prior to surgery. Histopathological evaluation of tissue excised from the ethmoid bulla was performed by a pathologist in a blinded fashion. Disease severity and patient-reported outcomes were measured via the Lund-Mackay computed tomography (CT) grading system and 22-item Sino-Nasal Outcome Test (SNOT-22), respectively. The associations between olfactory function, tissue eosinophilia, and disease severity were analyzed using Spearman rank order correlation and multiple linear regression. RESULTS Twenty-seven (27) subjects with CRS without nasal polyps (CRSsNP), 32 subjects with CRS with nasal polyps (CRSwNP), and 10 healthy non-CRS controls were enrolled. CRSwNP was associated with higher mean tissue eosinophil counts (71.6 vs 28.1 eosinophils/high-power field [HPF], p < 0.05) and lower age/sex-adjusted SIT scores (-17.4 vs -6.2, p < 0.001) when compared to CRSsNP. SIT scores were strongly negatively correlated with tissue eosinophil counts in CRSwNP (r = -0.60, p = 0.0003), but not CRSsNP (r = 0.16, p = 0.42). The correlation between olfactory function and tissue eosinophilia in CRSwNP persisted after adjusting for disease severity. CONCLUSION Tissue eosinophilia is associated with olfactory loss in CRSwNP, independent of disease severity. These results suggest a possible role for eosinophils or eosinophil-associated cytokines in CRS-associated olfactory loss.
Collapse
Affiliation(s)
- Leah J Hauser
- Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, TN
| | - Rakesh K Chandra
- Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, TN
| | - Ping Li
- Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, TN
| | - Justin H Turner
- Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, TN
| |
Collapse
|
|
31
|
TNF α Affects Ciliary Beat Response to Increased Viscosity in Human Pediatric Airway Epithelium. BIOMED RESEARCH INTERNATIONAL 2016; 2016:3628501. [PMID: 28025644 PMCID: PMC5153504 DOI: 10.1155/2016/3628501] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 10/20/2016] [Accepted: 10/30/2016] [Indexed: 01/09/2023]
Abstract
In airway epithelium, mucociliary clearance (MCC) velocity depends on the ciliary beat frequency (CBF), and it is affected by mucus viscoelastic properties. Local inflammation induces secretion of cytokines (TNFα) that can alter mucus viscosity; however airway ciliated cells have an autoregulatory mechanism to prevent the collapse of CBF in response to increase in mucus viscosity, mechanism that is associated with an increment in intracellular Ca+2 level ([Ca2+]i). We studied the effect of TNFα on the autoregulatory mechanism that regulates CBF in response to increased viscosity using dextran solutions, in ciliated cells cultured from human pediatric epithelial adenoid tissue. Cultures were treated with TNFα, before and after the viscous load was changed. TNFα treatment produced a significantly larger decrease in CBF in cultures exposed to dextran. Furthermore, an increment in [Ca2+]i was observed, which was significantly larger after TNFα treatment. In conclusion, although TNFα has deleterious effects on ciliated cells in response to maintaining CBF after increasing viscous loading, it has a positive effect, since increasing [Ca2+]i may prevent the MCC collapse. These findings suggest that augmented levels of TNFα associated with an inflammatory response of the nasopharyngeal epithelium may have dual effects that contribute to maintaining the effectiveness of MCC in the upper airways.
Collapse
|
|
32
|
Imamura F, Hasegawa-Ishii S. Environmental Toxicants-Induced Immune Responses in the Olfactory Mucosa. Front Immunol 2016; 7:475. [PMID: 27867383 PMCID: PMC5095454 DOI: 10.3389/fimmu.2016.00475] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 10/19/2016] [Indexed: 01/02/2023] Open
Abstract
Olfactory sensory neurons (OSNs) are the receptor cells for the sense of smell. Although cell bodies are located in the olfactory mucosa (OM) of the nasal cavity, OSN axons directly project to the olfactory bulb (OB) that is a component of the central nervous system (CNS). Because of this direct and short connection from this peripheral tissue to the CNS, the olfactory system has attracted attention as a port-of-entry for environmental toxicants that may cause neurological dysfunction. Selected viruses can enter the OB via the OM and directly affect the CNS. On the other hand, environmental toxicants may induce inflammatory responses in the OM, including infiltration of immune cells and production of inflammatory cytokines. In addition, these inflammatory responses cause the loss of OSNs that are then replaced with newly generated OSNs that re-connect to the OB after inflammation has subsided. It is now known that immune cells and cytokines in the OM play important roles in both degeneration and regeneration of OSNs. Thus, the olfactory system is a unique neuroimmune interface where interaction between nervous and immune systems in the periphery significantly affects the structure, neuronal circuitry, and immunological status of the CNS. The mechanisms by which immune cells regulate OSN loss and the generation of new OSNs are, however, largely unknown. To help develop a better understanding of the mechanisms involved, we have provided a review of key research that has investigated how the immune response in the OM affects the pathophysiology of OSNs.
