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1
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Aikawa G, Hoshino T, Sakuramoto H, Ouchi A, Ikeda M, Kotani M, Okamoto S, Enomoto Y, Shimojo N, Inoue Y. Quantitative visualization of gastrointestinal motility in critically ill patients using a non-invasive single-channel electro amplifier: A prospective observational cohort feasibility study. J Crit Care 2025; 87:155031. [PMID: 39893878 DOI: 10.1016/j.jcrc.2025.155031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 01/24/2025] [Accepted: 01/24/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND This study aimed to evaluate the feasibility of using electrogastrography (EGG)/electroenterography (EEnG) to quantitatively visualize gastrointestinal (GI) motor function in critically ill patients. METHODS EGG/EEnG were performed at baseline and before and after nutrition in critically ill patients with mechanical ventilation. Enteral nutrition varied in content. Dominant frequency (DF), dominant power (DP), and power ratio (PR) were calculated and compared with those from healthy controls (previous study; n = 50). RESULTS Data from 20 % of patients were unstable and could not be analyzed. Of the 54 patients analyzed, 41 were on enteral nutrition, and their age and body mass index differed from controls. Gastric DF differed significantly between critically ill patients and controls (p < 0.001). No significant difference was noted in gastric log10 DP between pre- and post-prandial periods in critically ill patients (2.79 vs 2.86, p = 0.328), but controls showed a significant increase (3.04 vs 3.22, p = 0.009). Critically ill patients had lower gastric log10 DP than controls (pre-prandial p = 0.038; post-prandial p = 0.003). In the small intestine, log10 DP did not differ significantly between pre- and post-prandial periods in critically ill patients (1.45 vs 1.52, p = 0.181), but controls showed a significant increase (1.70 vs 1.86, p < 0.001). Critically ill patients had lower small intestinal log10 DP than controls (pre-prandial p = 0.004; post-prandial p < 0.001). PR was inferior in critically ill patients than in controls. CONCLUSIONS EGG/EEnG could enable quantitative visualization of GI motor function in critically ill patients. Larger studies can determine the association of GI symptoms with risk factors and prognostic factors.
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Affiliation(s)
- Gen Aikawa
- College of Nursing, Kanto Gakuin University, Yokohama, Kanagawa, Japan; Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
| | - Tetsuya Hoshino
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Department of Intensive Care, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Kanagawa, Japan
| | - Hideaki Sakuramoto
- Department of Critical Care and Disaster Nursing, Japanese Red Cross Kyushu International College of Nursing, Munakata, Fukuoka, Japan
| | - Akira Ouchi
- Department of Adult Health Nursing, College of Nursing, Ibaraki Christian University, Hitachi, Ibaraki, Japan
| | - Mitsuki Ikeda
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Department of Nursing, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan
| | - Misaki Kotani
- Department of Nursing, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan
| | - Saiko Okamoto
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yuki Enomoto
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Nobutake Shimojo
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yoshiaki Inoue
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
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Dong XQ, Zhang YH, Luo J, Li MJ, Ma LQ, Qi YT, Miao YL. Keratin 1 modulates intestinal barrier and immune response via kallikrein kinin system in ulcerative colitis. World J Gastroenterol 2025; 31:102070. [PMID: 39958441 PMCID: PMC11752705 DOI: 10.3748/wjg.v31.i6.102070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/06/2024] [Accepted: 12/19/2024] [Indexed: 01/10/2025] Open
Abstract
BACKGROUND External factors in ulcerative colitis (UC) exacerbate colonic epithelial permeability and inflammatory responses. Keratin 1 (KRT1) is crucial in regulating these alterations, but its specific role in the progression of UC remains to be fully elucidated. AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC. METHODS A KRT1 antibody concentration gradient test, along with a dextran sulfate sodium (DSS)-induced animal model, was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system (KKS) and the cleavage of bradykinin (BK)/high molecular weight kininogen (HK) in UC. RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation, induced apoptosis, reduced HK expression, and increased BK expression. It further downregulated intestinal barrier proteins, including occludin, zonula occludens-1, and claudin, and negatively impacted the coagulation factor XII. These changes led to enhanced activation of BK and HK cleavage, thereby intensifying KKS-mediated inflammation in UC. In the DSS-induced mouse model, administration of KRT1 antibody mitigated colonic injury, increased colon length, alleviated weight loss, and suppressed inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α. It also facilitated repair of the intestinal barrier, reducing DSS-induced injury. CONCLUSION KRT1 inhibits BK expression, suppresses inflammatory cytokines, and enhances markers of intestinal barrier function, thus ameliorating colonic damage and maintaining barrier integrity. KRT1 is a viable therapeutic target for UC.
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Affiliation(s)
- Xiang-Qian Dong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Hui Zhang
- Department of Gastroenterology, Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Mao-Juan Li
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Lan-Qing Ma
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ya-Ting Qi
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Lei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
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King AP, Donovan TA, Cohen E, Marin J, Le Roux AB. Short colon syndrome in cats. J Vet Intern Med 2024; 38:2138-2150. [PMID: 38757679 PMCID: PMC11256177 DOI: 10.1111/jvim.17103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 05/01/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND Shortening of the colon has been described in cats, but its imaging and clinicopathological features remain poorly understood. OBJECTIVES Description of the signalment, clinical presentation, imaging, endoscopic and histological features of short colon syndrome in cats. ANIMALS Ninety-three cats diagnosed with short colon. METHODS Multi-institutional, descriptive, retrospective case series study. Medical records were searched for a diagnosis of short colon on abdominal ultrasonography, computed tomography, endoscopy, autopsy, or a combination of these modalities. RESULTS The median age of included cats was 12 years at the time of diagnosis. Diarrhea was the most common clinical sign (60/92; 65%), followed by vomiting (36/92; 39%), weight loss (36/92; 39%), and inappetence (24/92; 26%). Thirteen percent of cats (12/92) had no signs of gastrointestinal disease at the time of diagnosis. In addition to a shortened colonic length, 79% (66/84) of cats had concomitant colonic thickening on ultrasonographic examination. On colonoscopy, mucosal ulcerations of the colonic wall were seen in 39% (9/23) of cats. Histopathologically, all cats but 1 (diagnosed simultaneously with colonic small cell lymphoma) had lymphoplasmacytic colitis, and when small intestinal biopsies were performed, concurrent lymphoplasmacytic enteritis or small cell lymphoma of the small intestine. CONCLUSIONS AND CLINICAL IMPORTANCE Lymphoplasmacytic colitis is seen commonly in cats with short colon, suggesting a potential link between these entities.
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Affiliation(s)
- Audrey P. King
- Department of Diagnostic ImagingThe Schwarzman Animal Medical Center, 510 East 62nd StreetNew York, New York 10065USA
| | - Taryn A. Donovan
- Department of Anatomic PathologyThe Schwarzman Animal Medical Center, 510 East 62nd StreetNew York, New York 10065USA
| | - Eli Cohen
- Department of Molecular Biomedical SciencesNorth Carolina State College of Veterinary MedicineRaleigh, North Carolina 27607USA
- Dragonfly Imaging, PLLC, 1249 Kildaire Farm Road, #216Cary, North Carolina 27511USA
| | - Jenny Marin
- Department of Small Animal Clinical SciencesVA‐MD College of Veterinary Medicine, Virginia Tech, 205 Duck Pond DriveBlacksburg, Virginia 24061USA
| | - Alexandre B. Le Roux
- Department of Diagnostic ImagingThe Schwarzman Animal Medical Center, 510 East 62nd StreetNew York, New York 10065USA
- Present address:
Memorial Sloan Kettering Cancer Center, 417 East 68th StreetNew York, New York 10065USA
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Fietz SA, Kalusa M, Jergens AE, Sahoo DK, Stewart T, Heilmann RM. Ultrastructural changes in chronic inflammatory enteropathies-a comparison between dogs and humans. Front Cell Dev Biol 2024; 12:1379714. [PMID: 38872928 PMCID: PMC11173093 DOI: 10.3389/fcell.2024.1379714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 04/24/2024] [Indexed: 06/15/2024] Open
Abstract
Chronic inflammatory enteropathies (CIEs) are an important group of diseases in dogs and involve complex pathogenetic aspects. Endoscopy and histopathology are vital for documenting the disease but are less useful for subclassifying CIEs and predicting the response to treatment. However, healing of the mucosal disease process (deep remission) and ultrastructural evaluation of the mucosa have received little attention in canine CIE. Given that canine CIE shares many similarities with inflammatory bowel diseases (IBDs) in human patients-and presents a good spontaneous disease model for human IBD-this perspective article evaluates the literature on ultrastructural lesions in canine CIE and human IBD and offers future directions for the study of ultrastructural mucosal lesions in canine CIE. Such lesions might have a higher sensitivity of detection than structural changes revealed upon light microscopy and may even precede or remain after the resolution of the clinical signs and histologic lesions.
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Affiliation(s)
- Simone A. Fietz
- Institute of Anatomy, Histology and Embryology, College of Veterinary Medicine, Leipzig University, Leipzig, Saxony, Germany
| | - Mirjam Kalusa
- Institute of Anatomy, Histology and Embryology, College of Veterinary Medicine, Leipzig University, Leipzig, Saxony, Germany
| | - Albert E. Jergens
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Dipak Kumar Sahoo
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Tracey Stewart
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Romy M. Heilmann
- Department for Small Animals, College of Veterinary Medicine, Leipzig University, Leipzig, Saxony, Germany
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Choi EL, Taheri N, Zhang Y, Matsumoto K, Hayashi Y. The critical role of muscularis macrophages in modulating the enteric nervous system function and gastrointestinal motility. J Smooth Muscle Res 2024; 60:1-9. [PMID: 38462479 PMCID: PMC10921093 DOI: 10.1540/jsmr.60.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/14/2024] [Indexed: 03/12/2024] Open
Abstract
Macrophages are the originators of inflammatory compounds, phagocytic purifiers in their local environment, and wound healing protectors in oxidative environments. They are molded by the tissue milieu they inhabit, with gastrointestinal (GI) muscularis macrophages (MMs) being a prime example. MMs are located in the muscular layer of the GI tract and contribute to muscle repair and maintenance of GI motility. MMs are often in close proximity to the enteric nervous system, specifically near the enteric neurons and interstitial cells of Cajal (ICCs). Consequently, the anti-inflammatory function of MMs corresponds to the development and maintenance of neural networks in the GI tract. The capacity of MMs to shift from anti-inflammatory to proinflammatory states may contribute to the inflammatory aspects of various GI diseases and disorders such as diabetic gastroparesis or postoperative ileus, functional disorders such as irritable bowel syndrome, and organic diseases such as inflammatory bowel disease. We reviewed the current knowledge of MMs and their influence on neighboring cells due to their important role in the GI tract.
