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Wang Z, Stakenborg N, Boeckxstaens G. Postoperative ileus-Immune mechanisms and potential therapeutic interventions. Neurogastroenterol Motil 2024:e14951. [PMID: 39462772 DOI: 10.1111/nmo.14951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/22/2024] [Revised: 09/23/2024] [Accepted: 10/16/2024] [Indexed: 10/29/2024]
Abstract
BACKGROUND Postoperative ileus (POI) is a condition marked by a temporary suppression of gastrointestinal motility following abdominal surgery. The mechanism of POI encompasses various factors and is characterized by two phases: the early neurogenic phase involving both adrenergic and non-adrenergic neural pathways; the later immune-mediated phase is characterized by a sterile inflammatory response that lasts several days. Activation of muscularis macrophages triggers a sterile inflammatory process that results in dysfunction of the enteric nervous system (ENS) and a reversible inhibition of gastrointestinal motility. PURPOSE In this minireview, recent insights in the pathophysiological mechanisms underlying POI and potential new therapeutic strategies are described.
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Affiliation(s)
- Zheng Wang
- Center of Intestinal Neuro-Immune Interactions, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium
| | - Nathalie Stakenborg
- Center of Intestinal Neuro-Immune Interactions, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium
| | - Guy Boeckxstaens
- Center of Intestinal Neuro-Immune Interactions, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium
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2
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Iskander O. An outline of the management and prevention of postoperative ileus: A review. Medicine (Baltimore) 2024; 103:e38177. [PMID: 38875379 PMCID: PMC11175850 DOI: 10.1097/md.0000000000038177] [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] [Academic Contribution Register] [Received: 01/23/2024] [Revised: 04/14/2024] [Accepted: 04/18/2024] [Indexed: 06/16/2024] Open
Abstract
Postoperative ileus (POI) is a prevalent surgical complication, which results in prolonged hospitalization, patient distress, and substantial economic burden. The literature aims to present a brief outline of interventions for preventing and treating POI post-surgery. Data from 2014 to 2023 were gathered from reputable sources like PubMed, PubMed Central, Google Scholar, Research Gate, and Science Direct. Inclusion criteria focused on studies exploring innovative treatments and prevention strategies for POI, using keywords such as novel POI treatments, non-pharmacological prevention, POI incidence rates, POI management, and risk factors. The findings revealed that integration of preventive measures such as coffee consumption, chewing gum, probiotics, and use of dikenchuto within enhanced recovery programs has significantly reduced both the frequency and duration of POI, without any adverse effects, with minimally invasive surgical approaches showing promise as an additional preventive strategy. While treatment options such as alvimopan, NSAIDs, and acupuncture have demonstrated efficacy, the use of lidocaine has raised concerns due to associated adverse effects. The ongoing exploration of novel therapeutic strategies such as targeting the mast cells, vagal nerve stimulation and tight junction protein, and prokinetic-mediated instigation of the cholinergic anti-inflammatory trail not only holds promise for enhanced treatment but also deepens the understanding of intricate cellular and molecular pathways underlying POI. POI presents a complex challenge in various surgical specialties, necessitating a multifaceted management approach. The integration of preventive and treatment measures within enhanced recovery programs has significantly reduced POI frequency and duration.
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Affiliation(s)
- Othman Iskander
- Department of Surgery, Faculty of Medicine, Jazan University, Saudi Arabia
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3
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van Baarle L, Stakenborg M, Matteoli G. Enteric neuro-immune interactions in intestinal health and disease. Semin Immunol 2023; 70:101819. [PMID: 37632991 DOI: 10.1016/j.smim.2023.101819] [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] [Academic Contribution Register] [Received: 09/30/2022] [Revised: 07/19/2023] [Accepted: 08/11/2023] [Indexed: 08/28/2023]
Abstract
The enteric nervous system is an autonomous neuronal circuit that regulates many processes far beyond the peristalsis in the gastro-intestinal tract. This circuit, consisting of enteric neurons and enteric glial cells, can engage in many intercellular interactions shaping the homeostatic microenvironment in the gut. Perhaps the most well documented interactions taking place, are the intestinal neuro-immune interactions which are essential for the fine-tuning of oral tolerance. In the context of intestinal disease, compelling evidence demonstrates both protective and detrimental roles for this bidirectional neuro-immune signaling. This review discusses the different immune cell types that are recognized to engage in neuronal crosstalk during intestinal health and disease. Highlighting the molecular pathways involved in the neuro-immune interactions might inspire novel strategies to target intestinal disease.
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Affiliation(s)
- Lies van Baarle
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium
| | - Michelle Stakenborg
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium
| | - Gianluca Matteoli
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium.
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4
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Sui C, Tao L, Bai C, Shao L, Miao J, Chen K, Wang M, Hu Q, Wang F. Molecular and cellular mechanisms underlying postoperative paralytic ileus by various immune cell types. Front Pharmacol 2022; 13:929901. [PMID: 35991871 PMCID: PMC9385171 DOI: 10.3389/fphar.2022.929901] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/27/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
Postoperative ileus (POI) is a well-known complication following gut manipulation or surgical trauma, leading to an impaired gut motility and prolonged postoperative recovery time. Few current therapeutic strategies can prevent POI, and this disorder remains to be a major clinical challenge for patients undergoing surgery. Comprehensive understanding of cellular and molecular mechanisms related to the pathogenesis of POI stimulates the discovery of more promising targets for treatment. POI is closely associated with a series of inflammatory events within the bowel wall, and as key components of inflammatory mechanisms, different types of immune cells, including macrophages, dendritic cells, and T lymphocytes, play significant roles during the development of POI. A variety of immune cells are recruited into the manipulation sites after surgery, contributing to early inflammatory events or impaired gut motility. Our review intends to summarize the specific relationship between different immune cells and POI, mainly focusing on the relevant mechanisms underlying this disorder.
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Affiliation(s)
- Chao Sui
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Liang Tao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chunhua Bai
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Lihua Shao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ji Miao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Kai Chen
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Meng Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
| | - Qiongyuan Hu
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
| | - Feng Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
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5
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Docsa T, Sipos A, Cox CS, Uray K. The Role of Inflammatory Mediators in the Development of Gastrointestinal Motility Disorders. Int J Mol Sci 2022; 23:6917. [PMID: 35805922 PMCID: PMC9266627 DOI: 10.3390/ijms23136917] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/27/2022] [Revised: 06/20/2022] [Accepted: 06/20/2022] [Indexed: 02/04/2023] Open
Abstract
Feeding intolerance and the development of ileus is a common complication affecting critically ill, surgical, and trauma patients, resulting in prolonged intensive care unit and hospital stays, increased infectious complications, a higher rate of hospital readmission, and higher medical care costs. Medical treatment for ileus is ineffective and many of the available prokinetic drugs have serious side effects that limit their use. Despite the large number of patients affected and the consequences of ileus, little progress has been made in identifying new drug targets for the treatment of ileus. Inflammatory mediators play a critical role in the development of ileus, but surprisingly little is known about the direct effects of inflammatory mediators on cells of the gastrointestinal tract, and many of the studies are conflicting. Understanding the effects of inflammatory cytokines/chemokines on the development of ileus will facilitate the early identification of patients who will develop ileus and the identification of new drug targets to treat ileus. Thus, herein, we review the published literature concerning the effects of inflammatory mediators on gastrointestinal motility.
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Affiliation(s)
- Tibor Docsa
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.D.); (A.S.)
| | - Adám Sipos
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.D.); (A.S.)
| | - Charles S. Cox
- Department of Pediatric Surgery, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77204, USA;
| | - Karen Uray
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.D.); (A.S.)
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6
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Τhe Effect of Opioid Administration on Cytologic and Histopathologic Diagnosis of Canine Cutaneous Mast Cell Tumors Treated by Surgical Excision. Vet Sci 2022; 9:vetsci9050202. [PMID: 35622730 PMCID: PMC9143400 DOI: 10.3390/vetsci9050202] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/21/2022] [Revised: 04/17/2022] [Accepted: 04/19/2022] [Indexed: 12/04/2022] Open
Abstract
Mast cell tumor (MCT) is a frequent cutaneous tumor in dogs, with a variable biological behavior. Studies correlate cytologic and histopathologic features of MCTs with their biological behavior, prognosis, and response to treatment. The use of preoperative opioids is common in canine patients undergoing surgical removal of these tumors. Certain opioids can induce or downregulate mast cell degranulation and influence cancer progression. The aim of the present study was to investigate whether the administration of morphine or butorphanol during surgical excision of canine cutaneous MCTs affects their cytologic and histopathologic appearance, thus influencing cytologic and histopathologic grading. This was a prospective, blinded, randomized, cohort clinical study. Forty-five dogs with cutaneous MCTs were randomly allocated into three groups according to preanaesthetic medication: dexmedetomidine combined with morphine (group M) or butorphanol (group B) or normal saline (group C). Cytologic specimens and histopathologic samples were obtained both prior to and after surgery. Samples were graded according to Kiupel’s and Patnaik’s systems, examined immunohistochemically for Ki-67 protein (Ki-67) and c-kit proto-oncogene product (KIT) expression, and histochemically for argyrophilic nucleolar organizing regions (AgNORs). Based on both Kiupel’s and Patnaik’s systems, no statistically significant differences were noted concerning the number of cases with grading discrepancies in grades allocated prior to versus after surgery among the groups. The same applied for cytological grading and immunohistochemical and histochemical evaluation. It seems that administration of morphine or butorphanol as part of the preanesthetic medication for surgical removal of canine cutaneous mast cell tumors does not influence histopathologic and cytologic grading of MCTs.
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Buscail E, Deraison C. Postoperative Ileus: a Pharmacological Perspective. Br J Pharmacol 2022; 179:3283-3305. [PMID: 35048360 DOI: 10.1111/bph.15800] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/20/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 11/29/2022] Open
Abstract
Post-operative ileus (POI) is a frequent complication after abdominal surgery. The consequences of POI can be potentially serious such as bronchial inhalation or acute functional renal failure. Numerous advances in peri-operative management, particularly early rehabilitation, have made it possible to decrease POI. Despite this, the rate of prolonged POI ileus remains high and can be as high as 25% of patients in colorectal surgery. From a pathophysiological point of view, POI has two phases, an early neurological phase and a later inflammatory phase, to which we could add a "pharmacological" phase during which analgesic drugs, particularly opiates, play a central role. The aim of this review article is to describe the phases of the pathophysiology of POI, to analyse the pharmacological treatments currently available through published clinical trials and finally to discuss the different research areas for potential pharmacological targets.
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Affiliation(s)
- Etienne Buscail
- IRSD, INSERM, INRAE, ENVT, University of Toulouse, CHU Purpan (University Hospital Centre), Toulouse, France.,Department of digestive surgery, colorectal surgery unit, Toulouse University Hospital, Toulouse, France
| | - Céline Deraison
- IRSD, INSERM, INRAE, ENVT, University of Toulouse, CHU Purpan (University Hospital Centre), Toulouse, France
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8
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Fortea M, Albert-Bayo M, Abril-Gil M, Ganda Mall JP, Serra-Ruiz X, Henao-Paez A, Expósito E, González-Castro AM, Guagnozzi D, Lobo B, Alonso-Cotoner C, Santos J. Present and Future Therapeutic Approaches to Barrier Dysfunction. Front Nutr 2021; 8:718093. [PMID: 34778332 PMCID: PMC8582318 DOI: 10.3389/fnut.2021.718093] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/31/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
There is converging and increasing evidence, but also uncertainty, for the role of abnormal intestinal epithelial barrier function in the origin and development of a growing number of human gastrointestinal and extraintestinal inflammatory disorders, and their related complaints. Despite a vast literature addressing factors and mechanisms underlying changes in intestinal permeability in humans, and its connection to the appearance and severity of clinical symptoms, the ultimate link remains to be established in many cases. Accordingly, there are no directives or clinical guidelines related to the therapeutic management of intestinal permeability disorders that allow health professionals involved in the management of these patients to carry out a consensus treatment based on clinical evidence. Instead, there are multiple pseudoscientific approaches and commercial propaganda scattered on the internet that confuse those affected and health professionals and that often lack scientific rigor. Therefore, in this review we aim to shed light on the different therapeutic options, which include, among others, dietary management, nutraceuticals and medical devices, microbiota and drugs, and epigenetic and exosomes-manipulation, through an objective evaluation of the scientific publications in this field. Advances in the knowledge and management of intestinal permeability will sure enable better options of dealing with this group of common disorders to enhance quality of life of those affected.