Collapse
Affiliation(s)
- Fumiaki Imamura
- Department of Pharmacology, Penn State College of Medicine , Hershey, PA , USA
| | | |
Collapse
|
|
33
|
Sousa Garcia D, Chen M, Smith AK, Lazarini PR, Lane AP. Role of the type I tumor necrosis factor receptor in inflammation-associated olfactory dysfunction. Int Forum Allergy Rhinol 2016; 7:160-168. [PMID: 27671548 DOI: 10.1002/alr.21855] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 08/18/2016] [Accepted: 08/28/2016] [Indexed: 11/11/2022]
Abstract
BACKGROUND To understand mechanisms of human olfactory dysfunction in chronic rhinosinusitis, an inducible olfactory inflammation (IOI) model has been utilized to chronically express inflammatory cytokines locally, resulting in neuronal loss, diminished odorant responses, and repressed olfactory regeneration. Knockout of the minor tumor necrosis factor α receptor 2 (TNFR2) was previously shown to partially rescue these olfactory changes. The purpose of current study was to investigate the role of the major TNF receptor, TNFR1, in chronic olfactory inflammation. METHODS Two experimental groups of mice were studied: TNFR1 knockout in IOI background and TNFR1 knockout with allergen-induced inflammation. Olfactory function was assayed by electro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. RESULTS TNF-α was dramatically induced in IOI-TNFR1 knockout mice, but the olfactory epithelium did not show inflammation. EOG responses were normal after either 2 or 8 weeks of TNF-α expression. Ovalbumin-sensitized TNFR1 knockout mice developed markedly diminished eosinophilic inflammatory infiltration. CONCLUSION Genetic deletion of TNFR1 completely blocks TNF-α-induced inflammation and reduces allergen-induced inflammation. Preserved EOG responses suggest a TNFR1-dependent mechanism of TNF-α-induced olfactory neuron dysfunction.
Collapse
Affiliation(s)
- Davi Sousa Garcia
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Otolaryngology, Santa Casa de Sao Paulo School of Medical Sciences, Sao Paulo, Brazil
| | - Mengfei Chen
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Amy K Smith
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Paulo Roberto Lazarini
- Department of Otolaryngology, Santa Casa de Sao Paulo School of Medical Sciences, Sao Paulo, Brazil
| | - Andrew P Lane
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| |
Collapse
|
|
34
|
Aydın E, Tekeli H, Karabacak E, Altunay İK, Aydın Ç, Çerman AA, Altundağ A, Salihoğlu M, Çayönü M. Olfactory functions in patients with psoriasis vulgaris: correlations with the severity of the disease. Arch Dermatol Res 2016; 308:409-14. [PMID: 27299882 DOI: 10.1007/s00403-016-1662-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 05/24/2016] [Accepted: 06/06/2016] [Indexed: 01/05/2023]
Abstract
It is well known that psoriasis is not only limited to skin, but a systemic autoimmune disease with various comorbidities. Olfactory dysfunction, one of as a common but lesser known symptom of patients with autoimmune diseases, often presents with smell loss. The aim of this study was to assess the olfactory functions in patients with psoriasis and to compare with healthy controls. A total of 50 patients with psoriasis and 43 control subjects were included to the study. The clinical severity of psoriasis was calculated by psoriasis area and severity index (PASI). Patients were classified into two groups according to PASI score as mild (PASI ≤10) and moderate-severe (PASI >10). Olfactory function was evaluated with "Sniffin'Sticks" test. Total test scores (max. 48 points) of threshold, discrimination, and identification (TDI) were classified as normal olfaction = normosmia (>30.3 points), decreased olfaction = hyposmia (16.5-30.3 points) and loss of olfaction = anosmia (<16.5 points). Psoriasis patients had significantly lower smell scores compared with healthy controls (p < 0.001). Of the 50 psoriasis patients, 40 (80 %) were hyposmic. We found negative correlation between TDI and PASI (r = -0.34, p = 0.014). The TDI scores of the patients with moderate-severe psoriasis (PASI score >10) were found to be significantly lower than the patients with mild psoriasis (PASI ≤10) (p < 0.001). Olfactory dysfunction in patients with psoriasis could be thought as a comorbidity as in other inflammatory disorders. Physicians should be aware of olfactory impairment when evaluating psoriasis patients in their clinical practice.