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Affiliation(s)
- Egan L. Choi
- Graduate Research Education Program in the Department of
Physiology and Biomedical Engineering, Mayo Clinic Graduate School of Biomedical Sciences,
200 First Street SW, Rochester, MN 55905, USA
| | - Negar Taheri
- Research Fellow in the Department of Physiology and
Biomedical Engineering, Mayo Clinic School of Graduate Medical Education, 200 First Street
SW, Rochester, MN 55905, USA
| | - Yuebo Zhang
- Department of Physiology and Biomedical Engineering, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Kenjiro Matsumoto
- Laboratory of Pathophysiology, Faculty of Pharmaceutical
Sciences, Doshisha Woman’s College of Liberal Arts, Kodo, Kyotanabe City, Kyoto 610-0395,
Japan
| | - Yujiro Hayashi
- Department of Physiology and Biomedical Engineering, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905, USA
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Mischopoulou M, D'Ambrosio M, Bigagli E, Luceri C, Farrugia G, Cipriani G. Role of Macrophages and Mast Cells as Key Players in the Maintenance of Gastrointestinal Smooth Muscle Homeostasis and Disease. Cell Mol Gastroenterol Hepatol 2022; 13:1849-1862. [PMID: 35245688 PMCID: PMC9123576 DOI: 10.1016/j.jcmgh.2022.02.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 02/18/2022] [Accepted: 02/22/2022] [Indexed: 12/18/2022]
Abstract
The gut contains the largest macrophage pool in the body, with populations of macrophages residing in the mucosa and muscularis propria of the gastrointestinal (GI) tract. Muscularis macrophages (MMs), which are located within the muscularis propria, interact with cells essential for GI function, such as interstitial cells of Cajal, enteric neurons, smooth muscle cells, enteric glia, and fibroblast-like cells, suggesting that these immune cells contribute to several aspects of GI function. This review focuses on the latest insights on the factors contributing to MM heterogeneity and the functional interaction of MMs with other cell types essential for GI function. This review integrates the latest findings on macrophages in other organs with increasing knowledge of MMs to better understand their role in a healthy and diseased gut. We describe the factors that contribute to (muscularis macrophage) MM heterogeneity, and the nature of MM interactions with cells regulating GI function. Finally, we also describe the increasing evidence suggesting a critical role of another immune cell type, the mast cell, in normal and diseased GI physiology.
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Affiliation(s)
| | - Mario D'Ambrosio
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Elisabetta Bigagli
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Cristina Luceri
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
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7
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Li H, Chen X, Liu J, Chen M, Huang M, Huang G, Chen X, Du Q, Su J, Lin R. Ethanol extract of Centella asiatica alleviated dextran sulfate sodium-induced colitis: Restoration on mucosa barrier and gut microbiota homeostasis. JOURNAL OF ETHNOPHARMACOLOGY 2021; 267:113445. [PMID: 33022343 DOI: 10.1016/j.jep.2020.113445] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 07/25/2020] [Accepted: 09/30/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ulcerative colitis (UC) is a relapsing inflammatory disease that still demands for effective remedies due to various adverse effects of the current principal treatments. Centella asiatica is a traditional medical herb with long application history in anti-inflammation. AIM OF THE STUDY To explore the anti-inflammatory effect and possible mechanism of C. asiatica ethanol extract (CA) in a murine colitis model induced by dextran sulfate sodium (DSS). MATERIALS AND METHODS CA was analyzed by high performance liquid chromatograph (HPLC). The colitis model was induced by free access to 3% DSS in distilled water for 7 days. CA (100, 200, and 400 mg/kg) and 5-aminosalicylic acid (5-ASA, 400 mg/kg) were administrated by gavage during the 7-day DSS challenge. At the end of experiment, mice were sacrificed and the brain, colon and cecum contents were harvested for analysis. Colitis was evaluated by disease activity index (DAI), colon length and colon lesion macroscopic score with hematoxylin-eosin staining. Myeloperoxidase (MPO) activity in colon and 5-hydroxytryptamine (5-HT) in brain were determined by ELISA. Tight junction protein expressions (ZO-1, E-Cadherin, Claudin-1) and c-Kit in colon were assessed by western blot and immunohistochemistry, respectively. Microbiota of cecum content was analyzed by 16S rRNA sequencing. RESULTS Data showed that with recovery on the colon length and histological structure, CA prominently decreased DAI and macroscopic score for lesion in the suffering mice. CA relieved the colitis by suppressing inflammatory cell infiltration with decreased MPO activity in the colon, and up-regulated the expression of tight junction protein (ZO-1, E-cadherin) to enhance the permeability of intestinal mucosa. Moreover, CA restored intestinal motility by promoting c-Kit expression in the colon and 5-HT in the brain. Moreover, CA was able to reshape the gut microbiota in the suffering mice. It increased the α-diversity and shifted the community by depleting the colitis-associated genera, Helicobacter, Jeotgalicoccus and Staphylococcus, with impact on several metabolism signaling pathways, which possibly contributes to the renovation on the impaired intestinal mucosal barrier. CONCLUSIONS CA displayed the anti-inflammatory activity against the DSS-induced colitis, which would possibly rely on the restoration on mucosa barrier and gut microbiota homeostasis, highlights a promising application of C. asiatica in the clinical treatment of UC.
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Affiliation(s)
- Huibiao Li
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China; The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, PR China
| | - Xiaohong Chen
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China; Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, PR China
| | - Jiayao Liu
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China
| | - Muyuan Chen
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China; The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, PR China
| | - Ming Huang
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China
| | - Guoxin Huang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, PR China
| | - Xinlin Chen
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China
| | - Qin Du
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China
| | - Jiyan Su
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, PR China.
| | - Rongfeng Lin
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China.
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8
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Xu X, Lin S, Yang Y, Gong X, Tong J, Li K, Li Y. Histological and ultrastructural changes of the colon in dextran sodium sulfate-induced mouse colitis. Exp Ther Med 2020; 20:1987-1994. [PMID: 32782508 PMCID: PMC7401218 DOI: 10.3892/etm.2020.8946] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 04/24/2020] [Indexed: 12/13/2022] Open
Abstract
Ulcerative colitis (UC) is a complex disease that results from a dysregulated immune response in the gastrointestinal tract. A mouse model orally administered with dextran sodium sulfate (DSS) is the most widely used experimental animal model of UC. However, the ultrastructure of the colon in mouse colitis is poorly understood. In the present study, colonic specimens from DSS-induced UC mice underwent hematoxylin and eosin staining, Masson's trichrome staining and Verhoeff's elastic staining. In addition, the ultrastructure of samples was examined by transmission electron microscopy. UC was successfully induced by 7 consecutive days of DSS oral administration. The goblet cell architecture of the UC tissue was damaged in the mucosa. Additionally, a significant number of inflammatory cells infiltrated into the stroma and the structure of the intestinal gland was destroyed. The tissue in the submucosa showed significant edema. Hyperplasia was also identified in the submucosa, promoting a disorganized microstructure within the colon wall. Numerous collagen fibers in the muscular layer were disrupted, and the fiber bundles were thinner compared with those in the normal control group. Furthermore, in the DSS-induced UC group, the smooth muscle cell showed edema, the cell membrane structure was unclear and the shape of the nucleus was irregular. In conclusion, the present study revealed important histological and ultrastructural changes in the colon of DSS-induced UC mice. These features may contribute to improved understanding of the pathogenesis and mechanism of UC.
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Affiliation(s)
- Xiaojuan Xu
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, P.R. China.,Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Shanghai 200120, P.R. China
| | - Sisi Lin
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, P.R. China
| | - Yanhua Yang
- Department of Pathology, Qingdao Municipal Hospital, Qingdao, Shandong 266011, P.R. China
| | - Xiaohui Gong
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Shanghai 200120, P.R. China
| | - Jianhua Tong
- Shanghai East Hospital, Institute for Biomedical Engineering and Nano Science, Tongji University School of Medicine, Shanghai 200092, P.R. China
| | - Kun Li
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, P.R. China
| | - Yongyu Li
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, P.R. China
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9
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Veress B, Ohlsson B. Spatial relationship between telocytes, interstitial cells of Cajal and the enteric nervous system in the human ileum and colon. J Cell Mol Med 2020; 24:3399-3406. [PMID: 31983076 PMCID: PMC7131924 DOI: 10.1111/jcmm.15013] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/17/2019] [Accepted: 01/10/2020] [Indexed: 12/16/2022] Open
Abstract
Telocytes (TCs) are recently described interstitial cells, present in almost all human organs. Among many other functions, TCs regulate gastrointestinal motility together with the interstitial cells of Cajal (ICCs). TCs and ICCs have close localization in the human myenteric plexus; however, the exact spatial relationship cannot be clearly examined by previously applied double immunofluorescence/confocal microscopy. Data on TCs and submucosal ganglia and their relationship to intestinal nerves are scarce. The aim of the study was to analyse the spatial relationship among these components in the normal human ileum and colon with double CD34/CD117 and CD34/S100 immunohistochemistry and high‐resolution light microscopy. TCs were found to almost completely encompass both myenteric and submucosal ganglia in ileum and colon. An incomplete monolayer of ICCs was localized between the TCs and the longitudinal muscle cells in ileum, whereas only scattered ICCs were present on both surfaces of the colonic myenteric ganglia. TC‐telopodes were observed within colonic myenteric ganglia. TCs, but no ICCs, were present within and around the interganglionic nerve fascicles, submucosal nerves and mesenterial nerves, but were only observed along small nerves intramuscularly. These anatomic differences probably reflect the various roles of TCs and ICCs in the bowel function.
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Affiliation(s)
- Béla Veress
- Department of Pathology, Skåne University Hospital, Malmö, Sweden
| | - Bodil Ohlsson
- Department of Internal Medicine, Skane University Hospital, Lund University, Malmö, Sweden
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10
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Mogilevski T, Burgell R, Aziz Q, Gibson PR. Review article: the role of the autonomic nervous system in the pathogenesis and therapy of IBD. Aliment Pharmacol Ther 2019; 50:720-737. [PMID: 31418887 DOI: 10.1111/apt.15433] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/25/2019] [Accepted: 07/01/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND There is a growing body of evidence implicating a role for the brain-gut axis in the pathogenesis of inflammation in patients with IBD. AIMS To perform a narrative review of published literature regarding the association of the autonomic nervous system and intestinal inflammation and to describe the rationale for and emerging use of autonomic manipulation as a therapeutic agent METHODS: Current relevant literature was summarised and critically examined. RESULTS There is substantial pre-clinical and clinical evidence for a multifaceted anti-inflammatory effect of the vagus at both systemic and local intestinal levels. It acts via acetylcholine-mediated activation of α-7-acetylcholine receptors involving multiple cell types in innate and adaptive immunity and the enteric nervous system with subsequent protective influences on the intestinal barrier, inflammatory mechanisms and the microbiome. In patients with IBD, there is evidence for a sympatho-vagal imbalance, functional enteric neuronal depletion and hyporeactivity of the hypothalamic-pituitary-adrenal axis. Direct or transcutaneous vagal neuromodulation up-regulates the cholinergic anti-inflammatory pathway in pre-clinical and clinical models with down-regulation of systemic and local intestinal inflammation. This is supported by two small studies in Crohn's disease although remains to be investigated in ulcerative colitis. CONCLUSIONS Modulating the cholinergic anti-inflammatory pathway influences inflammation both systemically and at a local intestinal level. It represents a potentially underutilised anti-inflammatory therapeutic strategy. Given the likely pathogenic role of the autonomic nervous system in patients with IBD, vagal neuromodulation, an apparently safe and successful means of increasing vagal tone, warrants further clinical exploration.