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Affiliation(s)
- Marina Fortea
- Laboratory for Enteric NeuroScience, Translational Research Center for GastroIntestinal Disorders, University of Leuven, Leuven, Belgium
| | - Mercé Albert-Bayo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Mar Abril-Gil
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - John-Peter Ganda Mall
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Xavier Serra-Ruiz
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Alejandro Henao-Paez
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Elba Expósito
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Ana María González-Castro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Danila Guagnozzi
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz Lobo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Carmen Alonso-Cotoner
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
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Hellstrom EA, Ziegler AL, Blikslager AT. Postoperative Ileus: Comparative Pathophysiology and Future Therapies. Front Vet Sci 2021; 8:714800. [PMID: 34589533 PMCID: PMC8473635 DOI: 10.3389/fvets.2021.714800] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/25/2021] [Accepted: 08/19/2021] [Indexed: 12/11/2022] Open
Abstract
Postoperative ileus (POI), a decrease in gastrointestinal motility after surgery, is an important problem facing human and veterinary patients. 37.5% of horses that develop POI following small intestinal (SI) resection will not survive to discharge. The two major components of POI pathophysiology are a neurogenic phase which is then propagated by an inflammatory phase. Perioperative care has been implicated, namely the use of opioid therapy, inappropriate fluid therapy and electrolyte imbalances. Current therapy for POI variably includes an early return to feeding to induce physiological motility, reducing the inflammatory response with agents such as non-steroidal anti-inflammatory drugs (NSAIDs), and use of prokinetic therapy such as lidocaine. However, optimal management of POI remains controversial. Further understanding of the roles of the gastrointestinal microbiota, intestinal barrier function, the post-surgical inflammatory response, as well as enteric glial cells, a component of the enteric nervous system, in modulating postoperative gastrointestinal motility and the pathogenesis of POI may provide future targets for prevention and/or therapy of POI.
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Affiliation(s)
| | | | - Anthony T. Blikslager
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC, United States
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Wattchow D, Heitmann P, Smolilo D, Spencer NJ, Parker D, Hibberd T, Brookes SSJ, Dinning PG, Costa M. Postoperative ileus-An ongoing conundrum. Neurogastroenterol Motil 2021; 33:e14046. [PMID: 33252179 DOI: 10.1111/nmo.14046] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/07/2020] [Revised: 11/02/2020] [Accepted: 11/05/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Postoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder. PURPOSE This review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non-pharmacological) and their efficacy are summarized and graded consistent with current clinical guidelines. The review is not intended to provide a comprehensive overview of ileus, but rather a general understanding of the major clinical problems associated with it, how animal models have been useful to elucidate key mechanisms and, finally, some perspectives from both scientists and clinicians as to how we may move forward with this debilitating yet common condition.
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Affiliation(s)
- David Wattchow
- Department of Surgery, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia
| | - Paul Heitmann
- Department of Surgery, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia
| | - David Smolilo
- Department of Human Physiology, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia
| | - Nick J Spencer
- Department of Human Physiology, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia
| | - Dominic Parker
- Department of Surgery, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia.,Department of Human Physiology, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia
| | - Timothy Hibberd
- Department of Human Physiology, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia
| | - Simon S J Brookes
- Department of Human Physiology, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia
| | - Phil G Dinning
- Department of Surgery, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia.,Department of Human Physiology, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia
| | - Marcello Costa
- Department of Human Physiology, College of Medicine and Public Health, The Flinders University and Flinders Medical Centre, Bedford Park, SA, Australia
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11
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Perioperative Electroacupuncture Can Accelerate the Recovery of Gastrointestinal Function in Cancer Patients Undergoing Pancreatectomy or Gastrectomy: A Randomized Controlled Trial. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5594263. [PMID: 33859707 PMCID: PMC8026294 DOI: 10.1155/2021/5594263] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 01/16/2021] [Revised: 03/11/2021] [Accepted: 03/20/2021] [Indexed: 12/01/2022]
Abstract
The effect of perioperative acupuncture on accelerating gastrointestinal function recovery has been reported in colorectal surgery and distal gastrectomy (Billroth-II). However, the evidence in pancreatectomy and other gastrectomy is still limited. A prospective, randomized controlled trial was conducted between May 2018 and August 2019. Consecutive patients undergoing pancreatectomy or gastrectomy in our hospital were randomly assigned to the electroacupuncture (EA) group and the control group. The patients in the EA group received transcutaneous EA on Bai-hui (GV20), Nei-guan (PC6), Tian-shu (ST25), and Zu-san-li (ST36) once a day in the afternoon, and the control group received sham EA. Primary outcomes were the time to first flatus and time to first defecation. In total, 461 patients were randomly assigned to the groups, and 385 were analyzed finally (EA group, n = 201; control group, n = 184). Time to first flatus (3.0 ± 0.7 vs 4.2 ± 1.0, P < 0.001) and first defecation (4.2 ± 0.9 vs 5.4 ± 1.2, P < 0.001) in the EA group were significantly shorter than those in the control group. Of patients undergoing pancreatectomy, those undergoing pancreaticoduodenectomy and intraoperative radiation therapy (IORT) surgery benefitted from EA in time to first flatus (P < 0.001) and first defecation (P < 0.001), while those undergoing distal pancreatectomy did not (Pflatus=0.157, Pdefecation=0.007) completely. Of patients undergoing gastrectomy, those undergoing total gastrectomy and distal gastrectomy (Billroth-II) benefitted from EA (P < 0.001), as did those undergoing proximal gastrectomy (P=0.015). Patients undergoing distal gastrectomy (Billroth-I) benefitted from EA in time to first defecation (P=0.012) but not flatus (P=0.051). The time of parenteral nutrition, hospital stay, and time to first independent walk in the EA group were shorter than those in the control group. No severe EA complications were reported. EA was safe and effective in accelerating postoperative gastrointestinal function recovery. Patients undergoing pancreaticoduodenectomy, IORT surgery, total gastrectomy, proximal gastrectomy, or distal gastrectomy (Billroth-II) could benefit from EA. This trial is registered with NCT03291574.
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12
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Gao Y, Zhang X, Li X, Qi R, Han Y, Kang Y, Cai R, Peng C, Qi Y. Aloe-emodin, a naturally occurring anthraquinone, is a highly potent mast cell stabilizer through activating mitochondrial calcium uniporter. Biochem Pharmacol 2021; 186:114476. [PMID: 33607072 DOI: 10.1016/j.bcp.2021.114476] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/06/2021] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 01/07/2023]
Abstract
Mast cells play a fundamental role in immune system. Upon stimulation, they are activated via IgE dependent or independent pathway and then release granules which contain plenty of preformed constituents. Mast cell stabilizers are commonly used clinically for inhibiting the degranulation of mast cells. In the current study, we firstly identified aloe-emodin, a naturally occurring anthraquinone, was a prominent mast cell stabilizer. It could strikingly dampen IgE/FcεRI- and MAS-related G protein coupled receptor (Mrgpr)-mediated mast cell degranulation in vitro and in vivo. Mechanism study indicated that aloe-emodin rapidly and reversibly decreased cytosolic Ca2+ (Ca2+[c]) concentration through enhancing the mitochondrial Ca2+ (Ca2+[m]) uptake. After genetically silencing or pharmacologic inhibiting mitochondrial calcium uniporter (MCU), the effects of aloe-emodin on the Ca2+[c] level and mast cell degranulation were significantly weakened. In contrast to six clinical drugs with mast cell stabilizing properties (amlexanox, tranilast, ketotifen, cromolyn disodium salt, dexamethasone and pimecrolimus), aloe-emodin showed an impressive and potent inhibitory action on the mast cell degranulation. Collectively, aloe-emodin is a highly potent mast cell stabilizer. By directly activating MCU, it decreases Ca2+[c] level to suppress mast cell degranulation. Our study may provide a promising candidate for the treatment of mast cell activation-related diseases.
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Affiliation(s)
- Yuan Gao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
| | - Xiaoyu Zhang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
| | - Ximeng Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
| | - Ruijuan Qi
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
| | - Yixin Han
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
| | - Yuan Kang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
| | - Runlan Cai
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
| | - Cheng Peng
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
| | - Yun Qi
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China.
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13
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Ahmad MU, Riley KD, Ridder TS. Acute Colonic Pseudo-Obstruction After Posterior Spinal Fusion: A Case Report and Literature Review. World Neurosurg 2020; 142:352-363. [PMID: 32659357 DOI: 10.1016/j.wneu.2020.07.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/03/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Acute colonic pseudo-obstruction (ACPO) or Ogilvie's syndrome occurs in 0.22%-7% of patients undergoing surgery, with a mortality of up to 46%. ACPO increased median hospital days versus control in spinal surgery (14 vs. 6 days; P < 0.001). If defined as postoperative ileus, the incidence was 7%-13.4%. Postoperative ileus is associated with 2.9 additional hospital days and an $80,000 increase in cost per patient. We present a case of ACPO in an adult patient undergoing spinal fusion for correction of scoliosis and review the available literature to outline clinical characteristics and surgical outcomes. CASE DESCRIPTION The patient was a 31-year-old woman with untreated advanced scoliosis with no history of neurologic issues. T2-L3 spinal instrumentation and fusion was completed. Plain abdominal radiography showed of dilated cecum 11 cm and the department of general surgery was consulted. Neostigmine administration was planned after conservative treatment failure after transfer to the intensive care unit. The patient was discharged home with no recurrence >60 days. Thirty cases were found in our literature review using PubMed and Embase databases and summarized. CONCLUSIONS Of 30 cases reviewed, only 3 cases of ACPO were specific to patients undergoing spinal fusion for scoliosis. According to the literature, 20% of patients had resolution with conservative treatment, 40% with neostigmine, and 30% with surgical intervention. Other noninvasive treatments may have similar efficacy in preventing complications leading to surgical invention. Sixty clinical trials and 9 systematic reviews were summarized with an updated management algorithm.
