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Kocot N, Pękala E, Koczurkiewicz-Adamczyk P, Chłoń-Rzepa G, Łapa A, Wójcik-Pszczoła K. Airway and cardiovascular remodeling in chronic obstructive pulmonary disease (COPD) as a target for transient receptor potential ankyrin 1 (TRPA1) channel modulators. Bioorg Chem 2025; 158:108301. [PMID: 40058223 DOI: 10.1016/j.bioorg.2025.108301] [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: 11/08/2024] [Revised: 02/06/2025] [Accepted: 02/19/2025] [Indexed: 03/19/2025]
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, which leads to airway remodeling (AR). AR refers to various structural changes occurring in the airway wall, resulting in thickening, and narrowing of the airways. Apart from airways, and lung tissue, pulmonary vasculature also undergoes remodeling. Thus, the pressure in vascular bed is increased, leading to pulmonary hypertension and further right and left ventricle hypertrophy, as well as myocardial fibrosis. Currently, there is lack of effective treatment directly targeting airway and cardiovascular remodeling in the course of COPD. Due to a lot of research showing involvement of transient receptor potential ankyrin 1 (TRPA1) in respiratory disorders, it seems reasonable to consider this ion channel as a molecular target in treatment of remodeling consequences of COPD. The aim of this review is to summarize current knowledge of its role in this case and to identify areas requiring further research. Moreover, we provide few patented structures intended to treat chronic respiratory diseases, which may be worth investigating in the context of airway remodeling.
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Affiliation(s)
- Natalia Kocot
- Jagiellonian University, Doctoral School of Medical and Health Sciences, Łazarza 16, 31-530 Kraków, Poland; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland.
| | - Elżbieta Pękala
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland.
| | - Paulina Koczurkiewicz-Adamczyk
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland.
| | - Grażyna Chłoń-Rzepa
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, Medyczna 9, 30-688 Kraków, Poland.
| | - Aleksandra Łapa
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland.
| | - Katarzyna Wójcik-Pszczoła
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland.
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Li Y, Xu F, Fang Y, Cui Y, Zhu Z, Wu Y, Tong Y, Hu J, Zhu L, Shen H. Inflammation-fibrosis interplay in inflammatory bowel disease: mechanisms, progression, and therapeutic strategies. Front Pharmacol 2025; 16:1530797. [PMID: 40093318 PMCID: PMC11906429 DOI: 10.3389/fphar.2025.1530797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/05/2025] [Indexed: 03/19/2025] Open
Abstract
Background The incidence of intestinal fibrosis in Inflammatory bowel disease has increased in recent years, and the repair process is complex, leading to substantial economic and social burdens. Therefore, understanding the pathogenesis of intestinal fibrosis and exploring potential therapeutic agents is crucial. Purpose This article reviews the pathogenesis of IBD-related intestinal fibrosis, potential therapeutic targets, and the progress of research on Traditional Chinese Medicine (TCM) in inhibiting intestinal fibrosis. It also provides foundational data for developing innovative drugs to prevent intestinal fibrosis. Methods This article reviews the literature from the past decade on advancements in the cellular and molecular mechanisms underlying intestinal fibrosis. Data for this systematic research were obtained from electronic databases including PubMed, CNKI, SciFinder, and Web of Science. Additionally, a comprehensive analysis was conducted on reports regarding the use of TCM for the treatment of intestinal fibrosis. The study synthesizes and summarizes the research findings, presenting key patterns and trends through relevant charts. Results This study reviewed recent advancements in understanding the cellular and molecular mechanisms of intestinal fibrosis, the active ingredients of TCM that inhibit intestinal fibrosis, the efficacy of TCM formulae in preventing intestinal fibrosis, and dietary modification that may contribute to the inhibition of intestinal fibrosis. Conclusion This article examines the cellular and molecular mechanisms that promote the development of intestinal fibrosis, as well as potential therapeutic targets for its treatment. It also provides a theoretical basis for exploring and utilizing TCM resources in the management of intestinal fibrosis. Through the analysis of various TCM medicines, this article underscores the clinical significance and therapeutic potential of TCM and dietary modifications in treating intestinal fibrosis.
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Affiliation(s)
- Yanan Li
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Xu
- Department of Gastroenterology, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastroenterology, The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yulai Fang
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuan Cui
- Department of Gastroenterology, Ningxian second People's Hospital, Qing Yang, China
| | - Zhenxing Zhu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuguang Wu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yiheng Tong
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingyi Hu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Lei Zhu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hong Shen
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Ke BJ, Dragoni G, Matteoli G. Fibroblast Heterogeneity in Inflammatory Bowel Disease. Int J Mol Sci 2024; 25:13008. [PMID: 39684719 DOI: 10.3390/ijms252313008] [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: 07/26/2024] [Revised: 10/15/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Intestinal fibroblasts are pivotal players in maintaining tissue homeostasis and orchestrating responses to injury and inflammation within the gastrointestinal (GI) tract. Fibroblasts contribute significantly to the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC), by secreting pro-inflammatory cytokines, modulating immune cell activity, and promoting fibrosis. In addition, fibroblasts play crucial roles in tissue repair and regeneration following acute injury or chronic inflammation. The dysregulation of fibroblast functions can lead to fibrotic complications, such as intestinal strictures and obstruction, which are common in advanced stages of IBD. Understanding the complex interplay between fibroblasts and other cell types in the intestine is essential to elucidate the underlying mechanisms of intestinal diseases and identify novel therapeutic targets. Future research aimed at deciphering the heterogeneity of intestinal fibroblasts and their dynamic roles in disease progression holds promise for the development of precision therapies to mitigate fibrosis and inflammation in intestinal disorders.
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Affiliation(s)
- Bo-Jun Ke
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium
| | - Gabriele Dragoni
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Gianluca Matteoli
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium
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Matsushita H, Mukudai S, Hashimoto K, Kaneko M, Sugiyama Y, Branski RC, Hirano S. Transient Receptor Potential Ankyrin 1 Channel Alters Transforming Growth Factor Beta 1/Smad Signaling in Rat Vocal Fold Fibroblasts. Laryngoscope 2024; 134:4593-4598. [PMID: 38860441 DOI: 10.1002/lary.31570] [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: 02/14/2024] [Revised: 05/08/2024] [Accepted: 05/29/2024] [Indexed: 06/12/2024]
Abstract
OBJECTIVES Vocal fold scar remains a therapeutic challenge. Vocal fold fibroblasts (VFFs) secrete extracellular matrix (ECM), and transforming growth factor-beta 1 (TGF-β1)-mediated fibroblast to myofibroblast differentiation is central to the development of fibrosis. The transient receptor potential (TRP) channel superfamily is a group of nonselective cation channels, and activation of TRP ankyrin 1 (TRPA1) channel has been shown to have antifibrotic effects through TGF-β1/Smad signaling in various organs. This study aimed to elucidate expression of TRPA1 and the impact of TRPA1 activation on TGF-β1/Smad signaling in VFFs. METHODS Vocal folds were dissected from 10-week-old, male Sprague-Dawley rats and primary VFFs were established. TRPA1 was examined in VFFs and lamina propria via immunostaining. VFFs were treated with allyl isothiocyanate (AITC, TRP channel agonist, 10-5 M) ± TGF-β1 (10 ng/ml) ± A-967079 (selective TRPA1 channel antagonist, 5.0 × 10-7 M) for 4 or 24 h. Trpa1, Smad3, Smad7, Col1a1, Acta2, and Has1 mRNA expression were quantified via qPCR. RESULTS TRPA1 was expressed in cultured VFFs and the lamina propria. TGF-β1 administration significantly increased Trpa1 compared to control. AITC alone did not alter Smad3, Smad7, Acta2, or ECM related genes. However, the combination of AITC and TGF-β1 significantly increased Smad3 and decreased Smad7 and Acta2 compared to TGF-β1 alone; A-967079 significantly reduced this response. CONCLUSIONS VFFs expressed TRPA1, and the activation of TRPA1 regulated TGF-β1/Smad signaling in VFFs. These findings provide preliminary insights into potential anti-fibrotic mechanisms of TRPA1 activation through TGF-β1/Smad signaling in VFFs. LEVEL OF EVIDENCE NA Laryngoscope, 134:4593-4598, 2024.