Collapse
Affiliation(s)
- Ersin Aydın
- Department of Dermatology, Kasimpasa Military Hospital, Beyoglu, 34440, Istanbul, Turkey.
| | - Hakan Tekeli
- Department of Norology, GATA Haydarpasa Training Hospital, Istanbul, Turkey
| | - Ercan Karabacak
- Department of Dermatology, GATA Haydarpasa Training Hospital, Istanbul, Turkey
| | - İlknur Kıvanç Altunay
- Department of Dermatology, Şişli Etfal Training and Research Hospital, Istanbul, Turkey
| | - Çigdem Aydın
- Department of Dermatology, Şişli Etfal Training and Research Hospital, Istanbul, Turkey
| | - Aslı Aksu Çerman
- Department of Dermatology, Şişli Etfal Training and Research Hospital, Istanbul, Turkey
| | - Aytuğ Altundağ
- Department of Otorhinolaryngology, Istanbul Surgery Hospital, Istanbul, Turkey
| | - Murat Salihoğlu
- Department of Otorhinolaryngology, GATA Haydarpasa Training Hospital, Istanbul, Turkey
| | - Melih Çayönü
- Department of Otorhinolaryngology, Amasya University Training and Research Hospital, Istanbul, Turkey
| |
Collapse
|
|
35
|
Alarabawy RA, Eltomey MA, Shehata EM. Volumetric study of the olfactory bulb in patients with chronic rhinonasal sinusitis using MRI. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2016. [DOI: 10.1016/j.ejrnm.2016.02.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
|
|
36
|
Pacharra M, Kleinbeck S, Schäper M, Blaszkewicz M, van Thriel C. Multidimensional assessment of self-reported chemical intolerance and its impact on chemosensory effects during ammonia exposure. Int Arch Occup Environ Health 2016; 89:947-59. [DOI: 10.1007/s00420-016-1134-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 04/21/2016] [Indexed: 11/28/2022]
|
|
37
|
Jung YG, Lane AP. Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model. Otolaryngol Head Neck Surg 2016; 154:1149-54. [PMID: 26932943 DOI: 10.1177/0194599816632177] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 01/22/2016] [Indexed: 01/11/2023]
Abstract
OBJECTIVE To determine the effect of a soluble human tumor necrosis factor alpha (TNF-α) receptor blocker (etanercept) on an inducible olfactory inflammation (IOI) mouse model. STUDY DESIGN An in vivo study using a transgenic mouse model. SETTING Research laboratory. SUBJECTS AND METHODS To study the impact of chronic inflammation on the olfactory system, a transgenic mouse model of chronic rhinosinusitis-associated olfactory loss was utilized (IOI mouse), expressing TNF-α in a temporally controlled fashion within the olfactory epithelium. In one group of mice (n = 4), etanercept was injected intraperitoneally (100 μg/dose, 3 times/week) concurrent with a 2-week period of TNF-α expression. A second group of mice (n = 2) underwent induction of TNF-α expression for 8 weeks, with etanercept treatment administered during the final 2 weeks of inflammation. Olfactory function was assayed by elecro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. Each group was compared with an equal-number control group. RESULTS Compared with nontreated IOI mice, etanercept-treated IOI mice showed significantly improved EOG responses after 2 weeks (P < .001). After 8 weeks of induced inflammation, there was massive loss of olfactory epithelium and no EOG response in nontreated IOI mice. However, in etanercept-treated mice, regeneration of olfactory epithelium was observed. CONCLUSION Concomitant administration of etanercept in IOI mice results in interruption of TNF-α-induced olfactory loss and induction of neuroepithelial regeneration. This demonstrates that etanercept has potential utility as a tool for elucidating the role of TNF-α in other olfactory inflammation models.
Collapse
Affiliation(s)
- Yong Gi Jung
- Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon-Si, Korea
| | - Andrew P Lane
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
38
|
Schubert CR, Cruickshanks KJ, Fischer ME, Klein BEK, Klein R, Pinto AA. Inflammatory and vascular markers and olfactory impairment in older adults. Age Ageing 2015; 44:878-82. [PMID: 26082178 DOI: 10.1093/ageing/afv075] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 03/05/2015] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND the incidence of olfactory impairment increases sharply in the eighth and ninth decades of life but the aetiology of age-related olfactory decline is not well understood. Inflammation and atherosclerosis are associated with many age-related conditions and atherosclerosis has been associated with olfactory decline in middle-aged adults. OBJECTIVE to determine if inflammatory markers and atherosclerosis are associated with the development of olfactory impairment in older adults. DESIGN longitudinal, population-based study. SETTING/PARTICIPANTS a total of 1,611 participants, aged 53-97 years in the Epidemiology of Hearing Loss Study without olfactory impairment at the 1998-2000 examination and with follow-up at a subsequent examination 5 and/or 10 years later. METHODS the San Diego Odor Identification Test was used to measure olfaction. High sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor-α were measured in serum and carotid ultrasound images were obtained for the measurement of carotid intima media thickness (IMT) and plaque assessment. Medical history, behavioural and lifestyle information were obtained by interview. RESULTS inflammatory markers, IMT and plaque were not associated with the 10-year cumulative incidence of olfactory impairment in adjusted Cox proportional hazard models. Among those <60 years, the mean IMT [hazard ratio (HR) = 4.35, 95% confidence interval (CI) = 1.69-11.21, tertile 3 versus tertile 1] and the number of sites with plaque (HR = 1.56, 95% CI = 1.17-2.08, per site) were associated with an increased risk of developing an olfactory impairment at follow-up. CONCLUSION subclinical atherosclerosis at a younger age may be a risk factor for the development of olfactory impairment.