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Affiliation(s)
- M Usman Ahmad
- Department of Surgery, University of Colorado School of Medicine, Aurora, Colorado, USA.
| | - Keyan D Riley
- Trauma and Acute Care Surgery, Memorial Hospital, University of Colorado Health, Colorado Springs, Colorado, USA
| | - Thomas S Ridder
- Pediatric and Adult Neurosurgery, UCHealth Brain & Spine Clinic, Children's Hospital of Colorado, Colorado Springs, Colorado, USA
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14
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Kim JY, Zaghiyan K, Lightner A, Fleshner P. Risk of postoperative complications among ulcerative colitis patients treated preoperatively with vedolizumab: a matched case-control study. BMC Surg 2020; 20:46. [PMID: 32138717 PMCID: PMC7059353 DOI: 10.1186/s12893-020-00698-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/16/2019] [Accepted: 02/14/2020] [Indexed: 12/11/2022] Open
Abstract
Background Although biologic agents have revolutionized the medical management of severe ulcerative colitis (UC), there is considerable controversy regarding adverse effects of vedolizumab on surgical outcomes. We evaluated 30-day postoperative morbidity in UC patients undergoing abdominal colectomy (AC) treated with vedolizumab before surgery. Methods From 2007 to 2017, 285 patients were enrolled in prospectively maintained database evaluating the role of clinical, serologic markers with clinical phenotypes in UC. The patients treated with vedolizumab within 12 weeks of AC was queried, then matched 1:3:3 into 3 preoperative treatment groups based on age, gender and surgical treatment of UC; ileal pouch-anal anastomosis (IPAA) with ileostomy vs total colectomy with end stoma: a) vedolizumab (n = 25); b) anti-tumor necrosis factor (anti-TNF) (n = 74); and c) no biologics (n = 54). Thirty-day postoperative complications among patient groups were compared. Results The 3 patient groups were well-matched in other characteristics including disease duration, disease extent, medication history and preoperative serological data. There were no significant differences in the overall incidence of postoperative complications among patients treated preoperatively with vedolizumab, anti-TNFs, or no biologics (44% vs. 45% vs. 37%; p = 0.67). Although there was no significant difference between patient cohorts in infectious complications (p = 0.20), postoperative ileus (POI) was significantly more common among the vedolizumab group (n = 9; 36%) compared to anti-TNF (n = 12; 16%) or no biologics (n = 5; 9%) (p = 0.01). Multivariable analysis showed that vedolizumab treatment prior to surgery was an independent risk factor for POI (OR: 5.16, 95% CI; 1.71–15.52; p = .004). Conclusion Although preoperative vedolizumab exposure did not influence the rate of overall 30-day postoperative complications, vedolizumab tends to increase incidence of POI.
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Affiliation(s)
- Jeong Yeon Kim
- Department of Surgery, Hallym University College of Medicine, Dongtan, South Korea
| | - Karen Zaghiyan
- Division of Colorectal Surgery, Cedars-Sinai Medical Center, 7 Beverly Blvd., Suite 101, Los Angeles, California, 90048, USA
| | - Amy Lightner
- Department of Colon and Rectal Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Phillip Fleshner
- Division of Colorectal Surgery, Cedars-Sinai Medical Center, 7 Beverly Blvd., Suite 101, Los Angeles, California, 90048, USA.
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15
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Sun DL, Qi YX, Yang T, Lin YY, Li SM, Li YJ, Xu QW, Sun YB, Li WM, Chen XZ, Xu PY. Early oral nutrition improves postoperative ileus through the TRPA1/CCK1-R-mediated mast cell-nerve axis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:179. [PMID: 32309326 PMCID: PMC7154392 DOI: 10.21037/atm.2020.01.95] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Abstract
Background The mechanism of early oral nutrition that regulates the mast cell-nerve axis to improve postoperative ileus (POI) remains unclear. This study aims to investigate whether early oral nutrition can improve POI through Transient receptor potential ankyrin-1 (TRPA1)/cholecystokinin 1 receptor (CCK1-R) in the mast cell-nerve axis. Methods Experiment 1: Male Sprague-Dawley (SD) rats were randomly divided into the TRPA1 inhibitor + oral nutrition group (TI + ON + POI), oral nutrition group (ON + POI), POI group (POI) and sham surgery group (Sham). Nine rats in each group were treated. Experiment 2: Primary cultures of mast cells and dorsal root ganglion cells were created, and a non-contact co-culture system was established. The cells were divided into the dorsal root ganglion (DRG) group, mast cell group, DRG + mast cell group, TRPA1 inhibitor or enhancer group, mast cell stabilizer or enhancer group, CCK1-R inhibitor or enhancer group. The results of expression of TRPA1, CCK1-R and histamine in colon tissue, portal vein blood, supernatant or dorsal root ganglia, intestinal transport test and mast cell morphology were analysed. Results In experiment 1, Early oral nutrition could alleviate the degranulation and activation of mast cells and alleviate the inflammatory reaction of intestinal wall muscles (P<0.05). Early oral nutrition improved POI by stabilizing mast cells with TRPA1. TRPA1 inhibitor decreased CCK1-R concentrations in portal vein blood and CCK1-R expression in colonic smooth muscle (P<0.05). In experiment 2, the change in mast cell function regulated the secretion of CCK1-R by neurons, CCK1-R negatively regulated the degranulation and activation of mast cells (P<0.05), and mast cells positively regulated the expression of TRPA1 protein in DRG (P<0.05). Conclusions Early enteral nutrition can improve POI through the TRPA1/CCK1-R-mediated mast cell-nerve axis. TRPA1 positively regulates CCK1-R to stabilize mast cells, but TRPA1 is not the target of the downstream CCK1-R pathway.
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Affiliation(s)
- Da-Li Sun
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Yu-Xing Qi
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Ting Yang
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Yue-Ying Lin
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Shu-Min Li
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Yi-Jun Li
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Qing-Wen Xu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Yan-Bo Sun
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Wei-Ming Li
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Xiong-Zhi Chen
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Peng-Yuan Xu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
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16
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Sun Y, Shi H, Hong Z, Chi P. Inhibition of JAK1 mitigates postoperative ileus in mice. Surgery 2019; 166:1048-1054. [DOI: 10.1016/j.surg.2019.07.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/14/2019] [Revised: 07/02/2019] [Accepted: 07/22/2019] [Indexed: 12/31/2022]
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17
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Stakenborg N, Gomez-Pinilla PJ, Boeckxstaens GE. Postoperative Ileus: Pathophysiology, Current Therapeutic Approaches. Handb Exp Pharmacol 2017; 239:39-57. [PMID: 27999957 DOI: 10.1007/164_2016_108] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/26/2022]
Abstract
Postoperative ileus, which develops after each abdominal surgical procedure, is an iatrogenic disorder characterized by a transient inhibition of gastrointestinal motility. Its pathophysiology is complex involving pharmacological (opioids, anesthetics), neural, and immune-mediated mechanisms. The early neural phase, triggered by activation of afferent nerves during the surgical procedure, is short lasting compared to the later inflammatory phase. The latter starts after 3-6 h and lasts several days, making it a more interesting target for treatment. Insight into the triggers and immune cells involved is of great importance for the development of new therapeutic strategies. In this chapter, the pathogenesis and the current therapeutic approaches to treat postoperative ileus are discussed.
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Affiliation(s)
- N Stakenborg
- Division of Gastroenterology and Hepatology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, Leuven, 3000, Belgium
| | - P J Gomez-Pinilla
- Division of Gastroenterology and Hepatology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, Leuven, 3000, Belgium
| | - G E Boeckxstaens
- Division of Gastroenterology and Hepatology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, Leuven, 3000, Belgium. .,Division of Gastroenterology and Hepatology, University Hospital Leuven, Herestraat 49, Leuven, 3000, Belgium.
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18
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Gao Y, Hou R, Fei Q, Fang L, Han Y, Cai R, Peng C, Qi Y. The Three-Herb Formula Shuang-Huang-Lian stabilizes mast cells through activation of mitochondrial calcium uniporter. Sci Rep 2017; 7:38736. [PMID: 28045016 PMCID: PMC5206722 DOI: 10.1038/srep38736] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/21/2016] [Accepted: 11/14/2016] [Indexed: 12/31/2022] Open
Abstract
Mast cells (MCs) are key effector cells of IgE-FcεRI- or MrgprX2-mediated signaling event. Shuang-Huang-Lian (SHL), a herbal formula from Chinese Pharmacopoeia, has been clinically used in type I hypersensitivity. Our previous study demonstrated that SHL exerted a non-negligible effect on MC stabilization. Herein, we sought to elucidate the molecular mechanisms of the prominent anti-allergic ability of SHL. MrgprX2- and IgE-FcεRI-mediated MC activation in vitro and in vivo models were developed by using compound 48/80 (C48/80) and shrimp tropomyosin (ST), respectively. Our data showed that SHL markedly dampened C48/80- or ST-induced MC degranulation in vitro and in vivo. Mechanistic study indicated that cytosolic Ca2+ (Ca2+[c]) level decreased rapidly and sustainably after SHL treatment, and then returned to homeostasis when SHL was withdrawn. Moreover, SHL decreases Ca2+[c] levels mainly through enhancing the mitochondrial Ca2+ (Ca2+[m]) uptake. After genetically silencing or pharmacologic inhibiting mitochondrial calcium uniporter (MCU), the effect of SHL on the Ca2+[c] level and MC degranulation was significantly weakened. Simultaneously, the activation of SHL on Ca2+[m] uptake was completely lost. Collectively, by activating MCU, SHL decreases Ca2+[c] level to stabilize MCs, thus exerting a remarkable anti-allergic activity, which could have considerable influences on clinical practice and research.
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Affiliation(s)
- Yuan Gao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Rui Hou
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China
| | - Qiaoling Fei
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China
| | - Lei Fang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China
| | - Yixin Han
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China
| | - Runlan Cai
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China
| | - Cheng Peng
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Yun Qi
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China
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19
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Vilz TO, Pantelis D, Lingohr P, Fimmers R, Esmann A, Randau T, Kalff JC, Coenen M, Wehner S. SmartPill® as an objective parameter for determination of severity and duration of postoperative ileus: study protocol of a prospective, two-arm, open-label trial (the PIDuSA study). BMJ Open 2016; 6:e011014. [PMID: 27401360 PMCID: PMC4947765 DOI: 10.1136/bmjopen-2015-011014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Postoperative ileus (POI) is a frequent complication after abdominal surgery (AS). Until today, neither a prophylaxis nor an evidence-based therapy exists. This originates from the absence of objective parameters evaluating the severity and duration of POI resulting in clinical trials of modest quality. The SmartPill(®), a capsule which frequently measures pH value, temperature and intraluminal pressure after swallowing, offers an elegant option for analysing gastrointestinal (GI) transit times and smooth muscle activity in vivo. As the use in patients in the first months after AS is not covered by the marketing authorisation, we aim to investigate the safety and feasibility of the SmartPill(®) immediately after surgery. Additionally, we analyse the influence of prokinetics and laxatives as well as standardised physiotherapy on postoperative bowel contractility, as scientific evidence of its effects is still lacking. METHODS AND ANALYSIS The PIDuSA study is a prospective, single-centre, two-arm, open-label trial. The SmartPill(®) will be applied to 55 patients undergoing AS having a high risk for POI and 10 patients undergoing extra-abdominal surgery rarely developing POI. The primary objective is the safety of the SmartPill(®) in patients after surgery on the basis of adverse device effects/serious adverse device effects (ADE/SADE). The sample size suggests that events with a probability of 3% could be seen with a certainty of 80% for at least once in the sample. Secondary objective is the analysis of postoperative intestinal activity in the GI tract in both groups. Furthermore, clinical signs of bowel motility disorders will be correlated to the data measured by the SmartPill(®) to evaluate its significance as an objective parameter for assessing POI severity. Additionally, effects of prokinetics, laxatives and physiotherapy on postoperative peristaltic activity recorded by the SmartPill(®) will be analysed. ETHICS AND DISSEMINATION The protocol was approved by the federal authority (94.1.05-5660-8976) and the local ethics committee (092/14-MPG). Findings will be disseminated through publications and conference presentations. TRIAL REGISTRATION NUMBER NCT02329912; Pre-results.