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Affiliation(s)
- Hiroki Matsushita
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shigeyuki Mukudai
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keiko Hashimoto
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mami Kaneko
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoichiro Sugiyama
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ryan C Branski
- Department of Otolaryngology-Head and Neck Surgery, NYU Grossman School of Medicine, New York, New York, USA
| | - Shigeru Hirano
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Neupane YR, Yogananda TM, Rompicharla SVK, Selaru FM, Ensign LM. Emerging therapeutics for the management of intestinal fibrosis and strictures. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2024; 101:107-139. [PMID: 39521597 DOI: 10.1016/bs.apha.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Chronic intestinal inflammation in patients with inflammatory bowel disease (IBD) can lead to the development of fibrosis and the formation of strictures. Endoscopic balloon dilation and surgical resection are currently the only available treatments for fibrotic strictures. However, both strategies are associated with potential complications and high rates of stricture recurrence, necessitating additional procedures and/or multiple surgical resections. IBD therapeutic modalities aimed at inflammation, including anti-inflammatory agents, such as corticosteroids, biologics and small molecules, have shown limited efficacy in altering the natural history of strictures, ameliorating fibrosis progression, or preventing recurrences. New and innovative therapeutic approaches targeted at fibrosis are urgently needed. Herein, we provide an overview of emerging therapeutics, including novel drug delivery systems, for the management of intestinal fibrosis and strictures.
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Affiliation(s)
- Yub Raj Neupane
- Center for Nanomedicine at the Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Thanuja Marasarakottige Yogananda
- Center for Nanomedicine at the Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Sri Vishnu Kiran Rompicharla
- Center for Nanomedicine at the Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Florin M Selaru
- Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Oncology, Sidney Kimmel Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; The Institute for Nanobiotechnology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Laura M Ensign
- Center for Nanomedicine at the Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Oncology, Sidney Kimmel Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Departments of Gynecology and Obstetrics, Pharmacology and Molecular Sciences, and Medicine (Infectious Diseases), The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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Drygiannakis I, Kolios G, Filidou E, Bamias G, Valatas V. Intestinal Stromal Cells in the Turmoil of Inflammation and Defective Connective Tissue Remodeling in Inflammatory Bowel Disease. Inflamm Bowel Dis 2024; 30:1604-1618. [PMID: 38581412 DOI: 10.1093/ibd/izae066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Indexed: 04/08/2024]
Abstract
In steady state, intestinal subepithelial myofibroblasts form a thin layer below the basement membrane. Unlike the rest of the stromal cells in the lamina propria, they express tensile proteins, guide epithelial regeneration, and sense luminal microbiota. Upon inflammation in inflammatory bowel disease (IBD), they express activation markers, accept trophic signaling by infiltrating neutrophils and macrophages, and are activated by cytokines from helper T cells to produce a narrow spectrum of cytokines and a wider spectrum of chemokines, attract cells of innate and adaptive immunity, orchestrate inflammatory responses, and qualitatively and quantitatively modify the extracellular matrix. Thus, beyond being structural tissue components, they assume active roles in the pathogenesis of complicated IBD. Discrimination between myofibroblasts and fibroblasts may be an oversimplification in light of single-cell sequencing data unveiling the complexity of multiple phenotypes of stromal cells with distinct roles and plasticity. Spatial transcriptomics revealed distinct phenotypes by histologic localization and, more intriguingly, the assembly of mucosal neighborhoods that support spatially distinct functions. Current IBD treatments target inflammation but fail in fibrostenotic or fistulizing disease. Baseline and recent findings on stromal cells, molecules, and pathways involved in disrupted extracellular matrix homeostasis are reviewed to provide relevant pharmacologic targets.
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Affiliation(s)
- Ioannis Drygiannakis
- Gastroenterology Research Laboratory, School of Medicine, University of Crete, Heraklion, Greece
- Gastroenterology Clinic, University Hospital of Heraklion, Heraklion, Greece
| | - George Kolios
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Eirini Filidou
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Giorgos Bamias
- Gastrointestinal Unit, Third Academic Department of Internal Medicine, Sotiria Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Vassilis Valatas
- Gastroenterology Research Laboratory, School of Medicine, University of Crete, Heraklion, Greece
- Gastroenterology Clinic, University Hospital of Heraklion, Heraklion, Greece
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Coppola G, Principessa C, Di Vincenzo F, Puca P, Del Gaudio A, Capobianco I, Bartocci B, Papa A, Cammarota G, Lopetuso LR, Scaldaferri F. Endoscopic Management of Strictures in Crohn's Disease: An Unsolved Case. J Clin Med 2024; 13:4842. [PMID: 39200984 PMCID: PMC11355190 DOI: 10.3390/jcm13164842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/07/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory disease associated with a significant burden in terms of quality of life and health care costs. It is frequently associated with several complications, including the development of intestinal strictures. Stricturing CD requires a careful multidisciplinary approach involving medical therapy and surgery, still posing a continuous management challenge; in this context, endoscopic treatment represents a valuable, in-between opportunity as a minimally invasive strategy endorsed by extensive yet heterogeneous evidence and evolving research and techniques. This review summarizes current knowledge on the role of therapeutic endoscopy in stricturing CD, focusing on evidence gaps, recent updates, and novel techniques intended for optimizing efficacy, safety, and tailoring of this approach in the view of precision endoscopy.
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Affiliation(s)
- Gaetano Coppola
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Chiara Principessa
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Federica Di Vincenzo
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Pierluigi Puca
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Angelo Del Gaudio
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Ivan Capobianco
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Bianca Bartocci
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Alfredo Papa
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Giovanni Cammarota
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Loris Riccardo Lopetuso
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Dipartimento di Medicina e Scienze dell’Invecchiamento, Università degli Studi “G. D’Annunzio”, 66100 Chieti, Italy
| | - Franco Scaldaferri
- CEMAD—IBD Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy (I.C.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
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Dvornikova KA, Platonova ON, Bystrova EY. The Role of TRP Channels in Sepsis and Colitis. Int J Mol Sci 2024; 25:4784. [PMID: 38731999 PMCID: PMC11084600 DOI: 10.3390/ijms25094784] [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: 03/31/2024] [Revised: 04/20/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
To date, several members of the transient receptor potential (TRP) channels which provide a wide array of roles have been found in the gastrointestinal tract (GI). The goal of earlier research was to comprehend the intricate signaling cascades that contribute to TRP channel activation as well as how these receptors' activity affects other systems. Moreover, there is a large volume of published studies describing the role of TRP channels in a number of pathological disorders, including inflammatory bowel disease (IBD) and sepsis. Nevertheless, the generalizability of these results is subject to certain limitations. For instance, the study of IBD relies on various animal models and experimental methods, which are unable to precisely imitate the multifactorial chronic disease. The diverse pathophysiological mechanisms and unique susceptibility of animals may account for the inconsistency of the experimental data collected. The main purpose of this study was to conduct a comprehensive review and analysis of existing studies on transient receptor potential (TRP) channels implicating specific models of colitis and sepsis, with particular emphasis on their involvement in pathological disorders such as IBD and sepsis. Furthermore, the text endeavors to evaluate the generalizability of experimental findings, taking into consideration the limitations posed by animal models and experimental methodologies. Finally, we also provide an updated schematic of the most important and possible molecular signaling pathways associated with TRP channels in IBD and sepsis.