Collapse
Affiliation(s)
- Carla R Schubert
- Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Karen J Cruickshanks
- Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Mary E Fischer
- Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Barbara E K Klein
- Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Ronald Klein
- Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - A Alex Pinto
- Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| |
Collapse
|
|
39
|
Abstract
It is unclear whether lifestyle modifications, such as dietary changes, should be advocated to prevent olfactory dysfunction. We investigated the association between dietary intakes of fats (saturated, mono-unsaturated and polyunsaturated fats, and cholesterol) and related food groups (nuts, fish, butter, margarine) with olfactory impairment. There were 1331 and 667 participants (older than 60 years) at baseline and 5-year follow-up, respectively, with complete olfaction and dietary data. Dietary data were collected using a validated semi-quantitative FFQ. Olfaction was measured using the San Diego Odor Identification Test. In a cross-sectional analysis of baseline data, those in the highest v. lowest quartile of n-6 PUFA intake had reduced odds of having any olfactory impairment, multivariable-adjusted OR 0.66 (95% CI 0.44, 0.97), P for trend = 0.06. Participants in the highest v. lowest quartile of margarine consumption had a 65% reduced odds of having moderate/severe olfactory impairment (P for trend = 0.02). Participants in the highest quartile compared to the lowest quartile (reference) of nut consumption had a 46% (P for trend = 0.01) and 58% (P for trend = 0.001) reduced odds of having any or mild olfactory impairment, respectively. Older adults in the highest v. lowest quartile of fish consumption had 35% (P for trend = 0.03) and 50% (P for trend = 0.01) reduced likelihood of having any or mild olfactory impairment, respectively. In longitudinal analyses, a marginally significant association was observed between nut consumption and incidence of any olfactory impairment, highest v. lowest quartile of nut consumption: OR 0.61 (95% CI 0.37, 1.00). Older adults with the highest consumption of nuts and fish had reduced odds of olfactory impairment, independent of potential confounding variables.
Collapse
|
|
40
|
Daulatzai MA. Olfactory dysfunction: its early temporal relationship and neural correlates in the pathogenesis of Alzheimer’s disease. J Neural Transm (Vienna) 2015; 122:1475-97. [DOI: 10.1007/s00702-015-1404-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 04/29/2015] [Indexed: 12/18/2022]
|
|
41
|
Evaluation of olfactory memory after coronary artery bypass grafting. POLISH JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2014; 11:381-4. [PMID: 26336453 PMCID: PMC4349045 DOI: 10.5114/kitp.2014.47336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 09/29/2013] [Accepted: 04/15/2014] [Indexed: 11/25/2022]
Abstract
Introduction This study determined whether coronary artery bypass grafting (CABG) surgery has any effect on olfactory function, employing the Brief Smell Identification Test (B-SIT). Material and methods All the participants were informed preoperatively about the B-SIT test and the mode of its application. The test was performed by each patient preoperatively (d0) as well as 1 (d1) and 3 (d3) days following the surgery. C-reactive protein (CRP) levels were recorded at the same time as the smell test. Results This prospective study included 45 patients. The mean age was 67 ± 7.55, and the group was 29% male. The mean durations of cross clamping and cardiopulmonary bypass were 54 ± 32 min and 62.5 ± 37.0 min, respectively. Eleven different odors were tested. Significant differences were observed for several odors: leather between d0 and d3, pine between d0 and d3, onion between d0 and d1, onion between d0 and d3, and soap between d0 and d1. The postoperative CRP levels were significantly higher than the preoperative levels. The correlation analysis determined that the postoperative CRP levels were negatively correlated with the B-SIT score (r = –0.48, p = 0.001). Conclusions Our findings suggest that patients after CABG are prone to develop olfactory dysfunction in the early postoperative period and that olfactory dysfunction is associated with postoperative CRP levels.