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Affiliation(s)
- Tim O Vilz
- Department of Surgery, University of Bonn, Bonn, Germany
| | | | | | - Rolf Fimmers
- Clinical Study Core Unit, Study Center Bonn (SZB), University of Bonn, Bonn, Germany
- Institute of Medical Biometrics, Informatics and Epidemiology, Study Center Bonn, University of Bonn, Bonn, Germany
| | - Anke Esmann
- Department of Surgery, University of Bonn, Bonn, Germany
| | - Thomas Randau
- Department of Orthopedics and Trauma Surgery, University of Bonn, Bonn, Germany
| | - Jörg C Kalff
- Department of Surgery, University of Bonn, Bonn, Germany
| | - Martin Coenen
- Clinical Study Core Unit, Study Center Bonn (SZB), University of Bonn, Bonn, Germany
- Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - Sven Wehner
- Department of Surgery, University of Bonn, Bonn, Germany
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20
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Berdún S, Rychter J, Vergara P. Surgical intestinal manipulation increases gene expression of TrkA, CGRP, and PAR-2 IN dorsal root ganglia in the rat. Neurogastroenterol Motil 2016; 28:816-26. [PMID: 26909771 DOI: 10.1111/nmo.12777] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/26/2015] [Accepted: 12/23/2015] [Indexed: 12/23/2022]
Abstract
BACKGROUND Surgical handling of the bowel evokes degranulation of peritoneal mast cells (PMC). Nonetheless, role of PMCs in postoperative ileus (POI) is somewhat controversial. We aimed to investigate if intestinal manipulation elicits changes in afferent mediators related to MC activation and alteration of gastrointestinal (GI) motility. METHODS Postoperative ileus was induced by intestinal manipulation in Sprague-Dawley rats. Additionally, compound 48/80 (C48/80) and ketotifen were used to modulate MC activity. Rat mast cell protease 6 (RMCP-6, ELISA) release was determined in peritoneal lavage 20 min after intestinal manipulation. At 24 h, GI transit was determined. Gene expression of calcitonin gene-related peptide (CGRP), protease-activated receptor-2 (PAR-2), nerve growth factor (NGF), and TrkA receptor was determined (PCR) in dorsal root ganglia (DRG). Ileal wall inflammation was assessed by myeloperoxidase (MPO) activity, interleukin-6 expression (IL-6). KEY RESULTS Intestinal manipulation and exposure to C48/80-induced degranulation of PMCs delayed GI transit and up-regulated IL-6 and MPO activity. Intestinal manipulation, but not C48/80, up-regulated CGRP, PAR-2, and NGF/TrkA in DRGs. Ketotifen only improved gastric emptying and fecal output. Up-regulation of CGRP and TrkA expression in DRG was not prevented by ketotifen. CONCLUSIONS & INFERENCES Postoperative ileus is accompanied by activation of CGRP, NGF-TrkA, and PAR-2 in DRGs. Our results suggest that these mediators could be a target in further POI studies in order to find new therapeutic targets for this medical condition.
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Affiliation(s)
- S Berdún
- Department of Cell Biology, Physiology and Immunology, Veterinary School, Universitat Autònoma de Barcelona, Barcelona, Spain
- Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J Rychter
- Department of Cell Biology, Physiology and Immunology, Veterinary School, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - P Vergara
- Department of Cell Biology, Physiology and Immunology, Veterinary School, Universitat Autònoma de Barcelona, Barcelona, Spain
- Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
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21
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Berdún S, Rychter J, Vergara P. Effects of nerve growth factor antagonist K252a on peritoneal mast cell degranulation: implications for rat postoperative ileus. Am J Physiol Gastrointest Liver Physiol 2015; 309:G801-6. [PMID: 26405114 DOI: 10.1152/ajpgi.00152.2015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 05/18/2015] [Accepted: 09/16/2015] [Indexed: 01/31/2023]
Abstract
Stabilization of mast cell (MC) degranulation has been proposed to prevent postoperative ileus (POI). Nerve growth factor (NGF) mediates MC degranulation. The aim of the study was to evaluate whether NGF receptor antagonist K252a acts as a MC stabilizer in vitro and in vivo model of POI. Peritoneal mast cells (PMCs) were obtained from Sprague-Dawley rats and were incubated with K252a and exposed to NGF or Compound 48/80 (C48/80). MC degranulation was assessed by β-hexosaminidase assay. POI was induced in rats by intestinal manipulation (IM). Rats were pretreated with K252a (100 μg/kg sc) 20 min prior to POI induction. At 20 min after IM, release of rat mast cell protease 6 (RMCP-6) was evaluated in peritoneal lavage. At 24 h, intestinal transit (IT) and gastric emptying (GE) were evaluated. Ileal inflammation was assessed by myeloperoxidase (MPO) activity, expression of IL-6, NGF, TrkA, RMCP-2 and 6, and MC density within the full-thickness ileum. C48/80 and NGF evoked degranulation of PMCs in a dose-dependent manner. K252a prevented NGF-evoked, but not C48/80-evoked, MC degranulation. IM evoked the release of peritoneal RMCP-6 and subsequently delayed IT and GE. IM increased MPO activity and expression of IL-6. In IM rats, K252a prevented upregulation of IL-6 expression and reduced TrkA. IT, GE, and inflammation were not affected by K252a. K252a inhibited NGF-evoked degranulation of PMCs in vitro. In vivo, K252a decreased IL-6 and PMC degranulation. This may be of relevance for the development of new therapeutic targets for POI.
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Affiliation(s)
- Sergio Berdún
- Department of Cell Biology, Physiology and Immunology, Veterinary School, Autonomous University of Barcelona, Barcelona, Spain; Neuroscience Institute, Autonomous University of Barcelona, Barcelona, Spain; and
| | - Jakub Rychter
- Department of Cell Biology, Physiology and Immunology, Veterinary School, Autonomous University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - Patri Vergara
- Department of Cell Biology, Physiology and Immunology, Veterinary School, Autonomous University of Barcelona, Barcelona, Spain; Neuroscience Institute, Autonomous University of Barcelona, Barcelona, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
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22
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Rychter J, Ortega O, Berdun S, Arenas C, Lopez I, Espin F, Vergara P, Clavé P. Mast cell degranulation inhibits motor patterns of human ileum and sigmoid colon in vitro: relevance for postoperative ileus. Neurogastroenterol Motil 2015; 27:1098-109. [PMID: 25974622 DOI: 10.1111/nmo.12589] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/04/2014] [Accepted: 04/16/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Local release of mast cell proteases during gastrointestinal surgery is associated with the inhibition of motility and postoperative ileus (POI). We determined whether activation of intramuscular mast cell affects the motor patterns of the human ileum and colon and whether proteases are involved. METHODS Motor response of ileal and colonic circular muscle strips was measured in organ bath. Mast cell degranulation was induced by compound 48/80 (c48/80; 25-675 μg/mL). Motor response was quantified as tone, rhythmic phasic contractions (RPCs) and contractions to electric field stimulation (EFS; 40 Hz), and bethanechol-evoked contractions. Ketotifen (10(-6) mol/L) and a protease inhibitor cocktail (P8340) were used to evaluate the role of mast cell mediators. KEY RESULTS (a) c48/80 impaired the spontaneous and the electrically evoked motor response in small bowel and colonic strips (sigmoid colon EC50 : 460.0 μg/mL for RPCs and 8.9 μg/mL for electrically evoked contraction amplitudes) and bethanechol-evoked contractions. (b) Preincubation with ketotifen (10(-6) mol/L, 1 h) prevented the impairment of RPCs and EFS-evoked contractions in the sigmoid colon and ileum but not in the right colon. (c) Preincubation with P8340 also prevented the impairment of contractions in the sigmoid colon but not in the ileum or the right colon. CONCLUSIONS & INFERENCES Mast cell degranulation by c48/80 inhibits the spontaneous and the nerve-mediated motor response in the human ileum and colon. The effect is partially mediated by mast cell proteases and could be relevant in the pathophysiology of POI.
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Affiliation(s)
- J Rychter
- CIBERehd, Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Instituto de Salud Carlos III, Barcelona, Catalonia, Spain.,Department of Cell Biology, Physiology and Immunology, Veterinary School, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - O Ortega
- Department of Surgery, Hospital de Mataró, Universitat Autónoma de Barcelona, Mataró, Catalonia, Spain
| | - S Berdun
- Department of Cell Biology, Physiology and Immunology, Veterinary School, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - C Arenas
- CIBERehd, Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Instituto de Salud Carlos III, Barcelona, Catalonia, Spain
| | - I Lopez
- Department of Surgery, Hospital de Mataró, Universitat Autónoma de Barcelona, Mataró, Catalonia, Spain
| | - F Espin
- Department of Surgery, Hospital de Mataró, Universitat Autónoma de Barcelona, Mataró, Catalonia, Spain
| | - P Vergara
- CIBERehd, Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Instituto de Salud Carlos III, Barcelona, Catalonia, Spain.,Department of Cell Biology, Physiology and Immunology, Veterinary School, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - P Clavé
- CIBERehd, Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Instituto de Salud Carlos III, Barcelona, Catalonia, Spain.,Department of Surgery, Hospital de Mataró, Universitat Autónoma de Barcelona, Mataró, Catalonia, Spain
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23
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Glowka TR, Steinebach A, Stein K, Schwandt T, Lysson M, Holzmann B, Tsujikawa K, de Jonge WJ, Kalff JC, Wehner S. The novel CGRP receptor antagonist BIBN4096BS alleviates a postoperative intestinal inflammation and prevents postoperative ileus. Neurogastroenterol Motil 2015; 27:1038-49. [PMID: 25929169 DOI: 10.1111/nmo.12584] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/22/2014] [Accepted: 04/13/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Abdominal surgery results in neuronal mediator release and subsequent acute intestinal hypomotility. This phase is followed by a longer lasting inflammatory phase resulting in postoperative ileus (POI). Calcitonin gene-related peptide (CGRP) has been shown to induce motility disturbances and in addition may be a candidate mediator to elicit neurogenic inflammation. We hypothesized that CGRP contributes to intestinal inflammation and POI. METHODS The effect of CGRP in POI was tested in mice treated with the highly specific CGRP receptor antagonist BIBN4096BS and in CGRP receptor-deficient (RAMP-1(-/-) ) mice. POI severity was analyzed by cytokine expression, muscular inflammation and gastrointestinal (GI) transit. Peritoneal and muscularis macrophages and mast cells were analyzed for CGRP receptor expression and functional response to CGRP stimulation. KEY RESULTS Intestinal manipulation (IM) resulted in CGRP release from myenteric nerves, and a concurrent increased interleukin (IL)-6 and IL-1β transcription and leukocyte infiltration in the muscularis externa and increased GI transit time. CGRP potentiates IM-induced cytokine transcription within the muscularis externa and peritoneal macrophages. BIBN4096BS reduced cytokine levels and leukocyte infiltration and normalized GI transit. RAMP1(-/-) mice showed a significantly reduced leukocyte influx. CGRP receptor was expressed in muscularis and peritoneal macrophages but not mast cells. CGRP mediated macrophage activation but failed to induce mast cell degranulation and cytokine expression. CONCLUSIONS & INFERENCES CGRP is immediately released during abdominal surgery and induces a neurogenic inflammation via activation of abdominal macrophages. BIBN4096BS prevented IM-induced inflammation and restored GI motility. These findings suggest that CGRP receptor antagonism could be instrumental in the prevention of POI.
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Affiliation(s)
- T R Glowka
- Department of Surgery, University of Bonn, Bonn, Germany
| | - A Steinebach
- Department of Surgery, University of Bonn, Bonn, Germany
| | - K Stein
- Department of Surgery, University of Bonn, Bonn, Germany
| | - T Schwandt
- Department of Surgery, University of Bonn, Bonn, Germany
| | - M Lysson
- Department of Surgery, University of Bonn, Bonn, Germany
| | - B Holzmann
- Department of Surgery, Technical University Munich, Munich, Germany
| | - K Tsujikawa
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka, Japan
| | - W J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - J C Kalff
- Department of Surgery, University of Bonn, Bonn, Germany
| | - S Wehner
- Department of Surgery, University of Bonn, Bonn, Germany.,Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
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24
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Eshuis WJ, de Bree K, Sprangers MAG, Bennink RJ, van Gulik TM, Busch ORC, Gouma DJ. Gastric emptying and quality of life after pancreatoduodenectomy with retrocolic or antecolic gastroenteric anastomosis. Br J Surg 2015; 102:1123-32. [DOI: 10.1002/bjs.9812] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/15/2014] [Revised: 11/07/2014] [Accepted: 02/24/2015] [Indexed: 02/06/2023]
Abstract
Abstract
Background
Delayed gastric emptying (DGE) is a major problem after pancreatoduodenectomy (PD). A recent multicentre randomized trial reported no difference in gastric emptying rates between retrocolic and antecolic reconstruction routes. The present study looked at quality of life with these two approaches and the correlation with gastric emptying.