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Affiliation(s)
| | | | - Elena Y. Bystrova
- I.P. Pavlov Institute of Physiology RAS, 199034 St. Petersburg, Russia; (K.A.D.); (O.N.P.)
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Yang B, Ma D, Zhu X, Wu Z, An Q, Zhao J, Gao X, Zhang L. Roles of TRP and PIEZO receptors in autoimmune diseases. Expert Rev Mol Med 2024; 26:e10. [PMID: 38659380 PMCID: PMC11140548 DOI: 10.1017/erm.2023.23] [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: 01/31/2023] [Revised: 04/15/2023] [Accepted: 08/21/2023] [Indexed: 04/26/2024]
Abstract
Autoimmune diseases are pathological autoimmune reactions in the body caused by various factors, which can lead to tissue damage and organ dysfunction. They can be divided into organ-specific and systemic autoimmune diseases. These diseases usually involve various body systems, including the blood, muscles, bones, joints and soft tissues. The transient receptor potential (TRP) and PIEZO receptors, which resulted in David Julius and Ardem Patapoutian winning the Nobel Prize in Physiology or Medicine in 2021, attracted people's attention. Most current studies on TRP and PIEZO receptors in autoimmune diseases have been carried out on animal model, only few clinical studies have been conducted. Therefore, this study aimed to review existing studies on TRP and PIEZO to understand the roles of these receptors in autoimmune diseases, which may help elucidate novel treatment strategies.
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Affiliation(s)
- Baoqi Yang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Dan Ma
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Xueqing Zhu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Zewen Wu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Qi An
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Jingwen Zhao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Xinnan Gao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Liyun Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
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10
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Wang Q, Ji C, Smith P, McCulloch CA. Impact of TRP Channels on Extracellular Matrix Remodeling: Focus on TRPV4 and Collagen. Int J Mol Sci 2024; 25:3566. [PMID: 38612378 PMCID: PMC11012046 DOI: 10.3390/ijms25073566] [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: 02/18/2024] [Revised: 03/11/2024] [Accepted: 03/18/2024] [Indexed: 04/14/2024] Open
Abstract
Disturbed remodeling of the extracellular matrix (ECM) is frequently observed in several high-prevalence pathologies that include fibrotic diseases of organs such as the heart, lung, periodontium, liver, and the stiffening of the ECM surrounding invasive cancers. In many of these lesions, matrix remodeling mediated by fibroblasts is dysregulated, in part by alterations to the regulatory and effector systems that synthesize and degrade collagen, and by alterations to the functions of the integrin-based adhesions that normally mediate mechanical remodeling of collagen fibrils. Cell-matrix adhesions containing collagen-binding integrins are enriched with regulatory and effector systems that initiate localized remodeling of pericellular collagen fibrils to maintain ECM homeostasis. A large cadre of regulatory molecules is enriched in cell-matrix adhesions that affect ECM remodeling through synthesis, degradation, and contraction of collagen fibrils. One of these regulatory molecules is Transient Receptor Potential Vanilloid-type 4 (TRPV4), a mechanically sensitive, Ca2+-permeable plasma membrane channel that regulates collagen remodeling. The gating of Ca2+ across the plasma membrane by TRPV4 and the consequent generation of intracellular Ca2+ signals affect several processes that determine the structural and mechanical properties of collagen-rich ECM. These processes include the synthesis of new collagen fibrils, tractional remodeling by contractile forces, and collagenolysis. While the specific mechanisms by which TRPV4 contributes to matrix remodeling are not well-defined, it is known that TRPV4 is activated by mechanical forces transmitted through collagen adhesion receptors. Here, we consider how TRPV4 expression and function contribute to physiological and pathological collagen remodeling and are associated with collagen adhesions. Over the long-term, an improved understanding of how TRPV4 regulates collagen remodeling could pave the way for new approaches to manage fibrotic lesions.
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Affiliation(s)
- Qin Wang
- Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
| | - Chenfan Ji
- Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Patricio Smith
- Faculty of Medicine, Pontifical Catholic University of Chile, Santiago 8320165, Chile;
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Xu F, Jiang H, Li X, Pan J, Li H, Wang L, Zhang P, Chen J, Qiu S, Xie Y, Li Y, Zhang D, Dong Z. Discovery of PRDM16-Mediated TRPA1 Induction as the Mechanism for Low Tubulo-Interstitial Fibrosis in Diabetic Kidney Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306704. [PMID: 38072665 PMCID: PMC10870028 DOI: 10.1002/advs.202306704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/03/2023] [Indexed: 02/17/2024]
Abstract
The pathogenesis of Diabetic kidney disease(DKD) involves pathological changes in both tubulo-interstitium and the glomerulus. Surprisingly, tubulo-interstitial fibrosis (TIF), does not develop significantly until the late stage of DKD. Here, it is demonstrated that PR domain-containing 16 (PRDM16) is a key to the low level of TIF in DKD. In the experiments, PRDM16 is upregulated in high glucose-treated renal tubular cells, DKD mouse kidneys, and renal biopsy of human DKD patients via activation of NF-κB signal pathway. High glucose-induced expression of fibrotic proteins in renal tubular cells is suppressed by PRDM16. Mechanistically, PRDM16 bound to the promotor region of Transient receptor potential ankyrin 1 (TRPA1) to transactivate its expression and then suppressed MAPK (P38, ERK1/2) activation and downstream expression of TGF-β1. Knockout of PRDM16 from kidney proximal tubules in mice blocked TRPA1 expression and enhanced MAPK activation, TGF-β1 production, TIF development, and DKD progression, whereas knock-in of PRDM16 has opposite effects. In addition, overexpression of PRDM16 or its induction by formononetin ameliorated renal dysfunction and fibrosis in db/db diabetic mice. Finally, the above finding are detected in renal biopsies of DKD patients. Together, these results unveil PRDM16/TRPA1 as the mechanism responsible for the low level of TIF in the early stage of DKD by suppressing and TGF-β1 expression.