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Affiliation(s)
- Tamara Mogilevski
- Centre for Neuroscience, Surgery and Trauma, Barts and the London School of Medicine and Dentistry, Blizard Institute, Wingate Institute of Neurogastroenterology, London, UK.,Barts Health NHS Trust, London, UK.,Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Australia
| | - Rebecca Burgell
- Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Australia
| | - Qasim Aziz
- Centre for Neuroscience, Surgery and Trauma, Barts and the London School of Medicine and Dentistry, Blizard Institute, Wingate Institute of Neurogastroenterology, London, UK.,Barts Health NHS Trust, London, UK
| | - Peter R Gibson
- Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Australia
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Interstitial cells of Cajal are diminished in critically ill patients: Autopsy cases. Nutrition 2019; 70:110591. [PMID: 31751930 DOI: 10.1016/j.nut.2019.110591] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 04/20/2019] [Accepted: 09/11/2019] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Gastrointestinal dysmotility in critically ill patients is important as enteral nutrition is crucial. However, normal gut motility is impaired under conditions of critical illness subsequent to severe insult. Interstitial cells of Cajal (ICC) form an extensive network associated with the myenteric plexus in the enteric nervous system. There are few reports about ICC distribution in critically ill patients. The aim of this study was to evaluate ICC in critically ill patients. METHODS Postmortem colon harvest was obtained from critically ill patients. Control specimens were obtained from patients without bowel movement problems who underwent hemicolectomy. The tissues were stained with c-Kit for ICC. The number of ICC was identified by counting from 10 high-power fields (HPFs). RESULTS Specimens from six patients were analyzed and compared with those from six control patients. All patients had abnormalities of crypt architecture and inflammatory cell infiltrations. Mucosal thickness tended to be lower in the critically ill patients than in the controls (147 ± 47 versus 231 ± 127 μm; P = 0.15). Muscle layer thickness tended to be higher in the critically ill patients than in the controls (494 ± 163 versus 394 ± 258 μm; P = 0.44). ICC in the critically ill patients were almost depleted in the colon compared with those in the controls. Significantly fewer ICC were present in the critically ill patients than in the controls (0.45 versus 7.25 cells/HPF; P < 0.05). CONCLUSIONS Critical illness is associated with diminished numbers of ICC in the colon. This finding could have implications for dysmotility in critically ill patients.
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12
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Fintl C, Lindberg R, McL Press C. Myenteric networks of interstitial cells of Cajal are reduced in horses with inflammatory bowel disease. Equine Vet J 2019; 52:298-304. [PMID: 31397916 DOI: 10.1111/evj.13160] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 07/27/2019] [Indexed: 11/29/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a well-recognised but poorly understood disease complex in the horse. Clinical signs may vary but often include weight loss, diarrhoea and colic. The effect this disease process may have on the gastrointestinal pacemaker cells (the interstitial cells of Cajal), enteric neurons and glial cells has not been previously evaluated in the horse. OBJECTIVES To compare the density of the interstitial cells of Cajal (ICC), enteric neurons and glial cells in horses with IBD to those of normal horses using immunohistochemical markers. STUDY DESIGN Retrospective, quantitative immunohistochemical study. METHODS Ileal samples were collected during post-mortem examinations from 14 horses with a clinical and histopathological diagnosis of IBD and from eight normal controls. All horses were Standardbreds 1-15 years of age. Six of the IBD cases had eosinophilic gastroenteritis (EG) while the remaining eight had granulomatous enteritis (GE). Tissue sections were labelled with anti-CD117 (c-Kit), anti-TMEM16 (TMEM16), anti-protein gene product (PGP9.5) and anti-glial fibrillary acidic protein (GFAP) using standard immunohistochemical labelling techniques. Image analysis was performed to quantify the presence of ICC (CD117, TMEM16) as well as neuronal (PGP9.5) and enteroglial (GFAP) networks. RESULTS Interstitial cells of Cajal networks were significantly reduced in the myenteric plexus (MP) region in IBD horses compared with the controls for both markers (P<0.05). There was no significant difference in the density of the neuronal or glial cell markers between the two groups (P>0.05). MAIN LIMITATIONS The number of horses included in the study. CONCLUSIONS Disruption to ICC networks may contribute to the clinical signs of colic in some horses with IBD. Further studies are needed to establish the pathophysiological mechanisms involved and the functional effects of the reduced ICC networks.
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Affiliation(s)
- C Fintl
- Norwegian University of Life Sciences, Oslo, Norway
| | - R Lindberg
- Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - C McL Press
- Norwegian University of Life Sciences, Oslo, Norway
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13
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Ren K, Yong C, Yuan H, Cao B, Zhao K, Wang J. TNF-α inhibits SCF, ghrelin, and substance P expressions through the NF-κB pathway activation in interstitial cells of Cajal. ACTA ACUST UNITED AC 2018; 51:e7065. [PMID: 29694505 PMCID: PMC5937728 DOI: 10.1590/1414-431x20187065] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 01/30/2018] [Indexed: 12/19/2022]
Abstract
Ulcerative colitis is a chronic inflammatory disease of the colon where intestinal motility is disturbed. Interstitial cells of Cajal (ICC) are required to maintain normal intestinal motility. In the present study, we assessed the effect of tumor necrosis factor-alpha (TNF-α) on viability and apoptosis of ICC, as well as on the expression of stem cell factor (SCF), ghrelin, and substance P. ICC were derived from the small intestines of Swiss albino mice. Cell viability and apoptosis were measured using CCK-8 assay and flow cytometry, respectively. ELISA was used to measure the concentrations of IL-1β, IL-6, ghrelin, substance P, and endothelin-1. Quantitative RT-PCR was used to measure the expression of SCF. Western blotting was used to measure the expression of apoptosis-related proteins, interleukins, SCF, and NF-κB signaling pathway proteins. TNF-α induced inflammatory injury in ICC by decreasing cell viability and increasing apoptosis and levels of IL-1β and IL-6. TNF-α decreased the levels of SCF, ghrelin, and substance P, but had no effect on endothelin-1. TNF-α down-regulated expressions of SCF, ghrelin, and substance P by activating the NF-κB pathway in ICC. In conclusion, TNF-α down-regulated the expressions of SCF, ghrelin, and substance P via the activation of the NF-κB pathway in ICC.
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Affiliation(s)
- Keyu Ren
- Department of Gastroenterology, Hospital of Qingdao University, Qingdao, China
| | - Chunming Yong
- Department of Emergency Medicine, Hospital of Qingdao University, Qingdao, China
| | - Hao Yuan
- Department of Gastroenterology, Hospital of Qingdao University, Qingdao, China
| | - Bin Cao
- Department of Gastroenterology, Hospital of Qingdao University, Qingdao, China
| | - Kun Zhao
- Department of Gastroenterology, Hospital of Qingdao University, Qingdao, China
| | - Jin Wang
- Department of Pathology, School of Basic Medicine, Medical College of Qingdao University, Qingdao, Shandong, China
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14
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Zhou J, O'Connor MD, Ho V. The Potential for Gut Organoid Derived Interstitial Cells of Cajal in Replacement Therapy. Int J Mol Sci 2017; 18:ijms18102059. [PMID: 28954442 PMCID: PMC5666741 DOI: 10.3390/ijms18102059] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 09/15/2017] [Accepted: 09/24/2017] [Indexed: 12/24/2022] Open
Abstract
Effective digestion requires propagation of food along the entire length of the gastrointestinal tract. This process involves coordinated waves of peristalsis produced by enteric neural cell types, including different categories of interstitial cells of Cajal (ICC). Impaired food transport along the gastrointestinal tract, either too fast or too slow, causes a range of gut motility disorders that affect millions of people worldwide. Notably, loss of ICC has been shown to affect gut motility. Patients that suffer from gut motility disorders regularly experience diarrhoea and/or constipation, insomnia, anxiety, attention lapses, irritability, dizziness, and headaches that greatly affect both physical and mental health. Limited treatment options are available for these patients, due to the scarcity of human gut tissue for research and transplantation. Recent advances in stem cell technology suggest that large amounts of rudimentary, yet functional, human gut tissue can be generated in vitro for research applications. Intriguingly, these stem cell-derived gut organoids appear to contain functional ICC, although their frequency and functional properties are yet to be fully characterised. By reviewing methods of gut organoid generation, together with what is known of the molecular and functional characteristics of ICC, this article highlights short- and long-term goals that need to be overcome in order to develop ICC-based therapies for gut motility disorders.
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Affiliation(s)
- Jerry Zhou
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia.
- Medical Sciences Research Group, Western Sydney University, Campbelltown, NSW 2560, Australia.
| | - Michael D O'Connor
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia.
- Medical Sciences Research Group, Western Sydney University, Campbelltown, NSW 2560, Australia.
| | - Vincent Ho
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia.
- Medical Sciences Research Group, Western Sydney University, Campbelltown, NSW 2560, Australia.
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15
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Dai YC, Zheng L, Zhang YL, Chen X, Chen DL, Wang LJ, Tang ZP. Jianpi Qingchang decoction regulates intestinal motility of dextran sulfate sodium-induced colitis through reducing autophagy of interstitial cells of Cajal. World J Gastroenterol 2017; 23:4724-4734. [PMID: 28765693 PMCID: PMC5514637 DOI: 10.3748/wjg.v23.i26.4724] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 04/30/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the underlying effect of Jianpi Qingchang decoction (JQD) regulating intestinal motility of dextran sulfate sodium (DSS)-induced colitis in mice.
METHODS C57BL/6 mice were randomly divided into four groups: the control group, the DSS group, the JQD group, and the 5-aminosalicylic acid group. Except for the control group, colitis was induced in other groups by giving distilled water containing 5% DSS. Seven days after modeling, the mice were administered corresponding drugs intragastrically. The mice were sacrificed on the 15th day. The disease activity index, macroscopic and histopathologic lesions, and ultrastructure of colon interstitial cells of Cajal (ICC) were observed. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-10 and interferon gamma (IFN-γ), the expression of nuclear factor-kappa B (NF-κB) p65, c-kit, microtubule-associated protein 1 light chain 3 (LC3-II) and Beclin-l mRNA, and the colonic smooth muscle tension were assessed.