Methods
This was a substudy of patients completing a panel of quality-of-life questionnaires within a randomized trial comparing retrocolic and antecolic gastroenteric reconstruction after PD. Gastric emptying was assessed by scintigraphy 1 week after surgery. Quality of life was measured with the EuroQoL – 5D questionnaire (EQ-5D™), the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30) with its pancreatic cancer module (PAN26), and the Gastrointestinal Quality of Life Index (GIQLI).
Results
There were 38 patients in the retrocolic and 35 in the antecolic group. Baseline characteristics and clinical outcomes were similar in the two groups. Median time to half-emptying of stomach content after surgery was 145 and 64 min in the retrocolic and antecolic group respectively (P = 0·189). Median percentages of residual activity after 2 h were 64 and 28 per cent respectively (P = 0·213). Quality of life did not differ at any time point between the groups. At 2 weeks after surgery, patients with DGE had significantly worse outcomes on two EQ-5D™ domains, ten QLQ-C30/PAN26 subscales, and two GIQLI subscales and total score. Effect sizes were moderate to large.
Conclusion
The route of gastroenteric reconstruction after PD does not influence either gastric emptying at scintigraphy or quality of life. The impact of DGE on quality of life is clinically significant. Registration number NTR1697 (www.trialregister.nl).
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Affiliation(s)
- W J Eshuis
- Department of Surgery, Academic Medical Centre, Amsterdam, The Netherlands
| | - K de Bree
- Department of Surgery, Academic Medical Centre, Amsterdam, The Netherlands
| | - M A G Sprangers
- Department of Medical Psychology, Academic Medical Centre, Amsterdam, The Netherlands
| | - R J Bennink
- Department of Nuclear Medicine, Academic Medical Centre, Amsterdam, The Netherlands
| | - T M van Gulik
- Department of Surgery, Academic Medical Centre, Amsterdam, The Netherlands
| | - O R C Busch
- Department of Surgery, Academic Medical Centre, Amsterdam, The Netherlands
| | - D J Gouma
- Department of Surgery, Academic Medical Centre, Amsterdam, The Netherlands
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25
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Peters EG, De Jonge WJ, Smeets BJJ, Luyer MDP. The contribution of mast cells to postoperative ileus in experimental and clinical studies. Neurogastroenterol Motil 2015; 27:743-9. [PMID: 26011782 DOI: 10.1111/nmo.12579] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/30/2015] [Accepted: 04/07/2015] [Indexed: 02/08/2023]
Abstract
The persistent phase of postoperative ileus (POI) is mediated by inflammatory activation of the resident myeloid immune cell population in the gut wall, likely elicited by neurogenic activation. Mast cells are thought to play a critical role in this inflammatory response and involvement of mast cells in POI has been investigated and described thoroughly in experimental studies. Intestinal manipulation (IM) leads to degranulation of mast cells, resulting in an increase in mast cell proteases in peritoneal fluid and gut tissue. The inflammatory infiltrate formed in the intestinal wall thereby impairs gastrointestinal motility. In the clinical study by Berdun et al., the experimentally known association between mast cell degranulation and delayed motility is shown in a clinical setting. These findings are important and open up therapeutic opportunities to reduce or prevent POI. In this mini-review, the role of mast cells in POI is discussed. Furthermore, an update is given on the involvement of the inflammatory response in POI and potential therapeutic strategies.
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Affiliation(s)
- E G Peters
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands.,Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
| | - W J De Jonge
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
| | - B J J Smeets
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - M D P Luyer
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
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26
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Berdún S, Bombuy E, Estrada O, Mans E, Rychter J, Clavé P, Vergara P. Peritoneal mast cell degranulation and gastrointestinal recovery in patients undergoing colorectal surgery. Neurogastroenterol Motil 2015; 27:764-74. [PMID: 25677271 DOI: 10.1111/nmo.12525] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/29/2014] [Accepted: 01/14/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Degranulation of peritoneal mast cells (MCs) induced by intestinal manipulation has been proposed as a pathophysiological factor in postoperative ileus (POI). We aimed to explore the relationship between peritoneal and colonic MC degranulation and gastrointestinal (GI) recovery following colectomy. METHODS Patients undergoing elective laparoscopic cholecystectomy (using a laparoscope and small abdominal incisions, n = 14), and elective laparoscopic (n = 32) or open partial colectomy (through a large abdominal incision, n = 10) were studied. MC protease tryptase and chymase were studied in peritoneal fluid at the beginning, middle, and end of each surgical intervention. Density of MCs in colectomy samples were examined and oro-caecal transit time by breath test, GI function recovery by clinical composite endpoint GI-2 and association between MC proteases and clinical recovery. KEY RESULTS Open and laparoscopic colectomy caused greater peritoneal release of tryptase and chymase (323.0 ng/mL [IQR: 53.05-381.4] and 118.6 ng/mL [IQR: 53.60-240.3]), than cholecystectomy (41.64 ng/mL [IQR: 11.17-90.93]) at the end of the surgical intervention. However, there were no differences between laparoscopic and open colectomy. Increased peritoneal protease release during surgery was observed in patients who developed POI after colectomy. CONCLUSIONS & INFERENCES Colorectal surgery causes protease release from peritoneal MCs. Protease release does not differ between both types of colectomy (laparoscopy vs laparotomy). However, MC activation is increased in colectomy patients developing POI. Therefore, degranulation of peritoneal MCs as a factor contributing to human POI after colectomy might be considered in future studies as a target to avoid POI.
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Affiliation(s)
- S Berdún
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - E Bombuy
- Department of Surgery, Consorci Sanitari del Maresme (CSdM) - Hospital de Mataró, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - O Estrada
- Department of Surgery, Consorci Sanitari del Maresme (CSdM) - Hospital de Mataró, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - E Mans
- Department of Surgery, Consorci Sanitari del Maresme (CSdM) - Hospital de Mataró, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J Rychter
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - P Clavé
- Department of Surgery, Consorci Sanitari del Maresme (CSdM) - Hospital de Mataró, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - P Vergara
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
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27
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Wu Z, Boersema GSA, Dereci A, Menon AG, Jeekel J, Lange JF. Clinical endpoint, early detection, and differential diagnosis of postoperative ileus: a systematic review of the literature. Eur Surg Res 2014; 54:127-38. [PMID: 25503902 DOI: 10.1159/000369529] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/02/2014] [Accepted: 11/03/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND This systematic review summarizes evidence regarding clinical endpoints, early detection, and differential diagnosis of postoperative ileus (POI). METHODS Using MEDLINE, EMBASE, Cochrane, and Web-of-Science, we identified 2,084 articles. Risk of bias and level of evidence (LOE) of the included articles were determined, and relevant results were summarized. RESULTS Eleven articles were included, most of which with substantial risks of bias. Bowel motility studies revealed that defecation together with solid food tolerance is the most representative clinical endpoint of POI (LOE: 2b); other clinical signs (e.g. bowel sounds, passage of flatus) did not correlate with a full recovery of bowel motility. Inflammatory parameters including interleukin (IL)-6, IL-1, and TNF-α might assist in an early detection of prolonged POI (LOE: 4). Clinical manifestations (e.g. nausea, vomiting, abdominal distension, bowel sounds, flatus) and X-ray examinations provided limited aid to the differential diagnosis of POI, while CT with Gastrografin had the best specificity and sensitivity (both 100%; LOE: 1c). CONCLUSIONS Postoperative defecation together with tolerance of solid food intake seems to be the best clinical endpoint of POI. CT has the best differential diagnostic value between POI and other complications. Prospective studies with a high LOE are in great need.
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Affiliation(s)
- Zhouqiao Wu
- Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
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28
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Vather R, O'Grady G, Bissett IP, Dinning PG. Postoperative ileus: mechanisms and future directions for research. Clin Exp Pharmacol Physiol 2014; 41:358-70. [PMID: 24754527 DOI: 10.1111/1440-1681.12220] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/18/2013] [Revised: 02/13/2014] [Accepted: 02/25/2014] [Indexed: 12/13/2022]
Abstract
Postoperative ileus (POI) is an abnormal pattern of gastrointestinal motility characterized by nausea, vomiting, abdominal distension and/or delayed passage of flatus or stool, which may occur following surgery. Postoperative ileus slows recovery, increases the risk of developing postoperative complications and confers a significant financial load on healthcare institutions. The aim of the present review is to provide a succinct overview of the clinical features and pathophysiological mechanisms of POI, with final comment on selected directions for future research.Terminology used when describing POI is inconsistent, with little differentiation made between the obligatory period of gut dysfunction seen after surgery ('normal POI') and the more clinically and pathologically significant entity of a 'prolonged POI'. Both normal and prolonged POI represent a fundamentally similar pathophysiological phenomenon. The aetiology of POI is postulated to be multifactorial, with principal mediators being inflammatory cell activation, autonomic dysfunction (both primarily and as part of the surgical stress response), agonism at gut opioid receptors, modulation of gastrointestinal hormone activity and electrolyte derangements. A final common pathway for these effectors is impaired contractility and motility and gut wall oedema. There are many potential directions for future research. In particular, there remains scope to accurately characterize the gastrointestinal dysfunction that underscores an ileus, development of an accurate risk stratification tool will facilitate early implementation of preventive measures and clinical appraisal of novel therapeutic strategies that target individual pathways in the pathogenesis of ileus warrant further investigation.
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Affiliation(s)
- Ryash Vather
- Department of Surgery, University of Auckland, Auckland, New Zealand
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29
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Hudson NPH, Pirie RS. Equine post operative ileus: A review of current thinking on pathophysiology and management. EQUINE VET EDUC 2014. [DOI: 10.1111/eve.12248] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Affiliation(s)
- N. P. H. Hudson
- Royal (Dick) School of Veterinary Studies and Roslin Institute; University of Edinburgh; Easter Bush Campus Roslin Midlothian UK
| | - R. S. Pirie
- Royal (Dick) School of Veterinary Studies and Roslin Institute; University of Edinburgh; Easter Bush Campus Roslin Midlothian UK
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30
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Gomez-Pinilla PJ, Binda MM, Lissens A, Di Giovangiulio M, van Bree SH, Nemethova A, Stakenborg N, Farro G, Bosmans G, Matteoli G, Deprest J, Boeckxstaens GE. Absence of intestinal inflammation and postoperative ileus in a mouse model of laparoscopic surgery. Neurogastroenterol Motil 2014; 26:1238-47. [PMID: 24966010 DOI: 10.1111/nmo.12376] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/17/2013] [Accepted: 05/08/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND Postoperative ileus (POI) is characterized by impaired gastrointestinal motility resulting from intestinal handling-associated inflammation. The introduction of laparoscopic surgery has dramatically reduced the duration of POI. However, it remains unclear to what extent this results in a reduction of intestinal inflammation. The aim of the present study is to compare the degree of intestinal inflammation and gastrointestinal transit following laparoscopic surgery and open abdominal surgery. METHODS Mice were subjected to laparoscopic surgery or laparotomy alone or, in combination with standardized intestinal manipulation of the small bowel (IM). Gastrointestinal transit and intestinal inflammation were assessed 24 h after surgery by the number of myeloperoxidase (MPO) positive cells and the level of cytokine expression. The recovery time and the degree of inflammation were also analyzed in patients subjected to colectomy under open conditions (laparotomy) or laparoscopic conditions. KEY RESULTS Mice undergoing IM by laparotomy (open IM), but not by laparoscopy (Lap IM) developed a significant delay in gastrointestinal transit compared to laparotomy or laparoscopy alone. In addition, there was significant intestinal inflammation only after open IM. Similarly, cytokine levels in peritoneal lavage fluid were lower while recovery time was faster in patients subjected to colectomy under laparoscopic conditions compared to open colectomy. CONCLUSIONS & INFERENCES Our data confirms that intestinal inflammation is underlying the delayed gastrointestinal transit observed after open surgery. Most importantly, we demonstrate that intestinal inflammation under laparoscopic conditions is significantly lower compared to open surgery, most likely explaining the faster recovery following laparoscopic surgery.