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Affiliation(s)
- Fang Xu
- Department of Emergency MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Emergency Medicine and Difficult Diseases InstituteSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Department of NephrologySecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Hongwei Jiang
- Department of EndocrinologyFirst Affiliated Hospital of Henan University of Science and TechnologyLuoyangHenan471000P. R. China
| | - Xiaozhou Li
- Department of Emergency MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Emergency Medicine and Difficult Diseases InstituteSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Jian Pan
- Department of Emergency MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Emergency Medicine and Difficult Diseases InstituteSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Huiling Li
- Department of OphthalmologyCentral South UniversityChangshaHunan410011P. R. China
| | - Luxiang Wang
- Department of Emergency MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Emergency Medicine and Difficult Diseases InstituteSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Pan Zhang
- Department of Emergency MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Emergency Medicine and Difficult Diseases InstituteSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Department of Epidemiology and Health StatisticsXiangya School of Public HealthCentral South UniversityChangshaHunan410011P. R. China
| | - Junxiang Chen
- Department of NephrologySecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Shuangfa Qiu
- Department of Emergency MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Emergency Medicine and Difficult Diseases InstituteSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Yuxin Xie
- Department of Emergency MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Emergency Medicine and Difficult Diseases InstituteSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Yijian Li
- Department of UrologySecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Dongshan Zhang
- Department of Emergency MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Emergency Medicine and Difficult Diseases InstituteSecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Department of NephrologySecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Department of EndocrinologyFirst Affiliated Hospital of Henan University of Science and TechnologyLuoyangHenan471000P. R. China
| | - Zheng Dong
- Department of NephrologySecond Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
- Department of Cellular Biology and AnatomyMedical College of Georgia at Augusta UniversityAugustaGeorgia30906USA
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Nakamoto T, Matsumoto K, Yasuda H, Mori Y, Kato S. Transient receptor potential melastatin 2 is involved in trinitrobenzene sulfonic acid-induced acute and chronic colitis-associated fibrosis progression in mice. J Pharmacol Sci 2024; 154:18-29. [PMID: 38081680 DOI: 10.1016/j.jphs.2023.11.004] [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: 08/30/2023] [Revised: 11/02/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Crohn's disease, a chronic and recurrent gastrointestinal disease, frequently causes intestinal fibrosis. Transient receptor potential melastatin 2 (TRPM2), a non-selective cation channel, is activated by reactive oxygen species. This study investigated the role of TRPM2 in acute colitis and chronic colitis-associated fibrosis progression. Acute colitis and chronic colitis-associated fibrosis were induced in TRPM2-deficient (TRPM2KO) and wild-type (WT) mice through single and repeated intrarectal injections of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Bone marrow-derived macrophages (BMDMs) from WT and TRPM2KO mice were stimulated using H2O2. In WT mice, a single TNBS injection induced acute colitis with upregulated inflammatory cytokines/chemokines and Th1/Th17-related cytokines, while repeated TNBS injections induced chronic colitis-associated fibrosis with upregulation of fibrogenic factors and Th2-related cytokines. Acute colitis and chronic colitis-associated fibrosis with cytokines/chemokine upregulation and fibrogenic factors were considerably suppressed in TRPM2KO mice. Treating BMDMs with H2O2 increased cytokine/chemokine expression and JNK, ERK, and p38 phosphorylation; however, these responses were significantly less in TRPM2KO than in WT mice. These findings suggest that TRPM2 contributes to acute colitis progression via Th1/Th17-mediated immune responses. Furthermore, TRPM2 may be directly involved in colitis-associated fibrosis induction, likely due to the regulation of Th2/TGF-β1-mediated fibrogenesis in addition to a consequence of acute colitis progression.
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Affiliation(s)
- Tomohiro Nakamoto
- Division of Pathological Science, Laboratory of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Kenjiro Matsumoto
- Division of Pathological Science, Laboratory of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Hiroyuki Yasuda
- Division of Pathological Science, Laboratory of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Yasuo Mori
- Department of Synthetic Chemistry and Biological Chemistry, Graduate of Engineering, Kyoto University, Kyoto, Japan
| | - Shinichi Kato
- Division of Pathological Science, Laboratory of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
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13
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Imamura T, Ogawa T, Minagawa T, Daimon H, Nagai T, Ueno M, Saito T, Ishizuka O. Transient receptor potential ankyrin 1 channels in the bladder mediate low temperature elicited bladder overactivity in rats. Neurourol Urodyn 2024; 43:276-288. [PMID: 38010891 DOI: 10.1002/nau.25335] [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: 06/21/2023] [Revised: 10/13/2023] [Accepted: 11/08/2023] [Indexed: 11/29/2023]
Abstract
AIMS This study aimed to investigate whether pathways involving transient receptor potential ankyrin 1 (TRPA1) channels in the urinary bladder mediate the bladder overactivity elicited by exposure to a low temperature in rats. METHODS At postnatal week 10, female Sprague-Dawley (SD) rats were intraperitoneally injected with the TRPA1 channel antagonist, HC030031, at room temperature (RT) and subsequently exposed to low temperature (LT). Bladder specimens treated with HC030031 were evaluated for contractions through cumulative addition of the TRPA1 channel agonist trans-cinnamaldehyde. Two days before cystometric investigation, small interfering RNA (siRNA) targeting TRPA1 was transfected into urinary bladders. Then, cystometric investigations were performed on rats subjected to TRPA1 siRNA transfection at both RT and LT. Expression of TRPA1 channels in the urinary bladder was assessed through immunohistochemistry and real-time reverse transcription-polymerase chain reaction. RESULTS At RT, micturition patterns were unaffected by HC030031 treatment. However, upon exposure to LT, rats treated with HC030031 exhibited a reduction of LT-elicited bladder overactivity, as evidenced by inhibited decreases in voiding interval, micturition volume, and bladder capacity. Additionally, HC030031 inhibited trans-cinnamaldehyde-induced contractions. Immunohistochemical analysis showed the presence of TRPA1 channels in the urinary bladder. Notably, rats with TRPA1 siRNA-transfected bladders could partially inhibit bladder overactivity during LT exposure. CONCLUSIONS These findings indicate that pathways involving TRPA1 channels expressed in the urinary bladder could mediate the LT-elicited bladder overactivity.
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Affiliation(s)
- Tetsuya Imamura
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Teruyuki Ogawa
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Tomonori Minagawa
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Hironori Daimon
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Takashi Nagai
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Manabu Ueno
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Tetsuichi Saito
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Osamu Ishizuka
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
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Li X, Yu M, Zhao Q, Yu Y. Prospective therapeutics for intestinal and hepatic fibrosis. Bioeng Transl Med 2023; 8:e10579. [PMID: 38023697 PMCID: PMC10658571 DOI: 10.1002/btm2.10579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/17/2023] [Accepted: 07/12/2023] [Indexed: 12/01/2023] Open
Abstract
Currently, there are no effective therapies for intestinal and hepatic fibrosis representing a considerable unmet need. Breakthroughs in pathogenesis have accelerated the development of anti-fibrotic therapeutics in recent years. Particularly, with the development of nanotechnology, the harsh environment of the gastrointestinal tract and inaccessible microenvironment of fibrotic lesions seem to be no longer considered a great barrier to the use of anti-fibrotic drugs. In this review, we comprehensively summarize recent preclinical and clinical studies on intestinal and hepatic fibrosis. It is found that the targets for preclinical studies on intestinal fibrosis is varied, which could be divided into molecular, cellular, and tissues level, although little clinical trials are ongoing. Liver fibrosis clinical trials have focused on improving metabolic disorders, preventing the activation and proliferation of hepatic stellate cells, promoting the degradation of collagen, and reducing inflammation and cell death. At the preclinical stage, the therapeutic strategies have focused on drug targets and delivery systems. At last, promising remedies to the current challenges are based on multi-modal synergistic and targeted delivery therapies through mesenchymal stem cells, nanotechnology, and gut-liver axis providing useful insights into anti-fibrotic strategies for clinical use.