Collapse
|
|
42
|
Pfister S, Weber T, Härtig W, Schwerdel C, Elsaesser R, Knuesel I, Fritschy JM. Novel role of cystic fibrosis transmembrane conductance regulator in maintaining adult mouse olfactory neuronal homeostasis. J Comp Neurol 2014; 523:406-30. [PMID: 25271146 DOI: 10.1002/cne.23686] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 09/25/2014] [Accepted: 09/26/2014] [Indexed: 02/03/2023]
Abstract
The olfactory epithelium (OE) of mice deficient in cystic fibrosis transmembrane conductance regulator (CFTR) exhibits ion transport deficiencies reported in human CF airways, as well as progressive neuronal loss, suggesting defects in olfactory neuron homeostasis. Microvillar cells, a specialized OE cell-subtype, have been implicated in maintaining tissue homeostasis. These cells are endowed with a PLCβ2/IP3 R3/TRPC6 signal transduction pathway modulating release of neuropeptide Y (NPY), which stimulates OE stem cell activity. It is unknown, however, whether microvillar cells also mediate the deficits observed in CFTR-null mice. Here we show that Cftr mRNA in mouse OE is exclusively localized in microvillar cells and CFTR immunofluorescence is coassociated with the scaffolding protein NHERF-1 and PLCβ2 in microvilli. In CFTR-null mice, PLCβ2 was undetectable, NHERF-1 mislocalized, and IP3 R3 more intensely stained, along with increased levels of NPY, suggesting profound alteration of the PLCβ2/IP3 R3 signaling pathway. In addition, basal olfactory neuron homeostasis was altered, shown by increased progenitor cell proliferation, differentiation, and apoptosis and by reduced regenerative capacity following methimazole-induced neurodegeneration. The importance of CFTR in microvillar cells was further underscored by decreased thickness of the OE mucus layer and increased numbers of immune cells within this tissue in CFTR-KO mice. Finally, we observed enhanced immune responses to an acute viral-like infection, as well as hyper-responsiveness to chemical and physical stimuli applied intranasally. Taken together, these data strengthen the notion that microvillar cells in the OE play a key role in maintaining tissue homeostasis and identify several mechanisms underlying this regulation through the multiple functions of CFTR.
Collapse
Affiliation(s)
- Sandra Pfister
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| | | | | | | | | | | | | |
Collapse
|
|
43
|
Proft F, Steinbach S, Dechant C, Witt M, Reindl C, Schulz S, Vielhauer V, Hilge R, Laubender RP, Manger K, Nüsslein H, Wendler J, Schuch F, Schulze-Koops H, Grunke M. Gustatory and olfactory function in patients with granulomatosis with polyangiitis (Wegener's). Scand J Rheumatol 2014; 43:512-8. [PMID: 25204208 DOI: 10.3109/03009742.2014.915056] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVES Recent findings suggest that autoimmune disorders predispose to a diminished capacity to taste and smell. This has been shown for patients with systemic lupus erythematosus as well as for patients with rheumatoid arthritis (RA). Granulomatosis with polyangiitis (GPA), with its particular manifestations in the upper respiratory tract, may therefore have an even higher impact on these senses. The aims of this study were to evaluate the gustatory and olfactory function in patients with GPA, to compare them to sex- and age-matched healthy controls, and to correlate these findings with their GPA disease severity. METHOD Patients with established GPA were analysed by standardized assessments for gustatory and olfactory functions and examined for disease activity, stage of disease, and treatment. RESULTS Forty-four GPA patients were tested for their chemosensory functions. Compared to age- and sex-matched healthy controls, GPA patients showed significantly decreased olfactory scores along with diminished scores for their gustatory functions. The diminished sense of smell in GPA patients correlated significantly with elevated C-reactive protein (CRP) values whereas the gustatory impairment correlated with the duration and extent of the disease. CONCLUSIONS Our results indicate that olfactory and gustatory functions are significantly decreased in GPA. As the olfactory function of these patients was comparable to patients with RA, chemosensory impairment may not simply be a consequence of the involvement of the upper respiratory tract, but rather a common complication of systemic autoimmune diseases.