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Affiliation(s)
- Pedro J Gomez-Pinilla
- Translational Research in GastroIntestinal Disorders (TARGID) and Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
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31
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Kim SJ, Jung HK, Lee DS, Yun SS, Kim HJ. The comparison of oncologic and clinical outcomes of laparoscopic liver resection for hepatocellular carcinoma. Ann Surg Treat Res 2014; 86:61-7. [PMID: 24761410 PMCID: PMC3994603 DOI: 10.4174/astr.2014.86.2.61] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/23/2013] [Revised: 10/14/2013] [Accepted: 10/24/2013] [Indexed: 02/06/2023] Open
Abstract
Purpose We evaluate the operative outcome and oncologic outcome of laparoscopic liver resection for hepatocellular carcinoma (HCC), and compare with open liver resection. Methods From January 2004 to December 2012, clinical data of 70 patients who underwent laparoscopic liver resection for HCC (laparoscopic liver resection group, lapa-group) were collected and analyzed retrospectively. Control group (open liver resection group, open-group) were retrospectively matched, and compared with lapa-group. Results Laparoscopic major liver resections were performed in 4 patients. Laparoscopic anatomical resections and nonanatomical resections were performed in 39 patients, and 31 patients, respectively. Mean operative time was shorter in lapa-group (215.5 ± 121.84 minutes vs. 282.30 ± 80.34 minutes, P = 0.001), mean intraoperative transfusion rate and total amount were small in lapa-group (24.28%, 148.57 ± 3,354.98 mL vs. 40.78%, 311.71 ± 477.01 mL). Open conversion occurred in 6 patients (8.57%) because of bleeding, inadequate resection, invisible mass on intraoperative ultrasonography, and tumor rupture. In lapa-group and open-group, 3-year disease-free survival rates were 58.3% ± 0.08%, and 62.6% ± 0.06%, respectively (P = 0.773). In lapa-group and open-group 3-year overall survival rates were 65.3% ± 0.8%, and 65.7% ± 0.6%, respectively (P = 0.610). Conclusion Laparoscopic liver resection for HCC is feasible and safe in a large number of patients, with reasonable operative and oncologic results.
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Affiliation(s)
- Sung-Jin Kim
- Department of Surgery, Yeungnam University Medical Center, Daegu, Korea
| | - Hwa-Kyung Jung
- Department of Surgery, Yeungnam University Medical Center, Daegu, Korea
| | - Dong-Shik Lee
- Department of Surgery, Yeungnam University Medical Center, Daegu, Korea
| | - Sung-Su Yun
- Department of Surgery, Yeungnam University Medical Center, Daegu, Korea
| | - Hong-Jin Kim
- Department of Surgery, Yeungnam University Medical Center, Daegu, Korea
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32
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Affiliation(s)
- Jakub Rychter
- CIBERehd, Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Instituto de Salud Carlos III, , Barcelona, Catalonia, Spain
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33
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van Bree SHW, Gomez-Pinilla PJ, van de Bovenkamp FS, Di Giovangiulio M, Farro G, Nemethova A, Cailotto C, de Jonge WJ, Lee K, Ramirez-Molina C, Lugo D, Skynner MJ, Boeckxstaens GEE, Matteoli G. Inhibition of spleen tyrosine kinase as treatment of postoperative ileus. Gut 2013; 62:1581-90. [PMID: 23242119 DOI: 10.1136/gutjnl-2012-302615] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Intestinal inflammation resulting from manipulation-induced mast cell activation is a crucial mechanism in the pathophysiology of postoperative ileus (POI). Recently it has been shown that spleen tyrosine kinase (Syk) is involved in mast cell degranulation. Therefore, we have evaluated the effect of the Syk-inhibitor GSK compound 143 (GSK143) as potential treatment to shorten POI. DESIGN In vivo: in a mouse model of POI, the effect of the Syk inhibitor (GSK143) was evaluated on gastrointestinal transit, muscular inflammation and cytokine production. In vitro: the effect of GSK143 and doxantrazole were evaluated on cultured peritoneal mast cells (PMCs) and bone marrow derived macrophages. RESULTS In vivo: intestinal manipulation resulted in a delay in gastrointestinal transit at t=24 h (Geometric Center (GC): 4.4 ± 0.3). Doxantrazole and GSK143 significantly increased gastrointestinal transit (GC doxantrazole (10 mg/kg): 7.2 ± 0.7; GSK143 (1 mg/kg): 7.6 ± 0.6), reduced inflammation and prevented recruitment of immune cells in the intestinal muscularis. In vitro: in PMCs, substance P (0-90 μM) and trinitrophenyl (0-4 μg/ml) induced a concentration-dependent release of β-hexosaminidase. Pretreatment with doxantrazole and GSK143 (0.03-10 μM) concentration dependently blocked substance P and trinitrophenyl induced β-hexosaminidase release. In addition, GSK143 was able to reduce cytokine expression in endotoxin-treated bone marrow derived macrophages in a concentration-dependent manner. CONCLUSIONS The Syk inhibitor GSK143 reduces macrophage activation and mast cell degranulation in vitro. In addition, it inhibits manipulation-induced intestinal muscular inflammation and restores intestinal transit in mice. These findings suggest that Syk inhibition may be a new tool to shorten POI.
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Affiliation(s)
- Sjoerd H W van Bree
- Department of Gastroenterology and Hepatology, Tytgat Institute of Liver and Intestinal Research, Academic Medical Center, , Amsterdam, The Netherlands
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34
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de Haan JJ, Hadfoune M, Lubbers T, Hodin C, Lenaerts K, Ito A, Verbaeys I, Skynner MJ, Cailotto C, van der Vliet J, de Jonge WJ, Greve JWM, Buurman WA. Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex. Am J Physiol Gastrointest Liver Physiol 2013; 305:G383-91. [PMID: 23812038 DOI: 10.1152/ajpgi.00333.2012] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/31/2023]
Abstract
Nutritional stimulation of the cholecystokinin-1 receptor (CCK-1R) and nicotinic acetylcholine receptor (nAChR)-mediated vagal reflex was shown to reduce inflammation and preserve intestinal integrity. Mast cells are important early effectors of the innate immune response; therefore modulation of mucosal mast cells is a potential therapeutic target to control the acute inflammatory response in the intestine. The present study investigates intestinal mast cell responsiveness upon nutritional activation of the vagal anti-inflammatory reflex during acute inflammation. Mucosal mast cell degranulation was induced in C57/Bl6 mice by administration of Salmonella enterica LPS. Lipid-rich enteral feeding prior to LPS significantly decreased circulatory levels of mouse mast cell protease at 30 min post-LPS compared with isocaloric low-lipid nutrition or fasting. CCK-1R blockage reversed the inhibitory effects of lipid-rich feeding, whereas stimulation of the peripheral CCK-1R mimicked nutritional mast cell inhibition. The effects of lipid-rich nutrition were negated by nAChR blockers chlorisondamine and α-bungarotoxin and vagal intestinal denervation. Accordingly, release of β-hexosaminidase by MC/9 mast cells following LPS or IgE-ovalbumin complexes was dose dependently inhibited by acetylcholine and nicotine. Application of GSK1345038A, a specific agonist of the nAChR α7, in bone marrow-derived mast cells from nAChR β2-/- and wild types indicated that cholinergic inhibition of mast cells is mediated by the nAChR α7 and is independent of the nAChR β2. Together, the present study reveals mucosal mast cells as a previously unknown target of the nutritional anti-inflammatory vagal reflex.
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Affiliation(s)
- Jacco J de Haan
- Dept. of Surgery at Maastricht Univ. Medical Centre+, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands.
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Reisinger KW, de Haan JJ, Schreinemacher MH. Word of caution before implementing ketotifen for gastrointestinal transit improvement. World J Gastroenterol 2013; 19:4445-4446. [PMID: 23885162 PMCID: PMC3718919 DOI: 10.3748/wjg.v19.i27.4445] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/21/2013] [Revised: 03/20/2013] [Accepted: 06/10/2013] [Indexed: 02/06/2023] Open
Abstract
The therapeutic potential of long-term ketotifen in irritable bowel syndrome and postoperative ileus is currently under investigation. Ambiguous results of prolonged postoperative ketotifen use on gastrointestinal passage have been found. The current data point at a hampered gastrointestinal transit after prolonged postoperative ketotifen use in a rodent ileus induction model. Therefore, caution should be taken when administering ketotifen in the perioperative phase.
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van den Broek MAJ, Shiri-Sverdlov R, Schreurs JJW, Bloemen JG, Bieghs V, Rensen SS, Dejong CHC, Olde Damink SWM. Liver manipulation during liver surgery in humans is associated with hepatocellular damage and hepatic inflammation. Liver Int 2013; 33:633-41. [PMID: 23356550 DOI: 10.1111/liv.12051] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/28/2012] [Accepted: 11/03/2012] [Indexed: 02/13/2023]
Abstract
BACKGROUND Manipulation of the liver during liver surgery results in profound hepatocellular damage. Experimental data show that mobilization-induced hepatocellular damage is related to hepatic inflammation. To date, information on this link in humans is lacking. As it is possible to modulate inflammation, it is clinically relevant to unravel this relationship. AIM This observational study aimed to establish the association between liver mobilization and hepatic inflammation in humans. METHODS Consecutive patients requiring mobilization of the right hemi-liver during liver surgery were studied. Plasma samples and liver biopsies were collected prior to and directly after mobilization and after transection of the liver. Hepatocellular damage was assayed by liver fatty acid-binding protein (L-FABP) and aminotransferase levels. Hepatic inflammation was determined by (a) immunohistochemical identification of myeloperoxidase (MPO) and CD68- positive cells and (b) hepatic gene expression of inflammatory and cell adhesion molecules (IL-1β, IL-6, IL-8, VCAM-1 and ICAM-1). RESULTS A total of 25 patients were included. L-FABP levels increased significantly during mobilization (301 ± 94 ng/ml to 1599 ± 362 ng/ml, P = 0.008), as did ALAT levels (36 ± 5 IU/L to 167 ± 21 IU/L, P < 0.001). A significant increase in MPO (P = 0.001) and CD68 (P = 0.002) positive cells was noticed in the liver after mobilization. The number of MPO-positive cells correlated with the duration of mobilization (Pearson correlation=0.505, P = 0.033). Hepatic gene expression of pro-inflammatory cytokines IL-1β and IL-6, chemo-attractant IL-8 and adhesion molecule ICAM-1 increased significantly during liver manipulation. CONCLUSIONS Liver mobilization is associated with hepatocellular damage and liver inflammation, as shown by infiltration of inflammatory cells and upregulation of genes involved in acute inflammation.