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Affiliation(s)
- Xin Li
- Department of Clinical Pharmacy, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Institute of Pharmaceutics, College of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - Mengli Yu
- Department of Gastroenterology, The Fourth Affiliated HospitalZhejiang University School of MedicineYiwuChina
| | - Qingwei Zhao
- Department of Clinical Pharmacy, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yang Yu
- College of Pharmaceutical SciencesSouthwest UniversityChongqingChina
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15
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Zhao M, Ding N, Wang H, Zu S, Liu H, Wen J, Liu J, Ge N, Wang W, Zhang X. Activation of TRPA1 in Bladder Suburothelial Myofibroblasts Counteracts TGF-β1-Induced Fibrotic Changes. Int J Mol Sci 2023; 24:ijms24119501. [PMID: 37298451 DOI: 10.3390/ijms24119501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/15/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
The activation of the transient receptor potential ankyrin 1 (TRPA1) channel has anti-fibrotic effects in the lung and intestine. Suburothelial myofibroblasts (subu-MyoFBs), a specialized subset of fibroblasts in the bladder, are known to express TRPA1. However, the role of the TRPA1 in the development of bladder fibrosis remains elusive. In this study, we use the transforming growth factor-β1 (TGF-β1) to induce fibrotic changes in subu-MyoFBs and assess the consequences of TRPA1 activation utilizing RT-qPCR, western blotting, and immunocytochemistry. TGF-β1 stimulation increased α-SMA, collagen type I alpha 1 chain(col1A1), collagen type III (col III), and fibronectin expression, while simultaneously suppressing TRPA1 in cultured human subu-MyoFBs. The activation of TRPA1, with its specific agonist allylisothiocyanate (AITC), inhibited TGF-β1-induced fibrotic changes, and part of these inhibition effects could be reversed by the TRPA1 antagonist, HC030031, or by reducing TRPA1 expression via RNA interference. Furthermore, AITC reduced spinal cord injury-induced fibrotic bladder changes in a rat model. The increased expression of TGF-β1, α-SMA, col1A1 and col III, and fibronectin, and the downregulation of TRPA1, were also detected in the mucosa of fibrotic human bladders. These findings suggest that TRPA1 plays a pivotal role in bladder fibrosis, and the negative cross talk between TRPA1 and TGF-β1 signaling may represent one of the mechanisms underlying fibrotic bladder lesions.
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Affiliation(s)
- Mengmeng Zhao
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Ning Ding
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Haoyu Wang
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Shulu Zu
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Hanwen Liu
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Jiliang Wen
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Jiaxin Liu
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Nan Ge
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Wenzhen Wang
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Xiulin Zhang
- Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
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16
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Solitano V, Dal Buono A, Gabbiadini R, Wozny M, Repici A, Spinelli A, Vetrano S, Armuzzi A. Fibro-Stenosing Crohn's Disease: What Is New and What Is Next? J Clin Med 2023; 12:jcm12093052. [PMID: 37176493 PMCID: PMC10179180 DOI: 10.3390/jcm12093052] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 04/03/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
Fibro-stenosing Crohn's disease (CD) is a common disease presentation that leads to impaired quality of life and often requires endoscopic treatments or surgery. From a pathobiology perspective, the conventional view that intestinal fibro-stenosis is an irreversible condition has been disproved. Currently, there are no existing imaging techniques that can accurately quantify the amount of fibrosis within a stricture, and managing patients is challenging, requiring a multidisciplinary team. Novel therapies targeting different molecular components of the fibrotic pathways are increasing regarding other diseases outside the gut. However, a large gap between clinical need and the lack of anti-fibrotic agents in CD remains. This paper reviews the current state of pathobiology behind fibro-stenosing CD, provides an updated diagnostic and therapeutic approach, and finally, focuses on clinical trial endpoints and possible targets of anti-fibrotic therapies.
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Affiliation(s)
- Virginia Solitano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Division of Gastroenterology, Department of Medicine, Western University, London, ON N6A 4V2, Canada
| | - Arianna Dal Buono
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Roberto Gabbiadini
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Marek Wozny
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Department of Endoscopy, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Division of Colon and Rectal Surgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Stefania Vetrano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Alessandro Armuzzi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
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17
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Geiger F, Zeitlmayr S, Staab-Weijnitz CA, Rajan S, Breit A, Gudermann T, Dietrich A. An Inhibitory Function of TRPA1 Channels in TGF-β1-driven Fibroblast-to-Myofibroblast Differentiation. Am J Respir Cell Mol Biol 2023; 68:314-325. [PMID: 36378826 DOI: 10.1165/rcmb.2022-0159oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
TRPA1 (transient receptor potential ankyrin 1) is a nonselective Ca2+-permeable cation channel, which was originally cloned from human lung fibroblasts (HLFs). TRPA1-mediated Ca2+ entry is evoked by exposure to several chemicals, including allyl isothiocyanate (AITC), and a protective effect of TRPA1 activation in the development of cardiac fibrosis has been proposed. Yet the function of TRPA1 in TGF-β1 (transforming growth factor-β1)-driven fibroblast-to-myofibroblast differentiation and the development of pulmonary fibrosis remains elusive. TRPA1 expression and function were analyzed in cultured primary HLFs, and mRNA concentrations were significantly reduced after adding TGF-β1. Expression of genes encoding fibrosis markers (e.g., ACTA2, SERPINE1 [plasminogen activator inhibitor 1], FN1 [fibronectin], COL1A1 [type I collagen]) was increased after siRNA-mediated downregulation of TRPA1 mRNA in HLFs. Moreover, AITC-induced Ca2+ entry in HLFs was decreased after TGF-β1 treatment and by application of TRPA1 siRNAs, while AITC treatment alone did not reduce cell viability or enhance apoptosis. Most interestingly, AITC-induced TRPA1 activation augmented ERK1/2 (extracellular signal-regulated kinase 1/2) and SMAD2 linker phosphorylation, which might inhibit TGF-β-receptor signaling. Our results suggest an inhibitory function of TRPA1 channels in TGF-β1-driven fibroblast-to-myofibroblast differentiation. Therefore, activation of TRPA1 channels might be protective during the development of pulmonary fibrosis in patients.
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Affiliation(s)
- Fabienne Geiger
- Walther Straub Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research, Ludwig-Maximilians-University Munich, Munich, Germany, and
| | - Sarah Zeitlmayr
- Walther Straub Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research, Ludwig-Maximilians-University Munich, Munich, Germany, and
| | - Claudia A Staab-Weijnitz
- Comprehensive Pneumology Center with the CPC-M BioArchive and Institute of Lung Health and Immunity, Helmholtz Center Munich, Member of the German Center for Lung Research, Munich, Germany
| | - Suhasini Rajan
- Walther Straub Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research, Ludwig-Maximilians-University Munich, Munich, Germany, and
| | - Andreas Breit
- Walther Straub Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research, Ludwig-Maximilians-University Munich, Munich, Germany, and
| | - Thomas Gudermann
- Walther Straub Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research, Ludwig-Maximilians-University Munich, Munich, Germany, and
| | - Alexander Dietrich
- Walther Straub Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research, Ludwig-Maximilians-University Munich, Munich, Germany, and
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18
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Liu L, Xu M, Zhang Z, Qiao Z, Tang Z, Wan F, Lan L. TRPA1 protects mice from pathogenic Citrobacter rodentium infection via maintaining the colonic epithelial barrier function. FASEB J 2023; 37:e22739. [PMID: 36583647 DOI: 10.1096/fj.202200483rrr] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 12/07/2022] [Accepted: 12/16/2022] [Indexed: 12/31/2022]
Abstract
Transient receptor potential ankyrin 1 (TRPA1) is expressed in gastrointestinal tract and plays important roles in intestinal motility and visceral hypersensitivity. However, the potential role of TRPA1 in host defense, particularly against intestinal pathogens, is unknown. Here, we show that Trpa1 knockout mice exhibited increased susceptibility to Citrobacter rodentium infection, associated with the increased severity of diarrhea and intestinal permeability associated with the disrupted tight junctions (TJs) in colonic epithelia. We further demonstrated the expression of TRPA1 in murine colonic epithelial cells (CECs) and human epithelial Caco-2 cells both at protein level and transcription level. Using calcium imaging, TRPA1 agonists allyl isothiocyanates (AITC) and hydrogen peroxide were observed to induce a transient Ca2+ response in Caco-2 cells, respectively. Moreover, TRPA1 knockdown in Caco-2 cells resulted in the decreased expression of TJ proteins, ZO-1 and Occludin, and in the increased paracellular permeabilities and the reduced TEER values of Caco-2 monolayers in vitro. Furthermore, inhibition of TRPA1 by HC-030031 in the confluent Caco-2 cells caused the altered distribution and expression of TJ proteins, ZO-1, Occludin, and Claudin-3, and exacerbated the bacterial endotoxin lipopolysaccharide (LPS)-induced damage to these TJ proteins and actin cytoskeleton. By contrast, AITC pretreatment restored the distribution and expression of these TJ proteins in the confluent Caco-2 cells upon LPS challenge. Our results identify an unrecognized protective role of TRPA1 in host defense against an enteric bacterial pathogen by maintaining colonic epithelium barrier function, at least in part, via preserving the distribution and expression of TJ proteins in CECs.