Collapse
Affiliation(s)
- F Proft
- Division of Rheumatology and Clinical Immunology, Medical Clinic and Polyclinic IV, Ludwig-Maximilians-University Munich , Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Hyperlipidemic diet causes loss of olfactory sensory neurons, reduces olfactory discrimination, and disrupts odor-reversal learning. J Neurosci 2014; 34:6970-84. [PMID: 24828650 DOI: 10.1523/jneurosci.3366-13.2014] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Currently, 65% of Americans are overweight, which leads to well-supported cardiovascular and cognitive declines. Little, however, is known concerning obesity's impact on sensory systems. Because olfaction is linked with ingestive behavior to guide food choice, its potential dysfunction during obesity could evoke a positive feedback loop to perpetuate poor ingestive behaviors. To determine the effect of chronic energy imbalance and reveal any structural or functional changes associated with obesity, we induced long-term, diet-induced obesity by challenging mice to high-fat diets: (1) in an obesity-prone (C57BL/6J) and obesity-resistant (Kv1.3(-/-)) line of mice, and compared this with (2) late-onset, genetic-induced obesity in MC4R(-/-) mice in which diabetes secondarily precipitates after disruption of the hypothalamic axis. We report marked loss of olfactory sensory neurons and their axonal projections after exposure to a fatty diet, with a concomitant reduction in electro-olfactogram amplitude. Loss of olfactory neurons and associated circuitry is linked to changes in neuronal proliferation and normal apoptotic cycles. Using a computer-controlled, liquid-based olfactometer, mice maintained on fatty diets learn reward-reinforced behaviors more slowly, have deficits in reversal learning demonstrating behavioral inflexibility, and exhibit reduced olfactory discrimination. When obese mice are removed from their high-fat diet to regain normal body weight and fasting glucose, olfactory dysfunctions are retained. We conclude that chronic energy imbalance therefore presents long-lasting structural and functional changes in the operation of the sensory system designed to encode external and internal chemical information and leads to altered olfactory- and reward-driven behaviors.
Collapse
|
|
45
|
Fischer M, Zopf Y, Elm C, Pechmann G, Hahn EG, Schwab D, Kornhuber J, Thuerauf NJ. Subjective and objective olfactory abnormalities in Crohn's disease. Chem Senses 2014; 39:529-38. [PMID: 24862958 DOI: 10.1093/chemse/bju022] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The pathogenesis of Crohn's disease (CD) is still unknown, but the involvement of the olfactory system in CD appears possible. No study to date has systematically assessed the olfactory function in CD patients. We investigated the olfactory function in CD patients in active (n = 31) and inactive disease (n = 27) and in a control group of age- and sex-matched healthy subjects (n = 35). Subjective olfactory testing was applied using the Sniffin' Sticks test. For olfactory testing, olfactory event-related potentials (OERPs) were obtained with a 4-channel olfactometer using phenyl ethyl alcohol (PEA) and hydrogen sulfide (H(2)S). Carbon dioxide (CO(2)) was employed as control stimulus, and chemosomatosensory event-related potentials (CSSERPs) were registered. Results of the Sniffin' Sticks test revealed significantly different olfactory hedonic judgment with increased olfactory hedonic estimates for pleasant odorants in CD patients in active disease compared with healthy subjects. A statistical trend was found toward lower olfactory thresholds in CD patients. In objective olfactory testing, CD patients showed lower amplitudes of OERPs and CSSERPs. Additionally, OERPs showed significantly shorter N1- and P2 latencies following stimulation of the right nostril with H(2)S in CD patients in inactive disease compared with controls. Our study demonstrates specific abnormalities of olfactory perception in CD patients.
Collapse
Affiliation(s)
- Marie Fischer
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany and
| | - Yurdagül Zopf
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany
| | - Cornelia Elm
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany and
| | - Georg Pechmann
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany and
| | - Eckhart G Hahn
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany
| | - Dieter Schwab
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany and
| | - Norbert Joachim Thuerauf
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany and
| |
Collapse
|
|
46
|
Zhao K, Jiang J, Pribitkin EA, Dalton P, Rosen D, Lyman B, Yee KK, Rawson NE, Cowart BJ. Conductive olfactory losses in chronic rhinosinusitis? A computational fluid dynamics study of 29 patients. Int Forum Allergy Rhinol 2014; 4:298-308. [PMID: 24449655 DOI: 10.1002/alr.21272] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 11/06/2013] [Accepted: 11/26/2013] [Indexed: 11/06/2022]
Abstract
BACKGROUND Besides sensorineural factors, conductive impediments likely contribute to olfactory losses in chronic rhinosinusitis (CRS) patients, yet no conclusive evidence exists. We aimed to examine possible conductive factors using computational fluid dynamics (CFD) models. METHODS A total of 29 CRS patients were assessed via odorant detection thresholds (ODTs), rhinomanometry (nasal resistance [NR]), acoustic rhinometry (minimum-cross-sectional area [MCA]) and computed tomography (CT) staging. CFD simulations of nasal airflow and odorant absorption to olfactory region were carried out based on individual CTs. Biopsies of olfactory epithelium (OE) were collected, cryosectioned, stained, and scored for erosion. RESULTS Significant correlations to ODTs were found for 3 variables: odor absorption in the olfactory region (r = -0.60, p < 0.01), MCA (r = -0.40, p < 0.05), and CT staging (r = 0.42, p < 0.05). However, significant findings were limited to ODTs of the highly soluble l-carvone. Multiple regression analysis revealed that these variables combined, with the addition of NR, can account for 65% of the total variance in ODTs. CT staging correlated significantly with OE erosion (r = 0.77, p < 0.01) and can replace the latter in the regression with comparable outcomes. Partial correlations suggest the contributions of both conductive and sensorineural variables are more prominent if adjusted for the effects of the other. Olfactory loss and inflammatory factors have strong bilateral involvement, whereas conductive factors are independent between sides. As validation, CFD-simulated NRs significantly correlated with rhinomanometrically assessed NRs (r = 0.60, p < 0.01). CONCLUSION Both conductive and sensorineural mechanisms can contribute to olfactory losses in CRS. CFD modeling provides critical guidance in understanding the role of conductive impediments in olfactory dysfunction in CRS.