RESULTS Acute inflammation occurred in the mice administered DSS. Compared with the control group, the levels of IL-1β, TNF-α, IL-10 and IFN-γ, the expression of LC3-II, Beclin-1 and NF-κB p65 mRNA, and the contractile frequency increased (P < 0.05), the expression of c-kit mRNA and the colonic smooth muscle contractile amplitude decreased in the DSS group (P < 0.05). Compared with the DSS group, the levels of IL-10 and IFN-γ, the expression of c-kit mRNA, and the colonic smooth muscle contractile amplitude increased (P < 0.05), the levels of TNF-α and IL-1β, the expression of LC3-II, Beclin-1 and NF-κB p65 mRNA, and the contractile frequency decreased in the JQD group (P < 0.05).
CONCLUSION JQD can regulate the intestinal motility of DSS-induced colitis in mice through suppressing intestinal inflammatory cascade reaction, reducing autophagy of ICC, and regulating the network path of ICC/smooth muscle cells.
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16
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Sanders KM, Kito Y, Hwang SJ, Ward SM. Regulation of Gastrointestinal Smooth Muscle Function by Interstitial Cells. Physiology (Bethesda) 2017; 31:316-26. [PMID: 27488743 DOI: 10.1152/physiol.00006.2016] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Interstitial cells of mesenchymal origin form gap junctions with smooth muscle cells in visceral smooth muscles and provide important regulatory functions. In gastrointestinal (GI) muscles, there are two distinct classes of interstitial cells, c-Kit(+) interstitial cells of Cajal and PDGFRα(+) cells, that regulate motility patterns. Loss of these cells may contribute to symptoms in GI motility disorders.
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Affiliation(s)
- Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, Reno, Nevada; and
| | - Yoshihiko Kito
- Department of Pharmacology, Faculty of Medicine, Saga University, Nabeshima, Japan
| | - Sung Jin Hwang
- Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, Reno, Nevada; and
| | - Sean M Ward
- Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, Reno, Nevada; and
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17
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Identification of Candidate Genes Related to Inflammatory Bowel Disease Using Minimum Redundancy Maximum Relevance, Incremental Feature Selection, and the Shortest-Path Approach. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5741948. [PMID: 28293637 PMCID: PMC5331171 DOI: 10.1155/2017/5741948] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 01/11/2017] [Indexed: 02/08/2023]
Abstract
Identification of disease genes is a hot topic in biomedicine and genomics. However, it is a challenging problem because of the complexity of diseases. Inflammatory bowel disease (IBD) is an idiopathic disease caused by a dysregulated immune response to host intestinal microflora. It has been proven to be associated with the development of intestinal malignancies. Although the specific pathological characteristics and genetic background of IBD have been partially revealed, it is still an overdetermined disease and the blueprint of all genetic variants still needs to be improved. In this study, a novel computational method was built to identify genes related to IBD. Samples from two subtypes of IBD (ulcerative colitis and Crohn's disease) and normal samples were employed. By analyzing the gene expression profiles of these samples using minimum redundancy maximum relevance and incremental feature selection, 21 genes were obtained that could effectively distinguish samples from the two subtypes of IBD and the normal samples. Then, the shortest-path approach was used to search for an additional 20 genes in a large network constructed using protein-protein interactions based on the above-mentioned 21 genes. Analyses of the 41 genes obtained indicate that they are closely associated with this disease.
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18
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Patlevič P, Vašková J, Švorc P, Vaško L, Švorc P. Reactive oxygen species and antioxidant defense in human gastrointestinal diseases. Integr Med Res 2016; 5:250-258. [PMID: 28462126 PMCID: PMC5390420 DOI: 10.1016/j.imr.2016.07.004] [Citation(s) in RCA: 135] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 07/11/2016] [Accepted: 07/25/2016] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease and ulcerative colitis, known together as inflammatory bowel diseases (IBDs), and celiac disease are the most common disorders affecting not only adults but also children. Both IBDs and celiac disease are associated with oxidative stress, which may play a significant role in their etiologies. Reactive oxygen species (ROS) such as superoxide radicals (O2•-), hydroxyl radicals (•OH), hydrogen peroxide (H2O2), and singlet oxygen (1O2) are responsible for cell death via oxidation of DNA, proteins, lipids, and almost any other cellular constituent. To protect biological systems from free radical toxicity, several cellular antioxidant defense mechanisms exist to regulate the production of ROS, including enzymatic and nonenzymatic pathways. Superoxide dismutase catalyzes the dismutation of O2•- to H2O2 and oxygen. The glutathione redox cycle involves two enzymes: glutathione peroxidase, which uses glutathione to reduce organic peroxides and H2O2; and glutathione reductase, which reduces the oxidized form of glutathione with concomitant oxidation of nicotinamide adenine dinucleotide phosphate. In addition to this cycle, GSH can react directly with free radicals. Studies into the effects of free radicals and antioxidant status in patients with IBDs and celiac disease are scarce, especially in pediatric patients. It is therefore very necessary to conduct additional research studies to confirm previous data about ROS status and antioxidant activities in patients with IBDs and celiac disease, especially in children.
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Affiliation(s)
- Peter Patlevič
- Department of Ecology, Faculty of Humanities and Natural Sciences, Prešov University in Prešov, Prešov, Slovak Republic
| | - Janka Vašková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Košice, Slovak Republic
| | - Pavol Švorc
- Department of Physiology and Pathophysiology, Faculty of Medicine, University of Ostrava, Ostrava-Zábřeh, Czech Republic
| | - Ladislav Vaško
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Košice, Slovak Republic
| | - Pavol Švorc
- Department of Medical Physiology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Košice, Slovak Republic
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19
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Yang B, Zhou XC, Lan C. Impact of the alterations in the interstitial cells of Cajal on intestinal motility in post-infection irritable bowel syndrome. Mol Med Rep 2014; 11:2735-40. [PMID: 25484117 DOI: 10.3892/mmr.2014.3039] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 11/03/2014] [Indexed: 01/04/2023] Open
Abstract
The interstitial cells of Cajal (ICC) are basic components of gastrointestinal motility. However, changes in ICC and their role in post‑infection irritable bowel syndrome (PI‑IBS) remain to be elucidated. To observe the impact of alterations in the ICC on intestinal motility in a PI‑IBS mouse model, female C57BL\6 mice were infected by the oral administration of 400 Trichinella spiralis larvae. The abdominal withdrawal reflex, intestine transportation time (ITT), grain numbers, Bristol scores, wet/dry weights and the percentage water content of the mice feces every 2 h were used to assess changes in the intestinal motor function. The intestines were excised and sectioned for pathological and histochemical examination. These intestines were also used to quantify the protein and mRNA expression of c‑kit. The C57BL\6 mouse can act as a PI‑IBS model at day 56 post‑infection. Compared with the control mice, the ITT was shorter, the grain numbers, Bristol scores, wet weights and water contents of the mice feces were higher and the dry weights were unchanged in the PI‑IBS mice. The protein and mRNA expression levels of c‑kit were upregulated in the entire PI‑IBS mouse intestines. Following immunohistochemical staining, the increased number of c‑kit‑positive cells were detected predominantly in the submucosa and myenteron. These results suggested that the alterations of the ICC resulted in the changes of the intestinal motility patterns in the PI‑IBS mouse models induced by Trichinella spiralis infection, which may be the main mechanism underlying intestinal motility disorders in PI‑IBS.
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Affiliation(s)
- Bo Yang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xu-Chun Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Cheng Lan
- Department of Gastroenterology, Hainan Provincial People's Hospital, Haikou, Hainan 400016, P.R. China
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20
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Bassotti G, Antonelli E, Villanacci V, Baldoni M, Dore MP. Colonic motility in ulcerative colitis. United European Gastroenterol J 2014; 2:457-62. [PMID: 25452840 PMCID: PMC4245297 DOI: 10.1177/2050640614548096] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 07/23/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Inflammatory conditions affecting the gut may cause motility disturbances, and ulcerative colitis - one of the main disorders among the inflammatory bowel diseases - may display abnormal colonic motility. AIM To review the abnormalities of the large bowel in ulcerative colitis, by considering the motility, laboratory (in vitro) and pathological studies dealing with this topic. METHODS A comprehensive online search of Medline and the Science Citation Index was carried out. RESULTS Patients with ulcerative colitis frequently display colonic motor abnormalities, including lack of contractility, an increase of propulsive contractile waves, an excessive production of nitric oxide, vasoactive intestinal polypeptide nerves, interleukin 1 beta, neurotensin, tachykinins levels and the weaker action of substance P, likely related to a neuromuscular dysfunction due to the inflammatory process. CONCLUSIONS A better understanding of the pathophysiological grounds of altered colonic motility in ulcerative colitis may lead to a more in-depth knowledge of the accompanying symptoms and to better and more targeted therapeutic approaches.
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Affiliation(s)
- Gabrio Bassotti
- Gastroenterology Section, Department of Medicine, University of Perugia, Perugia, Italy
- Professor Gabrio Bassotti, Sezione di Gastroenterologia, Dipartimento di Medicina, Piazza Lucio Severi 1, 06132 San Sisto (Perugia), Italy.
| | | | - Vincenzo Villanacci
- Pathology Section, Department of Molecular and Translational Medicine, Spedali Civili and University of Brescia, Italy
| | - Monia Baldoni
- Gastroenterology Section, Department of Medicine, University of Perugia, Perugia, Italy
| | - Maria Pina Dore
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
- Baylor College of Medicine, Houston, Texas, USA
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21
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McCann CJ, Hwang SJ, Hennig GW, Ward SM, Sanders KM. Bone Marrow Derived Kit-positive Cells Colonize the Gut but Fail to Restore Pacemaker Function in Intestines Lacking Interstitial Cells of Cajal. J Neurogastroenterol Motil 2014; 20:326-37. [PMID: 24847840 PMCID: PMC4102151 DOI: 10.5056/jnm14026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 04/01/2014] [Accepted: 04/09/2014] [Indexed: 12/28/2022] Open
Abstract
Background/Aims Several motility disorders are associated with disruption of interstitial cells of Cajal (ICC), which provide important functions, such as pacemaker activity, mediation of neural inputs and responses to stretch in the gastrointestinal (GI) tract. Restoration of ICC networks may be therapeutic for GI motor disorders. Recent reports have suggested that Kit+ cells can be restored to the GI tract via bone marrow (BM) transplantation. We tested whether BM derived cells can lead to generation of functional activity in intestines naturally lacking ICC. Methods BM cells from Kit+/copGFP mice, in which ICC are labeled with a green fluorescent protein, were transplanted into W/WV intestines, lacking ICC. After 12 weeks the presence of ICC was analyzed by immunohistochemistry and functional analysis of electrical behavior and contractile properties. Results After 12 weeks copGFP+ BM derived cells were found within the myenteric region of intestines from W/WV mice, typically populated by ICC. Kit+ cells failed to develop interconnections typical of ICC in the myenteric plexus. The presence of Kit+ cells was verified with Western analysis. BM cells failed to populate the region of the deep muscular plexus where normal ICC density, associated with the deep muscular plexus, is found in W/WV mice. Engraftment of Kit+-BM cells resulted in the development of unitary potentials in transplanted muscles, but slow wave activity failed to develop. Motility analysis showed that intestinal movements in transplanted animals were abnormal and similar to untransplanted W/WV intestines. Conclusions BM derived Kit+ cells colonized the gut after BM transplantation, however these cells failed to develop the morphology and function of mature ICC.