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Affiliation(s)
- Lin Liu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, PR China
| | - Min Xu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, PR China
| | - Zhudi Zhang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, PR China
| | - Zhao Qiao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, PR China
| | - Zongxiang Tang
- Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, School of medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, PR China
| | - Fengyi Wan
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Lei Lan
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, PR China
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19
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Wei Y, Cai J, Zhu R, Xu K, Li H, Li J. Function and therapeutic potential of transient receptor potential ankyrin 1 in fibrosis. Front Pharmacol 2022; 13:1014041. [PMID: 36278189 PMCID: PMC9582847 DOI: 10.3389/fphar.2022.1014041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/26/2022] [Indexed: 11/18/2022] Open
Abstract
The transient receptor potential (TRP) protein superfamily is a special group of cation channels expressed in different cell types and signaling pathways. In this review, we focus on TRPA1 (transient receptor potential ankyrin 1), an ion channel in this family that exists in the cell membrane and shows a different function from other TRP channels. TRPA1 usually has a special activation effect that can induce cation ions, especially calcium ions, to flow into activated cells. In this paper, we review the role of TRPA1 in fibroblasts. To clarify the relationship between fibroblasts and TRPA1, we have also paid special attention to the interactions between TRPA1 and inflammatory factors leading to fibroblast activation. TRPA1 has different functions in the fibrosis process in different organs, and there have also been interesting discussions of the mechanism of TRPA1 in fibroblasts. Therefore, this review aims to describe the function of TRP channels in controlling fibrosis through fibroblasts in different organ inflammatory and immune-mediated diseases. We attempt to prove that TRPA1 is a target for fibrosis. In fact, some clinical trials have already proven that TRPA1 is a potential adjuvant therapy for treating fibrosis.
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Affiliation(s)
- Yicheng Wei
- Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital, Wenzhou, China
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jialuo Cai
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Ruiqiu Zhu
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ke Xu
- Musculoskeletal Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai, China
- Wenzhou Institute of Shanghai University, Wenzhou, China
- *Correspondence: Ke Xu, , ; Hongchang Li, ; Jianxin Li,
| | - Hongchang Li
- Department of General Surgery, Institute of Fudan–Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China
- *Correspondence: Ke Xu, , ; Hongchang Li, ; Jianxin Li,
| | - Jianxin Li
- Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital, Wenzhou, China
- *Correspondence: Ke Xu, , ; Hongchang Li, ; Jianxin Li,
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Activation of pancreatic stellate cells attenuates intracellular Ca 2+ signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites. Cell Death Dis 2022; 13:744. [PMID: 36038551 PMCID: PMC9421659 DOI: 10.1038/s41419-022-05186-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 08/05/2022] [Accepted: 08/12/2022] [Indexed: 01/21/2023]
Abstract
Alcohol abuse, an increasing problem in developed societies, is one of the leading causes of acute and chronic pancreatitis. Alcoholic pancreatitis is often associated with fibrosis mediated by activated pancreatic stellate cells (PSCs). Alcohol toxicity predominantly depends on its non-oxidative metabolites, fatty acid ethyl esters, generated from ethanol and fatty acids. Although the role of non-oxidative alcohol metabolites and dysregulated Ca2+ signalling in enzyme-storing pancreatic acinar cells is well established as the core mechanism of pancreatitis, signals in PSCs that trigger fibrogenesis are less clear. Here, we investigate real-time Ca2+ signalling, changes in mitochondrial potential and cell death induced by ethanol metabolites in quiescent vs TGF-β-activated PSCs, compare the expression of Ca2+ channels and pumps between the two phenotypes and the consequences these differences have on the pathogenesis of alcoholic pancreatitis. The extent of PSC activation in the pancreatitis of different aetiologies has been investigated in three animal models. Unlike biliary pancreatitis, alcohol-induced pancreatitis results in the activation of PSCs throughout the entire tissue. Ethanol and palmitoleic acid (POA) or palmitoleic acid ethyl ester (POAEE) act directly on quiescent PSCs, inducing cytosolic Ca2+ overload, disrupting mitochondrial functions, and inducing cell death. However, activated PSCs acquire remarkable resistance against ethanol metabolites via enhanced Ca2+-handling capacity, predominantly due to the downregulation of the TRPA1 channel. Inhibition or knockdown of TRPA1 reduces EtOH/POA-induced cytosolic Ca2+ overload and protects quiescent PSCs from cell death, similarly to the activated phenotype. Our results lead us to review current dogmas on alcoholic pancreatitis. While acinar cells and quiescent PSCs are prone to cell death caused by ethanol metabolites, activated PSCs can withstand noxious signals and, despite ongoing inflammation, deposit extracellular matrix components. Modulation of Ca2+ signals in PSCs by TRPA1 agonists/antagonists could become a strategy to shift the balance of tissue PSCs towards quiescent cells, thus limiting pancreatic fibrosis.
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21
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Kuronuma K, Otsuka M, Wakabayashi M, Yoshioka T, Kobayashi T, Kameda M, Morioka Y, Chiba H, Takahashi H. Role of transient receptor potential vanilloid 4 in therapeutic anti-fibrotic effects of pirfenidone. Am J Physiol Lung Cell Mol Physiol 2022; 323:L193-L205. [PMID: 35787697 DOI: 10.1152/ajplung.00565.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal lung disorder characterized by aberrant extracellular matrix deposition in the interstitium. Pirfenidone is an anti-fibrotic agent used to treat patients with IPF. Pirfenidone shows a pleiotropic mode of action, but its underlying anti-fibrotic mechanism is unclear. Transient receptor potential vanilloid 4 (TRPV4), which is a mechanosensitive calcium channel, was recently shown to be related to pulmonary fibrosis. To clarify the anti-fibrotic mechanisms of pirfenidone, we investigated whether TRPV4 blockade has a pharmacological effect in a murine model of pulmonary fibrosis and whether pirfenidone contributes to suppression of TRPV4. Our synthetic TRPV4 antagonist and pirfenidone treatment attenuated lung injury in the bleomycin mouse model. TRPV4-mediated increases in intracellular calcium were inhibited by pirfenidone. Additionally, TRPV4-stimulated interleukin-8 release from cells was reduced and a delay in cell migration was abolished by pirfenidone. Furthermore, pirfenidone decreased TRPV4 endogenous ligands in bleomycin-administered mouse lungs and their production by microsomes of human lungs. We found TRPV4 expression in the bronchiolar and alveolar epithelium and activated fibroblasts of the lungs in patients with IPF. Finally, we showed that changes in forced vital capacity of patients with IPF treated with pirfenidone were significantly correlated with metabolite levels of TRPV4 endogenous ligands in bronchoalveolar lavage fluid. These results suggest that the anti-fibrotic action of pirfenidone is partly mediated by TRPV4 and that TRPV4 endogenous ligands in bronchoalveolar lavage fluid may be biomarkers for distinguishing responders to pirfenidone.