Collapse
Affiliation(s)
- Kai Zhao
- Monell Chemical Senses Center, Philadelphia, PA; Department of Otolaryngology, Thomas Jefferson University, Philadelphia, PA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Pozharskaya T, Lane AP. Interferon gamma causes olfactory dysfunction without concomitant neuroepithelial damage. Int Forum Allergy Rhinol 2013; 3:861-5. [PMID: 24106006 DOI: 10.1002/alr.21226] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 07/19/2013] [Indexed: 12/31/2022]
Abstract
BACKGROUND Olfactory loss is a debilitating symptom of chronic rhinosinusitis (CRS). The pathophysiology of inflammatory olfactory dysfunction likely involves both conductive and sensorineural components. To study the interaction of CRS-associated inflammatory cytokines with the olfactory epithelium (OE), a transgenic mouse model was developed that allows temporally-controlled local gene expression. Interferon-gamma (IFN-γ) is a prototypical T helper 1 (Th1) cytokine linked to nonpolypoid CRS (CRSsNP), as well as sinonasal viral and bacterial infections. In this study, the effects of chronic IFN-γ expression on olfactory histology and function were investigated. METHODS IFN-γ secretion by olfactory sustentacular cells was induced in the transgenic mouse. Viability and gross behavior were unaffected. Mice were euthanized after 6 weeks of IFN-γ expression, and olfactory tissue was studied by histology, immunohistochemistry, and electro-olfactography (EOG). Findings were compared with uninduced littermates. RESULTS IFN-γ expression did not result in alteration of the normal histologic architecture of the neuroepithelium or lamina propria. However, EOG recordings demonstrated a significant decrease in odorant responses after IFN-γ expression. In addition, a marked increase in submucosal CD45-positive cells was observed, the majority of which were CD3-positive and CD4-positive lymphocytes. CONCLUSION Chronic IFN-γ expression in the mouse OE results in diminished odorant responsiveness, despite the absence of inflammatory tissue damage. This suggests a direct effect of IFN-γ on olfactory neuron function that may underlie olfactory loss in CRSsNP or viral infections. The infiltration of submucosal lymphocytes raises the possibility that other downstream cytokines also contribute to olfactory dysfunction.
Collapse
Affiliation(s)
- Tatyana Pozharskaya
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | | |
Collapse
|
|
48
|
Pozharskaya T, Liang J, Lane AP. Regulation of inflammation-associated olfactory neuronal death and regeneration by the type II tumor necrosis factor receptor. Int Forum Allergy Rhinol 2013; 3:740-7. [PMID: 23733314 DOI: 10.1002/alr.21187] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Revised: 04/08/2013] [Accepted: 04/30/2013] [Indexed: 11/09/2022]
Abstract
BACKGROUND Olfactory loss is a debilitating symptom of chronic rhinosinusitis. To study the impact of inflammation on the olfactory system, the inducible olfactory inflammation (IOI) transgenic mouse was created in which inflammation can be turned on and off within the olfactory epithelium. In this study, the type II tumor necrosis factor (TNF) receptor (TNFR2) was knocked out, and the effect on the olfactory loss phenotype was assessed. METHODS IOI mice were bred to TNFR2 knockout mice to yield progeny IOI mice lacking the TNFR2 receptor (TNFR2(-/-) ). TNF-α expression was induced within the olfactory epithelium for 6 weeks to generate chronic inflammation. Olfactory function was assayed by electro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. RESULTS Compared to IOI mice with wild-type TNFR2, IOI mice lacking the TNFR2 demonstrated similar levels of inflammatory infiltration and enlargement of the subepithelial layer. However, IOI-TNFR2(-/-) mice differed markedly in that the neuronal layer was largely preserved and active progenitor cell proliferation was present. Odorant responses were maintained in the IOI-TNFR2(-/-) mice, in contrast to IOI mice. CONCLUSION TNFR2 is the minor receptor for TNF-α, but appears to play an important role in mediating TNF-induced disruption of the olfactory system. This finding suggests that neuronal death and inhibition of proliferation in CRS may be mediated by TNFR2 on olfactory neurons and progenitor cells. Further studies are needed to elucidate the subcellular pathways involved and develop novel therapies for treating olfactory loss in the setting of CRS.