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Affiliation(s)
- Conor J McCann
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA; University College London Institute of Child Health, Birth Defects Research Center, Neural Development Unit, London, UK
| | - Sung-Jin Hwang
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - Grant W Hennig
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - Sean M Ward
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
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22
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Alkahtani R, Mahavadi S, Al-Shboul O, Alsharari S, Grider JR, Murthy KS. Changes in the expression of smooth muscle contractile proteins in TNBS- and DSS-induced colitis in mice. Inflammation 2013; 36:1304-15. [PMID: 23794034 PMCID: PMC3823744 DOI: 10.1007/s10753-013-9669-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Thin filament-associated proteins such as calponin, caldesmon, tropomyosin, and smoothelin are thought to regulate acto-myosin interaction and thus, muscle contraction. However, the effect of inflammation on the expression of thin filament-associated proteins is not known. The aim of the present study is to determine the changes in the expression of calponin, caldesmon, tropomyosin, and smoothelin in colonic smooth muscle from trinitrobenzene sulphonic acid (TNBS)- and dextran sodium sulphate (DSS)-induced colitis in mice. Expression of h-caldesmon, h2-calponin, α-tropomyosin, and smoothelin-A was measured by qRT-PCR and Western blot. Contraction in response to acetylcholine in dispersed muscle cells was measured by scanning micrometry. mRNA and protein expression of α-actin, h2-calponin, h-caldesmon, smoothelin, and α-tropomyosin in colonic muscle strips from mice with TNBS- or DSS-induced colitis was significantly increased compared to control animals. Contraction in response to acetylcholine was significantly decreased in muscle cells isolated from inflamed regions of TNBS- or DSS-treated mice compared to control mice. Our results show that increase in the expression of thin filament-associated contractile proteins, which inhibit acto-myosin interaction, could contribute to decrease in smooth muscle contraction in inflammation.
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Affiliation(s)
- Reem Alkahtani
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Sunila Mahavadi
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Othman Al-Shboul
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Shakir Alsharari
- Department of Pharmacology, Virginia Commonwealth University, Richmond, Virginia
| | - John R. Grider
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Karnam S. Murthy
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
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23
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McCann CJ, Hwang SJ, Bayguinov Y, Colletti EJ, Sanders KM, Ward SM. Establishment of pacemaker activity in tissues allotransplanted with interstitial cells of Cajal. Neurogastroenterol Motil 2013; 25:e418-28. [PMID: 23638836 PMCID: PMC3704156 DOI: 10.1111/nmo.12140] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 03/25/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Loss or disruption of Kit(+) -interstitial cells of Cajal (ICC) capable of generating pacemaker activity has been implicated in the development of numerous gastrointestinal motility disorders. We sought to develop a model where ICC could be allotransplanted into intestines naturally devoid of these cells. METHODS Enzymatically dispersed cells from the intestinal tunica muscularis of Kit(+/copGFP) and Kit(V558Δ) /+ gain-of-function mice were allotransplanted into myenteric plexus regions of W/W(V) mutant intestines that lack ICC at the level of the myenteric plexus (ICC-MY) and pacemaker activity. Immunohistochemical analysis fate mapped the development of ICC-MY networks and intracellular microelectrode recordings provided evidence for the development of functional pacemaker activity. KEY RESULTS Kit(+) -ICC developed into distinct networks at the level of the myenteric plexus in organotypic cultures over 28 days and displayed robust rhythmic pacemaker activity. CONCLUSIONS & INFERENCES This study demonstrates the feasibility of allotransplantation of ICC into the myenteric region of the small intestine and the establishment of functional pacemaker activity into tissues normally devoid of ICC-MY and slow waves, thus providing a possible basis for the therapeutic treatment of patients where ICC networks have been disrupted due to a variety of pathophysiological conditions.
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Affiliation(s)
- C. J. McCann
- Department of Physiology and Cell Biology; University of Nevada School of Medicine; Reno; NV; USA
| | - S. J. Hwang
- Department of Physiology and Cell Biology; University of Nevada School of Medicine; Reno; NV; USA
| | - Y. Bayguinov
- Department of Physiology and Cell Biology; University of Nevada School of Medicine; Reno; NV; USA
| | - E. J. Colletti
- Department of Physiology and Cell Biology; University of Nevada School of Medicine; Reno; NV; USA
| | - K. M. Sanders
- Department of Physiology and Cell Biology; University of Nevada School of Medicine; Reno; NV; USA
| | - S. M. Ward
- Department of Physiology and Cell Biology; University of Nevada School of Medicine; Reno; NV; USA
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Rumessen JJ, Vanderwinden JM, Hansen A, Horn T. Ultrastructure of Interstitial Cells in Subserosa of Human Colon. Cells Tissues Organs 2013; 197:322-32. [DOI: 10.1159/000346314] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2012] [Indexed: 11/19/2022] Open
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Bettolli M, De Carli C, Cornejo-Palma D, Jolin-Dahel K, Wang XY, Huizinga J, Krantis A, Rubin S, Staines WA. Interstitial cell of Cajal loss correlates with the degree of inflammation in the human appendix and reverses after inflammation. J Pediatr Surg 2012; 47:1891-9. [PMID: 23084203 DOI: 10.1016/j.jpedsurg.2012.05.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 05/02/2012] [Accepted: 05/06/2012] [Indexed: 01/15/2023]
Abstract
BACKGROUND Normal gut motility relies on the complex interaction between the interstitial cell of Cajal (ICC) and the enteric nerve networks. Inflammation of the gastrointestinal tract adversely affects both ICC and enteric nerves. We aimed to determine the distribution of ICC and nerve networks in patients with appendicitis. METHODS Specimens from controls and patients with appendicitis were examined with immunohistochemistry (c-Kit for ICC, beta III tubulin [Tuj-1] and neuronal nitric oxide synthase [histochemical diaphorase] for nitrergic neurons) and electron microscopy (EM). Data were quantified using image analysis. RESULTS We found a profound decrease in c-Kit immunoreactivity (c-Kit IR) in the advanced inflammatory stages of appendicitis, which correlated with the severity of inflammation. Electron microscopy confirmed ultrastructural injury in both ICC and nerve fiber networks during acute inflammation. After the inflammation resolved, interval appendices displayed a recovery in ICC c-Kit IR to control levels and normal ultrastructure. The neuronal network also displayed ultrastructural recovery; however, neuronal nitric oxide synthase activity did not recover. CONCLUSIONS Severe inflammation results in significant ultrastructural damage of nerves and ICC networks in appendicitis. The loss of c-Kit IR is likely due to impaired ICC cytophysiology because ICC was still present under EM. After resolution of acute inflammation, ICC recovers their normal ultrastructure and c-Kit IR.
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Affiliation(s)
- Marcos Bettolli
- Department of General Surgery, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada.
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Bernardini N, Segnani C, Ippolito C, De Giorgio R, Colucci R, Faussone-Pellegrini MS, Chiarugi M, Campani D, Castagna M, Mattii L, Blandizzi C, Dolfi A. Immunohistochemical analysis of myenteric ganglia and interstitial cells of Cajal in ulcerative colitis. J Cell Mol Med 2012; 16:318-27. [PMID: 21426484 PMCID: PMC3823295 DOI: 10.1111/j.1582-4934.2011.01298.x] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease with alterations of colonic motility, which influence clinical symptoms. Although morpho-functional abnormalities in the enteric nervous system have been suggested, in UC patients scarce attention has been paid to possible changes in the cells that control colonic motility, including myenteric neurons, glial cells and interstitial cells of Cajal (ICC). This study evaluated the neural-glial components of myenteric ganglia and ICC in the colonic neuromuscular compartment of UC patients by quantitative immunohistochemical analysis. Full-thickness archival samples of the left colon were collected from 10 patients with UC (5 males, 5 females; age range 45–62 years) who underwent elective bowel resection. The colonic neuromuscular compartment was evaluated immunohistochemically in paraffin cross-sections. The distribution and number of neurons, glial cells and ICC were assessed by anti-HuC/D, -S100β and -c-Kit antibodies, respectively. Data were compared with findings on archival samples of normal left colon from 10 sex- and age-matched control patients, who underwent surgery for uncomplicated colon cancer. Compared to controls, patients with UC showed: (i) reduced density of myenteric HuC/D+ neurons and S100β+ glial cells, with a loss over 61% and 38%, respectively, and increased glial cell/neuron ratio; (ii) ICC decrease in the whole neuromuscular compartment. The quantitative variations of myenteric neuro-glial cells and ICC indicate considerable alterations of the colonic neuromuscular compartment in the setting of mucosal inflammation associated with UC, and provide a morphological basis for better understanding the motor abnormalities often observed in UC patients.
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Affiliation(s)
- Nunzia Bernardini
- Department of Human Morphology and Applied Biology, University of Pisa, Pisa, Italy.
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Radenkovic G, Abramovic M. Differentiation of interstitial cells of Cajal in the human distal colon. Cells Tissues Organs 2012; 196:463-9. [PMID: 22652525 DOI: 10.1159/000336707] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2012] [Indexed: 01/06/2023] Open
Abstract
At the end of the embryonic period of human development, interstitial cells of Cajal (ICC) are present in the esophagus, stomach, and proximal duodenum, around the inception of the myenteric plexus (MP) ganglia. In the small and large bowel, ICC appear later. The object of the present study was to determine the timing of appearance and pattern of distribution of ICC in the human embryonic and fetal distal colon. Human distal colon specimens were obtained from 8 embryos and 14 fetuses without gastrointestinal disorders. The specimens were 7-16 weeks of gestational age. The specimens were exposed to anti-c-kit antibodies to investigate ICC differentiation. Enteric plexuses were immunohistochemically examined using anti-neuron-specific enolase, and the differentiation of smooth muscle cells was studied with anti-desmin antibodies. In the distal colon, ICC emerged at weeks 10-11 of the fetal period in the form of two parallel belts of densely packed cells extending at the submucous plexus (SMP) and the MP level. These cells correspond to ICC of the SMP (ICC-SMP) and ICC of the MP (ICC-MP). The simultaneous appearance of ICC at the SMP and MP level in the distal colon can be explained by the fact that there are differences in the migration of neural crest cells in particular portions of the digestive tube. In conclusion, in humans, there was a difference in the patterns of development of ICC in the distal colon compared to the rest of the gut.
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Affiliation(s)
- Goran Radenkovic
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Nis, Serbia.