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Affiliation(s)
- Koji Kuronuma
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Mitsuo Otsuka
- Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo, Japan
| | - Masato Wakabayashi
- Translational Research Unit, Biomarker R&D Department, Shionogi Co., Ltd., Osaka, Japan
| | - Takeshi Yoshioka
- Translational Research Unit, Biomarker R&D Department, Shionogi Co., Ltd., Osaka, Japan
| | - Tomofumi Kobayashi
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masami Kameda
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yasuhide Morioka
- Drug Discovery and Disease Research Laboratory, Shionogi Co., Ltd., Osaka, Japan
| | - Hirofumi Chiba
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroki Takahashi
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
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22
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Du Y, Chen J, Shen L, Wang B. TRP channels in inflammatory bowel disease: potential therapeutic targets. Biochem Pharmacol 2022; 203:115195. [DOI: 10.1016/j.bcp.2022.115195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 12/23/2022]
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Hirano S, Higashimori A, Nagami Y, Nadatani Y, Tanigawa T, Ominami M, Fukunaga S, Otani K, Hosomi S, Tanaka F, Kamata N, Taira K, Watanabe T, Fujiwara Y. Pirfenidone prevents esophageal stricture by inhibiting nucleotide binding oligomerization domain like receptor protein 3 inflammasome activation. J Gastroenterol Hepatol 2022; 37:1096-1106. [PMID: 35434849 DOI: 10.1111/jgh.15861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 03/21/2022] [Accepted: 04/11/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Esophageal injury often results in a scar, leading to refractory strictures. The NLRP3 inflammasome activates caspase-1, causing the maturation of interleukin (IL)-1β. Here, we aimed to investigate the preventive effect of pirfenidone (PFD), an antifibrotic drug, on esophageal stricture after ulcer healing and studied its mechanism by focusing on the activation of the NLRP3 inflammasome. METHODS Esophageal ulcers were induced in rats via the local application of acetic acid in the serosa. PFD was intraperitoneally administered to the rats 3 days after ulcer induction. The effect of PFD on esophageal stricture after ulcer healing was assessed by esophagography on day 9. The protein levels of mature caspase-1 and IL-1β were assessed by western blotting. RESULTS The ulcers fully developed 3 days after induction and were almost scarred by day 9 with severe strictures. PFD promoted ulcer healing and attenuated fibrotic collagen in the submucosa by suppressing the increase in NLRP3, cleaved caspase-1, and mature IL-1β expression, improving stricture rate (PFD vs vehicle = 55% vs 81%). Exogenous IL-1β abolished the therapeutic effects of PFD on ulcer healing and stricture formation. Furthermore, NLRP3 and caspase-1 inhibitors mimicked the effects of PFD on ulcer healing and stricture formation, with suppression of the increase in cleaved caspase-1 and mature IL-1β proteins and expression of fibrosis-related molecules including transforming growth factor (TGF)-β1. CONCLUSION The NLRP3 inflammasome promotes esophageal stricture formation following ulcer healing, and PFD exerts potential prophylactic activity against strictures, possibly via the inhibition of the NLRP3/IL-1β/TGF-β1 axis.
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Affiliation(s)
- Shinji Hirano
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akira Higashimori
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuji Nadatani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Premier Preventive Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tetsuya Tanigawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Gastroenterology, Osaka City Juso Hospital, Osaka, Japan
| | - Masaki Ominami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shusei Fukunaga
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koji Otani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shuhei Hosomi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Fumio Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Noriko Kamata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Taira
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Toshio Watanabe
- Department of Premier Preventive Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
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24
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Lee B, Dane B, Katz S. Current and Emerging Approaches to the Diagnosis and Treatment of Crohn's Disease Strictures. Gastroenterol Hepatol (N Y) 2022; 18:186-195. [PMID: 35505943 PMCID: PMC9053491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The management and understanding of Crohn's disease (CD) continues to evolve quickly. Intestinal strictures were previously thought to be an inevitable result of irreversible fibrosis caused by chronic inflammation. However, increased understanding of the dynamic nature of strictures and of the pathophysiology of this condition has highlighted emerging targets for potential treatment. In the diagnosis of strictures, a distinction must be made between inflammatory and fibrotic types, as the former may respond to medical therapy. Emerging technologies, such as dual-energy computed tomography enterography and iodine density, have allowed more accurate characterization of strictures. Surgical and endoscopic treatment remains the mainstay for fibrotic strictures, but developments in systemic and intralesional biologic therapy have shown efficacy. This article reviews the pathophysiology of this debilitating complication of CD as well as current and emerging diagnostics and treatments.
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Affiliation(s)
- Briton Lee
- Department of Medicine, NYU Langone Medical Center, New York, New York
| | - Bari Dane
- Department of Radiology, NYU Langone Medical Center, New York, New York
| | - Seymour Katz
- Department of Gastroenterology, NYU Langone Medical Center, New York, New York
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25
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D'Alessio S, Ungaro F, Noviello D, Lovisa S, Peyrin-Biroulet L, Danese S. Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat Rev Gastroenterol Hepatol 2022; 19:169-184. [PMID: 34876680 DOI: 10.1038/s41575-021-00543-0] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/27/2021] [Indexed: 12/11/2022]
Abstract
Intestinal fibrosis, which is usually the consequence of chronic inflammation, is a common complication of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. In the past few years, substantial advances have been made in the areas of pathogenesis, diagnosis and management of intestinal fibrosis. Of particular interest have been inflammation-independent mechanisms behind the gut fibrotic process, genetic and environmental risk factors (such as the role of the microbiota), and the generation of new in vitro and in vivo systems to study fibrogenesis in the gut. A huge amount of work has also been done in the area of biomarkers to predict or detect intestinal fibrosis, including novel cross-sectional imaging techniques. In parallel, researchers are embarking on developing and validating clinical trial end points and protocols to test novel antifibrotic agents, although no antifibrotic therapies are currently available. This Review presents the state of the art on the most recently identified pathogenic mechanisms of this serious IBD-related complication, focusing on possible targets of antifibrotic therapies, management strategies, and factors that might predict fibrosis progression or response to treatment.
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Affiliation(s)
| | - Federica Ungaro
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Daniele Noviello
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Sara Lovisa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.,IBD Centre, Laboratory of Gastrointestinal Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Laurent Peyrin-Biroulet
- INSERM NGERE, University of Lorraine, Vandoeuvre-les-Nancy, Nancy, France.,Nancy University Hospital, Vandoeuvre-les-Nancy, Nancy, France
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy. .,University Vita-Salute San Raffaele, Milan, Italy.