Collapse
Affiliation(s)
- Tatyana Pozharskaya
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | | |
Collapse
|
|
49
|
Lema Tomé CM, Tyson T, Rey NL, Grathwohl S, Britschgi M, Brundin P. Inflammation and α-synuclein's prion-like behavior in Parkinson's disease--is there a link? Mol Neurobiol 2013; 47:561-74. [PMID: 22544647 PMCID: PMC3589652 DOI: 10.1007/s12035-012-8267-8] [Citation(s) in RCA: 174] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Accepted: 04/04/2012] [Indexed: 01/24/2023]
Abstract
Parkinson's disease patients exhibit progressive spreading of aggregated α-synuclein in the nervous system. This slow process follows a specific pattern in an inflamed tissue environment. Recent research suggests that prion-like mechanisms contribute to the propagation of α-synuclein pathology. Little is known about factors that might affect the prion-like behavior of misfolded α-synuclein. In this review, we suggest that neuroinflammation plays an important role. We discuss causes of inflammation in the olfactory bulb and gastrointestinal tract and how this may promote the initial misfolding and aggregation of α-synuclein, which might set in motion events that lead to Parkinson's disease neuropathology. We propose that neuroinflammation promotes the prion-like behavior of α-synuclein and that novel anti-inflammatory therapies targeting this mechanism could slow disease progression.
Collapse
Affiliation(s)
- Carla M. Lema Tomé
- Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC B11, 221 84 Lund, Sweden
| | - Trevor Tyson
- Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC B11, 221 84 Lund, Sweden
| | - Nolwen L. Rey
- Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC B11, 221 84 Lund, Sweden
| | - Stefan Grathwohl
- F. Hoffmann-La Roche Ltd, pRED, Pharma Research & Early Development, DTA CNS, Grenzacherstrasse 124, Basel, 4070 Switzerland
| | - Markus Britschgi
- F. Hoffmann-La Roche Ltd, pRED, Pharma Research & Early Development, DTA CNS, Grenzacherstrasse 124, Basel, 4070 Switzerland
| | - Patrik Brundin
- Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC B11, 221 84 Lund, Sweden
- Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503 USA
| |
Collapse
|
|
50
|
The presence of CD209 expressing dendritic cells correlates with biofilm positivity in chronic rhinosinusitis with nasal polyposis. Eur Arch Otorhinolaryngol 2013; 270:2455-63. [PMID: 23358586 DOI: 10.1007/s00405-013-2372-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2012] [Accepted: 01/17/2013] [Indexed: 12/18/2022]
Abstract
Biofilm-positive cases of chronic rhinosinusitis with nasal polyposis (CRSwNP) may form a separate clinical entity, which is characterized by high recurrence rates and resistance against different therapeutic strategies. This can be explained by a special immunologic phenotype. Biofilm existence has been supposed to correlate with increased amount of dendritic cells that are responsible for antigen presentation in CRSwNP. A total of 20 patients with CRSwNP undergoing endoscopic sinus surgery (ESS) were analyzed. The negative control group consisted of ten patients undergoing septoplasty without CRSwNP. Three series of individual nasal polyps and control specimens were processed to hematoxylin-eosin (HE) and Gram staining and to CD209-specific immunofluorescent assay, respectively. Biofilm was detected in 13 of 20 patients (65 %) with CRSwNP and in none of the ten negative controls. The subepithelial layer of biofilm-positive nasal polyps displayed a statistically significant (p < 0.001) increase in the numbers of CD209-expressing dendritic cells compared to biofilm-negative specimens. It was found that biofilm detectability showed strong correlation to the architecture of respiratory mucosa and to the dominant inflammatory cell type of the subepithelial layer. Persisting bacterial biofilms may affect the type of antigen presentation and consecutive immune reactions in the subepithelial layer of nasal mucosa. This phenomenon may result in different inflammatory pathways with specific cytokine profile compared to biofilm-negative cases. Co-existence of bacterial biofilms and dominant pattern of dendritic cells suggest a biofilm-associated immunologic phenotype in CRSwNP. This can explain the mucosal changes, functional disorders and therapy resistance featuring CRSwNP.
Collapse
|