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Rumessen JJ, Vanderwinden JM, Horn T. Crohn's disease: ultrastructure of interstitial cells in colonic myenteric plexus. Cell Tissue Res 2011; 344:471-9. [PMID: 21562942 DOI: 10.1007/s00441-011-1175-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Accepted: 04/13/2011] [Indexed: 12/12/2022]
Abstract
The role of the interstitial cells of Cajal (ICC) in chronic inflammatory bowel disease, i.e., ulcerative colitis (UC) and Crohn's disease (CD), remains unclear. Ultrastructural alterations in ICC in the colonic myenteric plexus (ICC-MP) have been reported previously in UC, but descriptions of ICC-MP and other interstitial cells in the myenteric region of the colon are lacking for CD. In the present study, we characterized the ultrastructure of interstitial cells, nerves, and glial cells in the myenteric region in Crohn's colitis (CC). In comparison with controls, varicosities of the myenteric bundles were dilated and appeared to be empty. Lipid droplets and lipofuscin-bodies were prominent in glial cells and neurons. ICC-MP were scanty but, as in controls, had caveolae, prominent intermediate filaments, cytoplasmic dense bodies, and membrane-associated dense bands with a patchy basal lamina. ICC-MP were similar in the various colonic regions. ICC-MP in CC showed no signs of degeneration or cytological changes. As in controls, fibroblast-like cells had abundant coated vesicles but lacked prominent intermediate filaments and caveolae. Macrophages also appeared as in controls. In comparison with ICC-MP in UC, the cytology of ICC-MP in CC were thus undisturbed. The ultrastructural differences between UC and CC might reflect pathophysiological differences of importance for understanding pathogenetic differences between CD and UC.
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Affiliation(s)
- Jüri J Rumessen
- Department of Gastroenterology F, Gentofte Hospital, University of Copenhagen, Niels Andersensvej 65, 2900, Hellerup, Denmark.
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Rumessen JJ, Vanderwinden JM, Horn T. Ulcerative colitis: ultrastructure of interstitial cells in myenteric plexus. Ultrastruct Pathol 2011; 34:279-87. [PMID: 20568987 DOI: 10.3109/01913121003770701] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Interstitial cells of Cajal (ICC) are key regulatory cells in the gut. In the colon of patients with severe ulcerative colitis (UC), myenteric ICC had myoid ultrastructural features and were in close contact with nerve terminals. In all patients as opposed to controls, some ICC profiles showed degenerative changes, such as lipid droplets and irregular vacuoles. Nerve terminals often appeared swollen and empty. Glial cells, muscle cells, and fibroblast-like cells (FLC) showed no alterations. FLC enclosed macrophages (MLC), which were in close contact with naked axon terminals. The organization and cytological changes may be of pathophysiological significance in patients with UC.
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Affiliation(s)
- J J Rumessen
- Department of Gastroenterology F, Gentofte Hospital, Hellerup, Denmark.
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Identification and functional response of interstitial Cajal-like cells from rat mesenteric artery. Cell Tissue Res 2011; 343:509-19. [PMID: 21243375 DOI: 10.1007/s00441-010-1114-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2010] [Accepted: 12/02/2010] [Indexed: 01/06/2023]
Abstract
Cells with irregular shapes, numerous long thin filaments, and morphological similarities to the gastrointestinal interstitial cells of Cajal (ICCs) have been observed in the wall of some blood vessels. These ICC-like cells (ICC-LCs) do not correspond to the other cell types present in the arterial wall: smooth muscle cells (SMCs), endothelial cells, fibroblasts, inflammatory cells, or pericytes. However, no clear physiological role has as yet been determined for ICC-LCs in the vascular wall. The aim of this study has been to identify and characterize the functional response of ICC-LCs in rat mesenteric arteries. We have observed ICC-LCs and identified them morphologically and histologically in three different environments: isolated artery, freshly dispersed cells, and primary-cultured cells from the arterial wall. Like ICCs but unlike SMCs, ICC-LCs are positively stained by methylene blue. Cells morphologically resembling methylene-blue-positive cells are also positive for the ICC and ICC-LC markers α-smooth muscle actin and desmin. Furthermore, the higher expression of vimentin in ICC-LCs compared with SMCs allows a clear discrimination between these two cell types. At the functional level, the differences observed in the variations of cytosolic free calcium concentration of freshly dispersed SMCs and ICC-LCs in response to a panel of vasoactive molecules show that ICC-LCs, unlike SMCs, do not respond to exogenous ATP and [Arginine](8)-vasopressin.
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Rumessen JJ, Vanderwinden JM, Horn T. Crohn's disease of the colon: ultrastructural changes in submuscular interstitial cells of Cajal. Cell Tissue Res 2010; 343:421-8. [PMID: 21120534 DOI: 10.1007/s00441-010-1087-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Accepted: 11/03/2010] [Indexed: 01/29/2023]
Abstract
Interstitial cells of Cajal (ICC) at the submuscular border of the human colon (ICC-SMP) are the proposed pacemaker cells of the musculature. In patients with Crohn's disease (CD) of the colon, ICC-SMP showed characteristic cytological changes from controls. The changes comprised secondary lysosomes in connection with lipid droplets and cytoplasmic vacuoles or multiple empty, confluent and often outbulging vacuoles merging with cisterns of granular endoplasmic reticulum and clusters of glycogen granules. These changes were most pronounced in patients with macroscopical mucosal inflammation but were also demonstrable in uninvolved colonic segments. Relationships of ICC to other cells were undisturbed. The changes were selective to ICC-SMP, as glial cells, muscle cells and fibroblast-like cells at the submuscular border showed no cytological alterations compared with controls. Varicosities of the submuscular plexus were often empty and dilated. Fibroblast-like cells selectively encased macrophages and mast cells. The cytological changes in ICC-SMP in CD are thus similar to changes seen in ulcerative colitis and may be of pathophysiological significance with regard to the motility and sensory disturbances seen in patients with CD.
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Affiliation(s)
- Jüri J Rumessen
- Department of Gastroenterology F, Gentofte Hospital, University of Copenhagen, Niels Andersensvej 65, 2900, Hellerup, Denmark.
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Jee SR, Morales W, Low K, Chang C, Zhu A, Pokkunuri V, Chatterjee S, Soffer E, Conklin JL, Pimentel M. ICC density predicts bacterial overgrowth in a rat model of post-infectious IBS. World J Gastroenterol 2010; 16:3680-6. [PMID: 20677340 PMCID: PMC2915428 DOI: 10.3748/wjg.v16.i29.3680] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the interstitial cells of Cajal (ICC) number using a new rat model.
METHODS: Sprague-Dawley rats were assigned to two groups. The first group received gavage with Campylobacter jejuni (C. jejuni) 81-176. The second group was gavaged with placebo. Three months after clearance of Campylobacter from the stool, precise segments of duodenum, jejunum, and ileum were ligated in self-contained loops of bowel that were preserved in anaerobic bags. Deep muscular plexus ICC (DMP-ICC) were quantified by two blinded readers assessing the tissue in a random, coded order. The number of ICC per villus was compared among controls, Campylobacter recovered rats without small intestinal bacterial overgrowth (SIBO), and Campylobacter recovered rats with SIBO.
RESULTS: Three months after recovery, 27% of rats gavaged with C. jejuni had SIBO. The rats with SIBO had a lower number of DMP-ICC than controls in the jejunum and ileum. Additionally there appeared to be a density threshold of 0.12 DMP-ICC/villus that was associated with SIBO. If ileal density of DMP-ICC was < 0.12 ICC/villus, 54% of rats had SIBO compared to 9% among ileal sections with > 0.12 (P < 0.05). If the density of ICC was < 0.12 DMP-ICC/villus in more than one location of the bowel, 88% of these had SIBO compared to 6% in those who did not (P < 0.001).
CONCLUSION: In this post-infectious rat model, the development of SIBO appears to be associated with a reduction in DMP-ICC. Further study of this rat model might help understand the pathophysiology of post-infectious irritable bowel syndrome.
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Fintl C, Hudson NPH. The interstitial cells of Cajal of the equine gastrointestinal tract: what we know so far. Equine Vet J 2010; 42:372-7. [PMID: 20525058 DOI: 10.1111/j.2042-3306.2010.00073.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Gastrointestinal motility disorders are a serious problem in both veterinary and human medicine and may represent a dysfunction of the neural, muscular or pacemaker components (interstitial cells of Cajal) of bowel control. The interstitial cells of Cajal are considered to be the pacemakers and mediators of certain forms of neurotransmission in the gastrointestinal tract. These cells have been implicated, either primarily or secondarily, in the pathogenesis of gastrointestinal disease processes in which there is a prominent element of disturbance to intestinal motility. In the horse, their involvement has been implicated in large intestinal obstructive colic and grass sickness (equine dysautonomia). This review highlights the properties of the interstitial cells of Cajal and the role these cells play in orchestrating gastrointestinal motility patterns. In addition, it examines their role in intestinal motility disorders and summarises our current understanding of their importance in the equine gastrointestinal tract.
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Affiliation(s)
- C Fintl
- Norwegian School of Veterinary Science, Department of Companion Animal Clinical Sciences, PO Box 8146 Dep., 0033 Oslo, Norway
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Fujishiro J, Pech TC, Finger TF, Praktinjo M, Stoffels B, Standop J, Abu-Elmagd K, Tuerler A, Hirner A, Kalff JC, Schaefer N. Influence of immunosuppression on alloresponse, inflammation and contractile function of graft after intestinal transplantation. Am J Transplant 2010; 10:1545-55. [PMID: 20642681 DOI: 10.1111/j.1600-6143.2010.03117.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
In small bowel transplantation (SBTx), graft manipulation, ischemia/reperfusion injury and acute rejection initiate a severe cellular and molecular inflammatory response in the muscularis propria leading to impaired motility of the graft. This study examined and compared the effect of tacrolimus and sirolimus on inflammation in graft muscularis. After allogeneic orthotopic SBTx, recipient rats were treated with tacrolimus or sirolimus. Tacrolimus and sirolimus attenuated neutrophilic, macrophage and T-cell infiltration in graft muscularis, which was associated with reduced apoptotic cell death. Nonspecific inflammatory mediators (IL-6, MCP-1) and T-cell activation markers (IL-2, IFN-gamma) were highly upregulated in allogeneic control graft muscularis 24 h and 7 days after SBTx, and tacrolimus and sirolimus significantly suppressed upregulation of these mediators. In vitro organ bath method demonstrated a severe decrease in graft smooth muscle contractility in allogeneic control (22% of normal control). Correlating with attenuated upregulation of iNOS, tacrolimus and sirolimus treatment significantly improved contractility (64% and 72%, respectively). Although sirolimus reduced cellular and molecular inflammatory response more efficiently after 24 h, contrary tacrolimus prevented acute rejection more efficiently. In conclusion, tacrolimus and sirolimus attenuate cellular and molecular inflammatory response in graft muscularis and subsequent dysmotility of the graft after allogeneic SBTx.