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Fernández-Blanco JA, Hollenberg MD, Martínez V, Vergara P, Vergara P. PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat. Am J Physiol Gastrointest Liver Physiol 2013; 304:G390-400. [PMID: 23238933 DOI: 10.1152/ajpgi.00387.2012] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/31/2023]
Abstract
Proteinase-activated receptor-2 (PAR-2) and mast cell (MC) mediators contribute to inflammatory and functional gastrointestinal disorders. We aimed to characterize jejunal PAR-2-mediated responses and the potential MC involvement in the early and late phases of a rat model of postinfectious gut dysfunction. Jejunal tissues of control and Trichinella spiralis-infected (14 and 30 days postinfection) rats, treated or not with the MC stabilizer, ketotifen, were used. Histopathology and immunostaining were used to characterize inflammation, PAR-2 expression, and mucosal and connective tissue MCs. Epithelial barrier function (hydroelectrolytic transport and permeability) and motility were assessed in vitro in basal conditions and after PAR-2 activation. Intestinal inflammation on day 14 postinfection (early phase) was significantly resolved by day 30 (late phase) although MC counts and epithelial permeability remained increased. PAR-2-mediated ion transport (Ussing chambers, in vitro) and epithelial surface PAR-2 expression were reduced in the early phase, with a trend toward normalization during the late phase. In control conditions, PAR-2 activation (organ bath) induced biphasic motor responses (relaxation followed by excitation). At 14 days postinfection, spontaneous contractility and PAR-2-mediated relaxations were enhanced; motor responses were normalized on day 30. Postinfectious changes in PAR-2 functions were not affected by ketotifen treatment. We concluded that, in the rat model of Trichinella spiralis infection, alterations of intestinal PAR-2 function and expression depend on the inflammatory phase considered. A lack of a ketotifen effect suggests no interplay between MCs and PAR-2-mediated motility and ion transport alterations. These observations question the role of MC mediators in PAR-2-modulating postinfectious gut dysfunction.
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Affiliation(s)
- Joan Antoni Fernández-Blanco
- Department of Cell Biology, Physiology and Immunology, Veterinary School, Universitat Autònoma de Barcelona, Barcelona, Spain
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van Bree SHW, Nemethova A, Cailotto C, Gomez-Pinilla PJ, Matteoli G, Boeckxstaens GE. New therapeutic strategies for postoperative ileus. Nat Rev Gastroenterol Hepatol 2012; 9:675-83. [PMID: 22801725 DOI: 10.1038/nrgastro.2012.134] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/07/2023]
Abstract
Patients undergoing an abdominal surgical procedure develop a transient episode of impaired gastrointestinal motility or postoperative ileus. Importantly, postoperative ileus is a major determinant of recovery after intestinal surgery and leads to increased morbidity and prolonged hospitalization, which is a great economic burden to health-care systems. Although a variety of strategies reduce postoperative ileus, including multimodal postoperative rehabilitation (fast-track care) and minimally invasive surgery, none of these methods have been completely successful in shortening the duration of postoperative ileus. The aetiology of postoperative ileus is multifactorial, but insights into the pathogenesis of postoperative ileus have identified intestinal inflammation, triggered by surgical handling, as the main mechanism. The importance of this inflammatory response in postoperative ileus is underscored by the beneficial effect of pharmacological interventions that block the influx of leukocytes. New insights into the pathophysiology of postoperative ileus and the involvement of the innate and the adaptive (T-helper type 1 cell-mediated immune response) immune system offer interesting and important new approaches to prevent postoperative ileus. In this Review, we discuss the latest insights into the mechanisms behind postoperative ileus and highlight new strategies to intervene in the postoperative inflammatory cascade.
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Affiliation(s)
- Sjoerd H W van Bree
- Tytgat Institute of Liver and Intestinal Research, Department of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 69-71, 1105 BK Amsterdam, The Netherlands
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Schmidt J, Stoffels B, Chanthaphavong RS, Buchholz BM, Nakao A, Bauer AJ. Differential molecular and cellular immune mechanisms of postoperative and LPS-induced ileus in mice and rats. Cytokine 2012; 59:49-58. [PMID: 22503596 DOI: 10.1016/j.cyto.2012.03.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/18/2011] [Revised: 08/15/2011] [Accepted: 03/16/2012] [Indexed: 12/26/2022]
Abstract
Ileus is caused by the initiation of a complex cascade of molecular and cellular inflammatory responses within the intestinal muscularis, which might be species specific. Our objective was to investigate a possible immunological divergence in the mechanisms of postoperative- and endotoxin-induced ileus in C57BL/6 mice and Sprague-Dawley rats. Gastrointestinal transit (GIT) was measured at 24 h after the injurious stimulus. MPO-staining and F4/80 immunohistochemistry were used to quantify polymorphonuclear and monocyte infiltration of jejunal muscularis whole-mounts, and intestinal muscularis MCP-1, ICAM-1 and iNOS gene expression was assessed by RT-PCR. Intestinal muscularis subjected to in vivo surgical manipulation (SM) or LPS treatment was cultured for 24 h, and the liberation of nitric oxide and chemokines/cytokines into the culture medium was analyzed by Griess reaction and Luminex multiplex assay. Intestinal SM and lipopolysaccharide (LPS) (15 mg/kg) caused a significant delay in gastrointestinal transit, which was more severe in mice compared to rats in both injury models. Both SM- and LPS-triggered neutrophil and monocytic extravasation into the rat jejunal muscularis exceeded the cellular infiltration seen in mice. These results correlated with significantly greater increases in rat muscularis MCP-1 (syn. CCL2), ICAM-1 and iNOS message with more subsequent NO production after SM or LPS compared to mouse. The cultured muscularis obtained from SM mice released significantly more inflammatory proteins such as TNF-α, IL-1-α, IL-4 and GM-CSF compared to the manipulated rat muscularis. In contrast, LPS initiated the secretion of significantly more IL-1β by the inflamed rat muscularis compared to the mouse, but GM-CSF (syn. CSF2) liberation from mouse muscularis was markedly higher compared to LPS-treated rat muscularis. The data indicate that mechanistically the development of ileus in rat is mediated predominately through a leukocytic pathway consisting of chemotaxis, cellular extravasation and NO liberation. Whereas, the more intense mouse ileus evolves via a potent but injury-specific local cytokine response.
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Affiliation(s)
- Joachim Schmidt
- Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Wehner S, Vilz TO, Stoffels B, Kalff JC. Immune mediators of postoperative ileus. Langenbecks Arch Surg 2012; 397:591-601. [PMID: 22382699 DOI: 10.1007/s00423-012-0915-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/20/2012] [Accepted: 01/24/2012] [Indexed: 02/08/2023]
Abstract
UNLABELLED CLINICAL BACKGROUND: In all patients undergoing abdominal surgery, a transient phase of interruption of bowel motility, named postoperative ileus (POI) occurs. POI is often accepted as an unavoidable "physiological" response and a self-limiting complication after surgery although it has a significant impact on patient morbidity with prolonged hospitalization and increased costs. Annual economic burden has been estimated as much as US $1.47 billion in the USA (Iyer et al. in J Manag Care Pharm 15(6):485-494, 2009). PATHOPHYSIOLOGY The pathophysiology has been elucidated within the last decades, demonstrating that both, neurogenic and inflammatory mechanisms are involved in response to the surgical trauma. It is now generally accepted that POI pathogenesis processes in two phases: a first neurogenic phase is accountable for the immediate postoperative impairment of bowel motility. This is followed by a second immunological phase that can last for days and mainly affects strength and length of POI. More recent findings demonstrate a bidirectional interaction between the nervous and the immune system, and this interaction significantly contributed to our present understanding of POI pathophysiology. Although nerval mechanisms have a significant impact in the early phase of POI, the contribution of the immune system and subsequently its manipulation has risen as the most promising strategy in prevention or treatment of the clinically relevant prolonged form of POI. AIMS The present manuscript will give an update on the inflammatory responses, the involved cell types, and participating immune mediators in POI.
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Affiliation(s)
- Sven Wehner
- Department of Surgery, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
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Snoek SA, Dhawan S, van Bree SH, Cailotto C, van Diest SA, Duarte JM, Stanisor OI, Hilbers FW, Nijhuis L, Koeman A, van den Wijngaard RM, Zuurbier CJ, Boeckxstaens GE, de Jonge WJ. Mast cells trigger epithelial barrier dysfunction, bacterial translocation and postoperative ileus in a mouse model. Neurogastroenterol Motil 2012; 24:172-84, e91. [PMID: 22122661 DOI: 10.1111/j.1365-2982.2011.01820.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Abdominal surgery involving bowel manipulation commonly results in inflammation of the bowel wall, which leads to impaired intestinal motility and postoperative ileus (POI). Mast cells have shown to play a key role in the pathogenesis of POI in mouse models and human studies. We studied whether mast cells contribute to the pathogenesis of POI by eliciting intestinal barrier dysfunction. METHODS C57BL/6 mice, and two mast cell-deficient mutant mice Kit(W/W-v) , and Kit(W-sh/W-sh) underwent laparotomy (L) or manipulation of the small bowel (IM). Postoperative inflammatory infiltrates and cytokine production were assessed. Epithelial barrier function was determined in Ussing chambers, by measuring transport of luminal particles to the vena mesenterica, and by assessing bacterial translocation. KEY RESULTS In WT mice, IM resulted in pro-inflammatory cytokine and chemokine production, and neutrophil extravasation to the manipulated bowel wall. This response to IM was reduced in mast cell-deficient mice. IM caused epithelial barrier dysfunction in WT mice, but not in the two mast cell-deficient strains. IM resulted in a decrease in mean arterial pressure in both WT and mast cell-deficient mice, indicating that impaired barrier function was not explained by tissue hypoperfusion, but involved mast cell mediators. CONCLUSIONS & INFERENCES Mast cell activation during abdominal surgery causes epithelial barrier dysfunction and inflammation of the muscularis externa of the bowel. The impairment of the epithelial barrier likely contributes to the pathogenesis of POI. Our data further underscore that mast cells are bona fide cellular targets to ameliorate POI.
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Affiliation(s)
- S A Snoek
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, The Netherlands
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Hydrogen-enriched preservation protects the isogeneic intestinal graft and amends recipient gastric function during transplantation. Transplantation 2011; 92:985-92. [PMID: 21956195 DOI: 10.1097/tp.0b013e318230159d] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Inhaled hydrogen gas exerts antioxidant and anti-inflammatory effects in rat intestinal transplantation. Here, we investigated whether ex vivo donor organ treatment with dissolved hydrogen would prevent intestinal graft injury. METHODS Isogeneic intestinal transplantation was performed in Lewis rats with vascular flush, luminal preservation, and cold graft storage in nitrogen-bubbled (SITxN2) or hydrogen-bubbled (SITxH2) preservation solution. Lactated Ringer's solution and 3-hr cold ischemia time were used for mechanistic investigations, whereas survival experiments were performed with University of Wisconsin solution and 6-hr cold ischemia time. RESULTS During the early phase of ischemia-reperfusion injury, hydrogen-enriched solution significantly preserved mucosal graft morphology, diminished graft malondialdehyde levels demonstrating substantial reduction potential and blunted proinflammatory molecular responses (early growth response gene [EGR-1], interleukin [IL]-6, IL-1ß, and inducible nitric oxide synthase) within the reperfused intestinal graft muscularis. During the late phase of ischemia-reperfusion injury, circulating IL-6 protein and lactate dehydrogenase levels were significantly ameliorated in SITxH2 animals, which were associated with a favorable functional outcome in in vivo liquid gastrointestinal transit and recipient solid gastric emptying of chrome steel balls, and marked prevention of the posttransplant associated suppression of in vitro muscarinic jejunal contractility. Reflecting improved graft preservation, hydrogen preloading of grafts increased recipient survival rates from 41% to 80%. Anti-inflammatory and antiapoptotic heme oxygenase-1 was significantly upregulated in the hydrogen-treated graft muscularis but not mucosa before reperfusion. CONCLUSIONS Graft preloading with hydrogen demonstrated superior morphologic and functional graft protection in rodent intestinal transplantation, ultimately facilitating recipient survival. Antioxidant capacity and muscularis heme oxygenase-1 upregulation are possible protective mechanisms.