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Affiliation(s)
- J Fujishiro
- Department of Surgery, University of Bonn, Germany
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PAVONE S, MANDARA MT. A morphological and quantitative immunohistochemical study of the interstitial cells of Cajal in the normal equine intestinal tracts. Equine Vet J 2010; 42:358-66. [DOI: 10.1111/j.2042-3306.2010.00031.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Ro S, Park C, Jin J, Zheng H, Blair PJ, Redelman D, Ward SM, Yan W, Sanders KM. A model to study the phenotypic changes of interstitial cells of Cajal in gastrointestinal diseases. Gastroenterology 2010; 138:1068-78.e1-2. [PMID: 19917283 PMCID: PMC4793910 DOI: 10.1053/j.gastro.2009.11.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2009] [Revised: 10/27/2009] [Accepted: 11/05/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Interstitial cells of Cajal (ICC) express the receptor tyrosine kinase, KIT, the receptor for stem cell factor. In the gastrointestinal (GI) tract, ICC are pacemaker cells that generate spontaneous electrical slow waves, and mediate inputs from motor neurons. Absence or loss of ICC are associated with GI motility disorders, including those consequent of diabetes. Studies of ICC have been hampered by the low density of these cells and difficulties in recognizing these cells in cell dispersions. METHODS Kit(+/copGFP) mice harboring a copepod super green fluorescent protein (copGFP) complementary DNA, inserted at the Kit locus, were generated. copGFP(+) ICC from GI muscles were analyzed using confocal microscopy and flow cytometry. copGFP(+) ICC from the jejunum were purified by a fluorescence-activated cell sorter and validated by cell-specific markers. Kit(+/copGFP) mice were crossbred with diabetic Lep(+/ob) mice to generate compound Kit(+/copGFP);Lep(ob/ob) mutant mice. copGFP(+) ICC from compound transgenic mice were analyzed by confocal microscopy. RESULTS copGFP in Kit(+/copGFP) mice colocalized with KIT immunofluorescence and thus was predominantly found in ICC. In other smooth muscles, mast cells were also labeled, but these cells were relatively rare in the murine GI tract. copGFP(+) cells from jejunal muscles were Kit(+) and free of contaminating cell-specific markers. Kit(+/copGFP);Lep(ob/ob) mice displayed ICC networks that were dramatically disrupted during the development of diabetes. CONCLUSIONS Kit(+/copGFP) mice offer a powerful new model to study the function and genetic regulation of ICC phenotypes. Isolation of ICC from animal models will help determine the causes and responses of ICC to therapeutic agents.
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Affiliation(s)
- Seungil Ro
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
| | - Chanjae Park
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
| | - Jingling Jin
- Huffington Center on Aging and Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas
| | - Huili Zheng
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
| | - Peter J. Blair
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
| | - Doug Redelman
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
| | - Sean M. Ward
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
| | - Wei Yan
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
| | - Kenton M. Sanders
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
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Mikkelsen HB. Interstitial cells of Cajal, macrophages and mast cells in the gut musculature: morphology, distribution, spatial and possible functional interactions. J Cell Mol Med 2010; 14:818-32. [PMID: 20132411 PMCID: PMC3823114 DOI: 10.1111/j.1582-4934.2010.01025.x] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Interstitial cells of Cajal (ICC) are recognized as pacemaker cells for gastrointestinal movement and are suggested to be mediators of neuromuscular transmission. Intestinal motility disturbances are often associated with a reduced number of ICC and/or ultrastructural damage, sometimes associated with immune cells. Macrophages and mast cells in the intestinal muscularis externa of rodents can be found in close spatial contact with ICC. Macrophages are a constant and regularly distributed cell population in the serosa and at the level of Auerbach's plexus (AP). In human colon, ICC are in close contact with macrophages at the level of AP, suggesting functional interaction. It has therefore been proposed that ICC and macrophages interact. Macrophages and mast cells are considered to play important roles in the innate immune defence by producing pro-inflammatory mediators during classical activation, which may in itself result in damage to the tissue. They also take part in alternative activation which is associated with anti-inflammatory mediators, tissue remodelling and homeostasis, cancer, helminth infections and immunophenotype switch. ICC become damaged under various circumstances - surgical resection, possibly post-operative ileus in rodents - where innate activation takes place, and in helminth infections - where alternative activation takes place. During alternative activation the muscularis macrophage can switch phenotype resulting in up-regulation of F4/80 and the mannose receptor. In more chronic conditions such as Crohn's disease and achalasia, ICC and mast cells develop close spatial contacts and piecemeal degranulation is possibly triggered.
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Affiliation(s)
- Hanne B Mikkelsen
- Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen N, Denmark.
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Fintl C, Hudson NPH, Mayhew IG, Edwards GB, Proudman CJ, Pearson GT. Interstitial cells of Cajal (ICC) in equine colic: an immunohistochemical study of horses with obstructive disorders of the small and large intestines. Equine Vet J 2010; 36:474-9. [PMID: 15460070 DOI: 10.2746/0425164044877314] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
REASONS FOR PERFORMING STUDY The gastrointestinal pacemaker cells, the interstitial cells of Cajal (ICC), have been implicated in several human gastrointestinal dysmotility syndromes. Recently, the involvement of these cells in equine gastrointestinal diseases has been investigated in cases of equine grass sickness where a significant reduction in ICC density was observed. OBJECTIVE To investigate ICC density in equine obstructive gastrointestinal disorders using immunohistochemical labelling methods. METHODS Intestinal samples were analysed from 44 horses undergoing exploratory surgery for colic and from 11 control animals subjected to euthanasia for conditions not related to the gastrointestinal tract. Immunohistochemical labelling of ICC was carried out using an anti-c-Kit antibody. Two independent observers assessed ICC density using a semiquantitative grading system. RESULTS There was a significant reduction in ICC density in horses with large colon disorders compared to the controls (P<0.01). Horses with strangulating lesions of the small intestine showed no difference when compared to the controls. CONCLUSIONS There was a reduction in ICC density in horses with large intestinal disorders. POTENTIAL RELEVANCE The reduction in ICC density may be associated with the clinical findings as well as recurrent colic episodes observed in a number of these cases. This immunohistochemical study provides a basis for future functional electrophysiological investigations to determine the precise effect of ICC reduction on equine intestinal motility.
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Affiliation(s)
- C Fintl
- Gastrointestinal Motility and Disease Laboratory, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK
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Yang X, Zhang Y, Hu J. The expression of Cajal cells at the obstruction site of congenital pelviureteric junction obstruction and quantitative image analysis. J Pediatr Surg 2009; 44:2339-42. [PMID: 20006022 DOI: 10.1016/j.jpedsurg.2009.07.061] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2009] [Accepted: 07/31/2009] [Indexed: 01/19/2023]
Abstract
OBJECTIVE The study aimed to analyze the expression and significance of interstitial cells of Cajal (ICC) at the obstruction site of congenital pelviureteric junction obstruction (PUJO). METHODS Specimens of the strictured segment of the PUJ were obtained from 24 patients who were diagnosed to have PUJO (without aberrant vessels and adhesive band compression of ureteral junction) intraoperatively. In the control group, PUJ specimens were taken from 21 patients who had Wilms' tumor. Pelviureteric junction tissues were confirmed to be free of tumor invasion by histology. Immunohistochemistry with c-kit antibody was performed to detect the expression of ICC in specimens of the 2 groups. Quantitative analysis was made using image analysis technique and statistical analysis was carried out. RESULTS Immunoreactivity to ICC was predominantly detected in the muscle layers of PUJ. The mean area of ICC expression in the PUJO group was 14.86 +/- 1.37 x 10(4)microm(2) , which was lower than that in the control group (16.80 +/- 1.68) x 10(4)microm(2) (P < .01). The mean density of ICC expression in the PUJO was 0.207 +/- 0.020, which was also lower than that in the control group (0.262 +/- 0.026) (P < .05). CONCLUSIONS A reduction of the number of ICC may play an important role in the etiology and pathogenesis of PUJO.
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Affiliation(s)
- Xinghai Yang
- Department of Pediatric Surgery, Hubei Women and Children's Hospital, Wuhan 430070, People's Republic of China.
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40
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Ultrastructure of interstitial cells of Cajal in myenteric plexus of human colon. Cell Tissue Res 2009; 337:197-212. [PMID: 19506909 DOI: 10.1007/s00441-009-0818-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2009] [Accepted: 05/05/2009] [Indexed: 12/18/2022]
Abstract
The role of the interstitial cells of Cajal (ICC) associated with the myenteric plexus (ICC-MP) as regulators of the motility of the colonic external muscle remains unclear. Ultrastructural studies of myenteric interstitial cells are lacking in human colon. We therefore characterized the distinctive ultrastructure of these cells in the myenteric region of the colon by transmission electron microscopy of the region between the main muscle layers in all parts of the colon in unaffected areas of resected specimens from nine adult human patients. ICC-MP were similar in various colonic regions and had myoid features such as scattered caveolae, prominent intermediate filaments, and cytoplasmic dense bodies. We found characteristic dense membrane-associated bands with a patchy basal lamina, invaginating cellular protrusions (peg and socket junctions) between ICC and between ICC and muscle cells, and close contacts (<100 nm) between ICC and nerves. No gap junctions were observed. Fibroblast-like cells (FLC) were abundant showing well-developed secretory organelles, including coated vesicles, but lacked prominent intermediate filaments and caveolae. FLC had a patchy basal lamina, and peg and socket junctions were observed between them. Macrophage-like cells frequently occurred in close apposition with FLC and, more seldomly, with ICC-MP. The ultrastructure of ICC and FLC in the myenteric region of the human colon thus differs characteristically, but significant overlaps in the ultrastructure between ICC and FLC might complicate any interpretation in pathological ultrastructural studies of the human colonic muscle layer.
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Effects of excitatory and inhibitory neurotransmission on motor patterns of human sigmoid colon in vitro. Br J Pharmacol 2008; 155:1043-55. [PMID: 18846038 DOI: 10.1038/bjp.2008.332] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND AND PURPOSE To characterize the in vitro motor patterns and the neurotransmitters released by enteric motor neurons (EMNs) in the human sigmoid colon. EXPERIMENTAL APPROACH Sigmoid circular strips were studied in organ baths. EMNs were stimulated by electrical field stimulation (EFS) and through nicotinic ACh receptors. KEY RESULTS Strips developed weak spontaneous rhythmic contractions (3.67+/-0.49 g, 2.54+/-0.15 min) unaffected by the neurotoxin tetrodotoxin (TTX; 1 microM). EFS induced strong contractions during (on, 56%) or after electrical stimulus (off, 44%), both abolished by TTX. Nicotine (1-100 microM) inhibited spontaneous contractions. Latency of off-contractions and nicotine responses were reduced by N(G)-nitro-L-arginine (1 mM) and blocked after further addition of apamin (1 microM) or the P2Y(1) receptor antagonist MRS 2179 (10 microM) and were unaffected by the P2X antagonist NF279 (10 microM) or alpha-chymotrypsin (10 U mL(-1)). Amplitude of on- and off-contractions was reduced by atropine (1 microM) and the selective NK(2) receptor antagonist Bz-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH(2) (1 microM). MRS 2179 reduced the amplitude of EFS on- and off-contractions without altering direct muscular contractions induced by ACh (1 nM-1 mM) or substance P (1 nM-10 microM). CONCLUSIONS AND IMPLICATIONS Latency of EFS-induced off-contractions and inhibition of spontaneous motility by nicotine are caused by stimulation of inhibitory EMNs coreleasing NO and a purine acting at muscular P2Y(1) receptors through apamin-sensitive K(+) channels. EFS-induced on- and off-contractions are caused by stimulation of excitatory EMNs coreleasing ACh and tachykinins acting on muscular muscarinic and NK(2) receptors. Prejunctional P2Y(1) receptors might modulate the activity of excitatory EMNs. P2Y(1) and NK(2) receptors might be therapeutic targets for colonic motor disorders.
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Villanacci V, Bassotti G, Nascimbeni R, Antonelli E, Cadei M, Fisogni S, Salerni B, Geboes K. Enteric nervous system abnormalities in inflammatory bowel diseases. Neurogastroenterol Motil 2008; 20:1009-16. [PMID: 18492026 DOI: 10.1111/j.1365-2982.2008.01146.x] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Various studies have described abnormalities of the enteric nervous system (ENS) in tissue samples from patients with chronic idiopathic inflammatory bowel diseases (IBD). The distribution of density of the different cell types of the ENS was however not studied in a systematic way. The aim of this study was to examine the density of neurons, enteroglial cells and interstitial cells of Cajal (ICC) in the different plexuses of the ENS in samples from patients with Crohn's disease (CD), ulcerative colitis (UC) and controls. Tissue samples from 16 patients with CD (ileum) and 16 patients with UC obtained in involved and non-involved areas were studied using immunohistochemistry with antibodies directed against neuron-specific enolase, S100, C-Kit and CD3. Sections were analysed blindly by two pathologists and the number of positive cells was counted for each type. Overall, an increase was noted for neuronal cell bodies, enteroglia and ICC in the deep muscular plexus in CD. In uninvolved areas of CD patients, the number of enteroglial cells was decreased. In UC, an increase of ICC in the muscularis propria and enteroglial cells was observed in diseased tissue. The study confirms the presence of abnormalities of the different cells of the ENS in IBD. The presence of lesions in samples from uninvolved areas, such as a reduction of enteroglia, supports a pathogenetic role of the ENS.
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Affiliation(s)
- V Villanacci
- 2nd Department of Pathology, Spedali Civili and University of Brescia, Brescia, Italy
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Identification and distribution of interstitial Cajal cells in human pulmonary veins. Heart Rhythm 2008; 5:1063-7. [DOI: 10.1016/j.hrthm.2008.03.057] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2007] [Accepted: 03/27/2008] [Indexed: 01/08/2023]
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Kilic A, Luketich JD, Landreneau RJ, Owens SR, Krasinskas AM, Schuchert MJ. Alterations in the density of interstitial cells of Cajal in achalasia. Dig Dis Sci 2008; 53:1488-92. [PMID: 18030621 DOI: 10.1007/s10620-007-0053-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2007] [Accepted: 09/26/2007] [Indexed: 12/09/2022]
Abstract
The aim of this study was to assess the quantity of interstitial cells of Cajal (ICC) in the lower esophageal sphincter (LES) in achalasia. LES muscle was obtained from 11 achalasia and nine esophageal cancer (control) patients during surgery. Immunohistochemistry was performed and average cell counts per high-power field (HPF) were obtained. Overall, more ICC were observed in achalasia (median = 14.0 cells/HPF; range = 0-22.6 cells/HPF) as compared with controls (median = 6.2 cells/HPF; range = 1.6-10.8 cells/HPF) (P = 0.047). There were two subsets of findings within the achalasia group: 8/11(73%) had an increased quantity of ICC (median = 17.1 cells/HPF; range = 11.6-22.6; P = 0.015) as compared with controls, whereas the remaining 3/11(27%) had a paucity of ICC (median = 0 cells/HPF; range = 0-2; P = 0.02). ICC levels were positively correlated with age of the patient (P = 0.043). Our study demonstrates that subsets of abnormal ICC levels are observed in idiopathic achalasia of the esophagus.
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Affiliation(s)
- Arman Kilic
- Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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Abstract
The gastrointestinal tract serves the physiological function of digesting and absorbing nutrients from food and physically mixing and propelling these contents in an oral to anal direction. These functions require the coordinated interaction of several cell types, including enteric nerves, immune cells and smooth muscle. Interstitial cells of Cajal (ICC) are now recognized as another cell type that are required for the normal functioning of the gastrointestinal tract. Abnormalities in ICC numbers and networks are associated with several gastrointestinal motility disorders. This review will describe what is known about the function and role of ICC both in health and in a variety of motility disorders with a focus on unresolved issues pertaining to their role in the control of gastrointestinal motility.
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Affiliation(s)
- G Farrugia
- Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
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Abstract
The proposed functions of the interstitial cells of Cajal (ICC) are to 1) pace the slow waves and regulate their propagation, 2) mediate enteric neuronal signals to smooth muscle cells, and 3) act as mechanosensors. In addition, impairments of ICC have been implicated in diverse motility disorders. This review critically examines the available evidence for these roles and offers alternate explanations. This review suggests the following: 1) The ICC may not pace the slow waves or help in their propagation. Instead, they may help in maintaining the gradient of resting membrane potential (RMP) through the thickness of the circular muscle layer, which stabilizes the slow waves and enhances their propagation. The impairment of ICC destabilizes the slow waves, resulting in attenuation of their amplitude and impaired propagation. 2) The one-way communication between the enteric neuronal varicosities and the smooth muscle cells occurs by volume transmission, rather than by wired transmission via the ICC. 3) There are fundamental limitations for the ICC to act as mechanosensors. 4) The ICC impair in numerous motility disorders. However, a cause-and-effect relationship between ICC impairment and motility dysfunction is not established. The ICC impair readily and transform to other cell types in response to alterations in their microenvironment, which have limited effects on motility function. Concurrent investigations of the alterations in slow-wave characteristics, excitation-contraction and excitation-inhibition couplings in smooth muscle cells, neurotransmitter synthesis and release in enteric neurons, and the impairment of the ICC are required to understand the etiologies of clinical motility disorders.
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Affiliation(s)
- Sushil K Sarna
- Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, Neuroscience, and Cell Biology, The University of Texas Medical Branch at Gavelston, Galveston, TX 77555-1064, USA.
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Henry GP, Britt DW, Evans MI. Screening Advances and Diagnostic Choice: The Problem of Residual Risk. Fetal Diagn Ther 2008; 23:308-15. [DOI: 10.1159/000123619] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2007] [Accepted: 08/07/2007] [Indexed: 11/19/2022]
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Streutker CJ, Huizinga JD, Driman DK, Riddell RH. Interstitial cells of Cajal in health and disease. Part I: normal ICC structure and function with associated motility disorders. Histopathology 2007; 50:176-89. [PMID: 17222246 DOI: 10.1111/j.1365-2559.2006.02493.x] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Ramon y Cajal (1852-1934) is considered to be one of the founders of the field of neuroscience. In 1911, he described interstitial neurons in the gut, noting that they were primitive accessory components that perhaps modify smooth muscle contraction, themselves subject to regulation from principle neurons. The accuracy of his description of their appearance and activities has led to these cells now being called the interstitial cells of Cajal (ICC). Thuneberg and Faussone-Pellegrini were instrumental in bringing these cells to the attention of gastroenterologists and pathologists in the early 1980s. Subsequently, the development of antibodies to c-kit has allowed routine identification of the ICC in pathology specimens. c-Kit is a transmembrane protein kinase which has as ligand stem cell factor and is involved in cell development in a variety of cell lineages. In the gut musculature, ICC and mast cells are the only cells that have prominent c-kit expression. The ICC are now known to play an important role in gut motility and absent or disordered ICC networks have been identified in a variety of motility disorders.
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Affiliation(s)
- C J Streutker
- Division of Pathology, St Michael's Hospital and University of Toronto, Toronto, Ontario, Canada.
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De Ceulaer KMG, Van Ginneken CJD, Philips WA, Weyns A. Interstitial Cells of Cajal and their Role in Veterinary Gastrointestinal Pathologies. Anat Histol Embryol 2007; 36:300-10. [PMID: 17617109 DOI: 10.1111/j.1439-0264.2007.00766.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
This study highlights the importance of interstitial cells of Cajal (ICs) in gastrointestinal disease. Human research is already considering IC pathologies but in veterinary research IC pathologies are rarely studied. Nevertheless, recent studies of ICs show a growing interest in the pathophysiology of gastrointestinal diseases and emphasize the consideration of this cell type in the pathophysiology of veterinary gastrointestinal malfunctions.
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Affiliation(s)
- K M G De Ceulaer
- Laboratory of Veterinary Anatomy and Embryology, Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Antwerp University, Universiteitsplein 1, 2610 Wilrijk, Belgium.
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Ohlsson B, Veress B, Lindgren S, Sundkvist G. Enteric ganglioneuritis and abnormal interstitial cells of Cajal: features of inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:721-6. [PMID: 17230538 DOI: 10.1002/ibd.20095] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND An increased prevalence of irritable bowel syndrome (IBS) and disturbances in cardiac and blood pressure reflexes have been described in patients with Crohn's disease (CD) and ulcerative colitis (UC). These features could be due to abnormalities in the gastrointestinal neurotransmission. The aims of this study were to examine whether histopathologic changes in the enteric nervous system correlate with disturbances in cardiac and blood pressure reflexes and the occurrence of IBS- and dyspepsia-like symptoms in these patients. METHODS Thirty patients with CD and UC with bowel resection were examined by deep-breathing and orthostatic tests. The resection specimens were evaluated histologically regarding visceral neuro- or myopathy. All medical records were studied for treatment and clinical course. RESULTS Ganglioneuritis was observed in 11 of 19 patients with CD and in 5 of 11 with UC. Only patients with CD had ganglioneuritis in the small intestine. Moreover, in CD the interstitial cells of Cajal (ICCs) in the small bowel showed atrophy and vacuolar degeneration, along with a reduced number of cells (P = 0.005). In UC the colonic ICCs were hyperplastic (P = 0.05) without signs of degeneration. The indices of deep-breathing and orthostatic tests were impaired, except in CD with ganglioneuritis, who showed normal test values. There were no correlations between histopathologic alterations versus IBS and dyspepsia. CONCLUSIONS Visceral ganglioneuritis and pathologic ICCs were observed in patients with CD and UC. However, these histopathologic abnormalities could not be related to the clinical or autonomic features of the disease.
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Affiliation(s)
- Bodil Ohlsson
- Department of Clinical Sciences, Gastroenterology Division, Lund University, Malmö, Sweden.
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