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Abstract
PURPOSE OF REVIEW The pathophysiological riddle of the clinically important postoperative ileus (POI) has been solved more and more over the last decade. The POI is caused by inflammation and paralysis at the manipulated site propagating to the entire, unmanipulated gastrointestinal tract. Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how macrophages are activated, particularly those in unmanipulated areas. In addition to direct or neurally mediated activation of intestinal macrophages, a new immunologically mediated activation has been proposed. RECENT FINDINGS Recently, it has been shown that the surgical trauma induces interleukin-12 (IL-12) production by intestinal dendritic cells, which activates TH1-memory cells at the manipulated site. Those TH1-memory cells produce interferon-γ (IFN-γ). Those TH1 CCR9 cells also migrate to unmanipulated parts of the gastrointestinal tract. Their IFN-γ stimulates intestinal macrophages to produce nitirc oxide paralyzing myocytes leading to gastrointestinal hypomotility. SUMMARY The involvement of the adaptive (T-helper type 1 cell-mediated immune response) and of the innate (mast cells, intestinal macrophages) immune system in the pathophysiology of POI displays possible targets for objective monitoring and treatment of POI.
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van Bree SHW, Vlug MS, Bemelman WA, Hollmann MW, Ubbink DT, Zwinderman AH, de Jonge WJ, Snoek SA, Bolhuis K, van der Zanden EPM, The FO, Bennink RJ, Boeckxstaens GEE, de Jonge W, Snoek SA, Snoek S, Bolhuis K, van der Zanden EPM, van der Zanden E, The FO, The F, Bennink RJ, Bennink R, Boeckxstaens GEE, Boeckxstaens G. Faster recovery of gastrointestinal transit after laparoscopy and fast-track care in patients undergoing colonic surgery. Gastroenterology 2011; 141:872-880.e1-4. [PMID: 21699777 DOI: 10.1053/j.gastro.2011.05.034] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/01/2010] [Revised: 05/03/2011] [Accepted: 05/12/2011] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Postoperative ileus is characterized by delayed gastrointestinal (GI) transit and is a major determinant of recovery after colorectal surgery. Both laparoscopic surgery and fast-track multimodal perioperative care have been reported to improve clinical recovery. However, objective measures supporting faster GI recovery are lacking. Therefore, GI transit was measured following open and laparoscopic colorectal surgery with or without fast-track care. METHODS Patients (n = 93) requiring elective colonic surgery were randomized to laparoscopic or conventional surgery with fast-track multimodal management or standard care, resulting in 4 treatment arms. Gastric emptying and colonic transit were scintigraphically assessed from days 1 to 3 in 78 patients and compared with clinical parameters such as time to tolerance of solid food and/or bowel movement and time until (ready for) discharge. RESULTS A total of 71 patients without mechanical bowel obstructions or surgical complications requiring intervention were available for analysis. No differences in gastric emptying 24 hours after surgery between the different groups were observed (P = .61). However, the median colonic transit of patients undergoing laparoscopic/fast-track care was significantly faster compared with the laparoscopic/standard, open/fast-track, and open/standard care groups. Multiple linear regression analysis showed that both laparoscopic surgery and fast-track care were significant independent predictive factors of improved colonic transit. Both were associated with significantly faster clinical recovery and shorter time until tolerance of solid food and first bowel movement. CONCLUSIONS Colonic transit recovers significantly faster after laparoscopic surgery and the fast-track program; laparoscopy and fast-track care lead to faster recovery of GI motility and improve clinical recovery.
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Affiliation(s)
- Sjoerd H W van Bree
- Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
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Jiang W, Kirkup AJ, Grundy D. Mast cells drive mesenteric afferent signalling during acute intestinal ischaemia. J Physiol 2011; 589:3867-82. [PMID: 21669977 DOI: 10.1113/jphysiol.2011.209478] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/11/2022] Open
Abstract
Acute intestinal ischaemia stimulates visceral afferent nerves but the mechanisms responsible for this excitation are not fully understood. Mast cells may participate in this process as they are known to signal to mesenteric afferents during intestinal anaphylaxis and contribute to early inflammation and neuronal damage in response to cerebral ischaemia. We therefore hypothesised that mast cells are early responders to acute intestinal ischaemia and their activation initiates rapid signalling to the CNS via the excitation of mesenteric afferents. Primary afferent firing was recorded from a mesenteric nerve bundle supplying a segment of jejunum in anaesthetized adult rats. Acute focal ischaemia was produced by clamping theme senteric vessels for 8 min, and reperfusion followed removal of the vessel clip. Two episodes of ischaemia–reperfusion (I–R) separated by a 30 min interval were performed. Drugs or their vehicles were administered 10 min before the 2nd I–R episode. Ischaemia caused a reproducible, intense and biphasic afferent firing that was temporally dissociated from the concomitantly triggered complex pattern of intestinal motor activity. The L-type calcium channel blocker, nifedipine, significantly attenuated this afferent firing by a mechanism independent of its action on intestinal tone. Ischaemia-induced afferent firing was also abrogated by the mast cell stabilizer, doxantrazole, and the H1 histamine receptor antagonist, pyrilamine. In contrast, the nicotinic receptor antagonist, hexamethonium, and the N-type calcium channel toxin, ω-conotoxin GVIA, each reduced the ischaemia-evoked motor inhibition but not the concurrent afferent discharge. Similarly, the cyclooxygenase inhibitor, naproxen, had no effect on the ischaemic afferent response but reduced the intestinal tone shortly from the onset of ischaemia to the early period of reperfusion. These data support a critical role for mast cell-derived histamine in the direct chemoexcitation of mesenteric afferents during acute intestinal ischaemia, whereas enteric reflex mechanisms and cyclooxygenase products contribute primarily to ischaemia-induced changes in intestinal motility. Therefore, targeting mast cells may provide benefits in patients with abdominal pain resulting from an ischaemic insult to the gastrointestinal tract.
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Affiliation(s)
- Wen Jiang
- Department of Biomedical Science, Florey Building, Firth Court, University of Sheffield, Sheffield S10 2TN, UK
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De Winter BY, van den Wijngaard RM, de Jonge WJ. Intestinal mast cells in gut inflammation and motility disturbances. Biochim Biophys Acta Mol Basis Dis 2011; 1822:66-73. [PMID: 21497195 DOI: 10.1016/j.bbadis.2011.03.016] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/25/2011] [Revised: 03/20/2011] [Accepted: 03/25/2011] [Indexed: 12/12/2022]
Abstract
Mast cells may be regarded as prototypes of innate immune cells that can be controlled by neuronal mediators. Their activation has been implicated in many types of neuro-inflammatory responses, and related disturbances of gut motility, via direct or indirect mechanisms that involve several mechanisms relevant to disease pathogenesis such as changes in epithelial barrier function or activation of adaptive or innate immune responses. Here we review the evidence for the involvement of mast cells in the inflammation of the bowel wall caused by bowel manipulation that leads to motility disturbances such as postoperative gastroparesis and ileus. Also in IBD there is substantial evidence for the involvement of mast cells and a mast cell-mediated neuroimmune interaction showing an increased number and an increased degranulation of mast cells. We discuss the potential of mast cell inhibition as a bona fide drug target to relief postoperative ileus. Further research on mast cell-related therapy either by stabilizing the mast cells or by blocking specific mast cell mediators as adjunctive therapy in IBD is encouraged, bearing in mind that several drugs currently used in the treatment of IBD possess properties affecting mast cell activities. This article is part of a Special Issue entitled: Mast cells in inflammation.
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Affiliation(s)
- Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, Department of Gastroenterology, University of Antwerp, Antwerp, Belgium
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Abstract
INTRODUCTION Irritable bowel syndrome is a common disorder that is associated with a significant impact on both affected individuals and society. While the pathophysiology of irritable bowel syndrome remains unknown, knowledge regarding the normal and abnormal functions of the gut and its complex interaction with the body's nervous systems continues to shed light on the multifactorial origins of irritable bowel syndrome symptoms. This article provides an overview of the current knowledge of the therapeutic approaches to irritable bowel syndrome. AREAS COVERED A search of the online bibliographic databases MEDLINE and EMBASE was performed in order to identify all relevant articles published between 1980 and 2010. The search was enhanced with the use of a medical librarian. Bibliographies from potentially relevant articles were manually searched. EXPERT OPINION The therapeutic options for irritable bowel syndrome are rapidly evolving beyond traditional symptom-based therapies, such as fiber, antispasmodics, antidiarrheals and laxatives, and are moving toward agents with organ-specific receptor selectivity directed, in many cases, at specific gastrointestinal functions.
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Affiliation(s)
- Ruben D Acosta
- National Naval Medical Center and Walter Reed Army Medical Center, Division of Gastroenterology, 8901 Wisconsin Avenue, Bethesda, MD 20889-5000, USA
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De Winter BY, De Man JG. Interplay between inflammation, immune system and neuronal pathways: Effect on gastrointestinal motility. World J Gastroenterol 2010; 16:5523-35. [PMID: 21105185 PMCID: PMC2992670 DOI: 10.3748/wjg.v16.i44.5523] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023] Open
Abstract
Sepsis is a systemic inflammatory response representing the leading cause of death in critically ill patients, mostly due to multiple organ failure. The gastrointestinal tract plays a pivotal role in the pathogenesis of sepsis-induced multiple organ failure through intestinal barrier dysfunction, bacterial translocation and ileus. In this review we address the role of the gastrointestinal tract, the mediators, cell types and transduction pathways involved, based on experimental data obtained from models of inflammation-induced ileus and (preliminary) clinical data. The complex interplay within the gastrointestinal wall between mast cells, residential macrophages and glial cells on the one hand, and neurons and smooth muscle cells on the other hand, involves intracellular signaling pathways, Toll-like receptors and a plethora of neuroactive substances such as nitric oxide, prostaglandins, cytokines, chemokines, growth factors, tryptases and hormones. Multidirectional signaling between the different components in the gastrointestinal wall, the spinal cord and central nervous system impacts inflammation and its consequences. We propose that novel therapeutic strategies should target inflammation on the one hand and gastrointestinal motility, gastrointestinal sensitivity and even pain signaling on the other hand, for instance by impeding afferent neuronal signaling, by activation of the vagal anti-inflammatory pathway or by the use of pharmacological agents such as ghrelin and ghrelin agonists or drugs interfering with the endocannabinoid system.
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Augestad KM, Leblanc F, Delaney CP. Role of Pharmacologic Agents in Treating Postoperative Ileus. SEMINARS IN COLON AND RECTAL SURGERY 2010. [DOI: 10.1053/j.scrs.2010.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/11/2022]
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Abstract
Postoperative ileus is a frequently occurring surgical complication, leading to increased morbidity and hospital stay. Abdominal surgical interventions are known to result in a protracted cessation of bowel movement. Activation of inhibitory neural pathways by nociceptive stimuli leads to an inhibition of propulsive activity, which resolves shortly after closure of the abdomen. The subsequent formation of an inflammatory infiltrate in the muscular layers of the intestine results in a more prolonged phase of ileus. Over the last decade, clinical strategies focusing on reduction of surgical stress and promoting postoperative recovery have improved the course of postoperative ileus. Additionally, recent experimental evidence implicated antiinflammatory interventions, such as vagal stimulation, as potential targets to treat postoperative ileus and reduce the period of intestinal hypomotility. Activation of nicotinic receptors on inflammatory cells by vagal input attenuates inflammation and promotes gastrointestinal motility in experimental models of ileus. A novel physiological intervention to activate this neuroimmune pathway is enteral administration of lipid-rich nutrition. Perioperative administration of lipid-rich nutrition reduced manipulation-induced local inflammation of the intestine and accelerated recovery of bowel movement. The application of safe and easy to use antiinflammatory interventions, together with the current multimodal approach, could reduce postoperative ileus to an absolute minimum and shorten hospital stay.
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