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26
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Hu F, Song X, Long D. Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review). Exp Ther Med 2021; 22:1462. [PMID: 34737802 PMCID: PMC8561754 DOI: 10.3892/etm.2021.10897] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 08/04/2021] [Indexed: 12/20/2022] Open
Abstract
Calcium (Ca2+) is an essential signaling molecule in all cells. It is involved in numerous fundamental functions, including cell life and death. Abnormal regulation of Ca2+ homeostasis may cause human diseases. Usually known as a member of the transient receptor potential (TRP) family, TRP ankyrin 1 (TRPA1) is the only member of the ankyrin subfamily identified in mammals so far and widely expressed in cells and tissues. As it is involved in numerous sensory disorders such as pain and pruritus, TRPA1 is a potential target for the treatment of neuropathy. The functions of TRP family members are closely related to Ca2+. TRPA1 has a high permeability to Ca2+, sodium and potassium ions as a non-selective cation channel and the Ca2+ influx mediated by TRPA1 is involved in a variety of biological processes. In the present review, research on the relationship between the TRPA1 channel and Ca2+ ions and their interaction in disease-associated processes was summarised. The therapeutic potential of the TRPA1 channel is highlighted, which is expected to become a novel direction for the prevention and treatment of health conditions such as cancer and neurodegenerative diseases.
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Affiliation(s)
- Fangyan Hu
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaohua Song
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Dingxin Long
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
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27
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Yang Y, Wang D, Wan J, Ran F, Yang L, Chen S, Wang F, Liu S, Dai X, Zhou P, Wang P. The role of transient receptor potential ankyrin 1 in age-related endothelial dysfunction. Exp Gerontol 2021; 154:111517. [PMID: 34419618 DOI: 10.1016/j.exger.2021.111517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/10/2021] [Indexed: 10/20/2022]
Abstract
Oxidative stress plays a key role in age-related vascular disease. The present study aimed to investigate the role of an antioxidant channel, transient receptor potential ankyrin 1 (TRPA1), in age-related endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) were grown to induce replicative senescence, and 6-month-old young, 12-month-old middle-aged, and 24-month-old aged mice were used. TRPA1 was downregulated in senescent HUVECs, so were endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2), and uncoupling protein 2 (UCP2). Activating TRPA1 with cinnamaldehyde prevented downregulation of eNOS, Nrf2, and UCP2, inhibited superoxide production and apoptosis, and preserved nitric oxide bioavailability in senescent HUVECs. TRPA1, phosphorylated eNOS, Nrf2 and UCP2 were significantly downregulated in aged aortas compared with young aortas after a compensatory upregulation in middle-aged aortas. Dietary administration of cinnamaldehyde for 12 months prevented mitochondrial dysfunction, improved endothelium-dependent relaxation, and increased expression of eNOS, Nrf2, and UCP2 in aged aortas. Importantly, the effects of cinnamaldehyde can be blocked by a TRPA1 antagonist HC-030031. These findings suggest that TRPA1 may play a critical role in age-related endothelial dysfunction and may become a therapeutic target for the treatment and prevention of age-related vascular disease.
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Affiliation(s)
- Yi Yang
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Dan Wang
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Jindong Wan
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Fei Ran
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Lun Yang
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Shizhao Chen
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Fang Wang
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Sen Liu
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Xiaozhen Dai
- School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, Sichuan 610500, China
| | - Peng Zhou
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Peijian Wang
- Department of Cardiology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China; Department of Cardiology, Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China.
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28
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Virk HS, Biddle MS, Smallwood DT, Weston CA, Castells E, Bowman VW, McCarthy J, Amrani Y, Duffy SM, Bradding P, Roach KM. TGFβ1 induces resistance of human lung myofibroblasts to cell death via down-regulation of TRPA1 channels. Br J Pharmacol 2021; 178:2948-2962. [PMID: 33786825 DOI: 10.1111/bph.15467] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 02/06/2021] [Accepted: 03/17/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND AND PURPOSE TGFβ1-mediated myofibroblast activation contributes to pathological fibrosis in many diseases including idiopathic pulmonary fibrosis (IPF), where myofibroblast resistance to oxidant-mediated apoptosis is also evident. We therefore investigated the involvement of redox-sensitive TRPA1 ion channels on human lung myofibroblasts (HLMFs) cell death and TGFβ1-mediated pro-fibrotic responses. EXPERIMENTAL APPROACH The effects of TGFβ1 stimulation on TRPA1 expression and cell viability was studied in HLMFs derived from IPF patients and non-fibrotic patients. We also examined a model of TGFβ1-dependent fibrogenesis in human lung. We used qRT-PCR, immunofluorescent assays, overexpression with lentiviral vectors and electrophysiological methods. KEY RESULTS TRPA1 mRNA, protein and ion currents were expressed in HLMFs derived from both non-fibrotic patient controls and IPF patients, and expression was reduced by TGFβ1. TRPA1 mRNA was also down-regulated by TGFβ1 in a model of lung fibrogenesis in human lung. TRPA1 over-expression or activation induced HLMF apoptosis, and activation of TRPA1 channel activation by H2 O2 induced necrosis. TRPA1 inhibition following TGFβ1 down-regulation or pharmacological inhibition, protected HLMFs from both apoptosis and necrosis. Lentiviral vector mediated TRPA1 expression was also found to induce sensitivity to H2 O2 induced cell death in a TRPA1-negative HEK293T cell line. CONCLUSION AND IMPLICATIONS TGFβ1 induces resistance of HLMFs to TRPA1 agonist- and H2 O2 -mediated cell death via down-regulation of TRPA1 channels. Our data suggest that therapeutic strategies which prevent TGFβ1-dependent down-regulation of TRPA1 may reduce myofibroblast survival in IPF and therefore improve clinical outcomes.
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Affiliation(s)
- Harvinder S Virk
- NIHR Respiratory BRC, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Michael S Biddle
- NIHR Respiratory BRC, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Dawn T Smallwood
- School of Allied Health Sciences, De Montfort University, Leicester, UK
| | - Cathryn A Weston
- NIHR Respiratory BRC, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Emily Castells
- NIHR Respiratory BRC, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Viona W Bowman
- School of Allied Health Sciences, De Montfort University, Leicester, UK
| | - Jamie McCarthy
- NIHR Respiratory BRC, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Yassine Amrani
- NIHR Respiratory BRC, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - S Mark Duffy
- NIHR Respiratory BRC, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Peter Bradding
- NIHR Respiratory BRC, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Katy M Roach
- NIHR Respiratory BRC, Department of Respiratory Sciences, University of Leicester, Leicester, UK
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29
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Aloum L, Alefishat E, Shaya J, Petroianu GA. Remedia Sternutatoria over the Centuries: TRP Mediation. Molecules 2021; 26:1627. [PMID: 33804078 PMCID: PMC7998681 DOI: 10.3390/molecules26061627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/03/2021] [Accepted: 03/05/2021] [Indexed: 11/16/2022] Open
Abstract
Sneezing (sternutatio) is a poorly understood polysynaptic physiologic reflex phenomenon. Sneezing has exerted a strange fascination on humans throughout history, and induced sneezing was widely used by physicians for therapeutic purposes, on the assumption that sneezing eliminates noxious factors from the body, mainly from the head. The present contribution examines the various mixtures used for inducing sneezes (remedia sternutatoria) over the centuries. The majority of the constituents of the sneeze-inducing remedies are modulators of transient receptor potential (TRP) channels. The TRP channel superfamily consists of large heterogeneous groups of channels that play numerous physiological roles such as thermosensation, chemosensation, osmosensation and mechanosensation. Sneezing is associated with the activation of the wasabi receptor, (TRPA1), typical ligand is allyl isothiocyanate and the hot chili pepper receptor, (TRPV1), typical agonist is capsaicin, in the vagal sensory nerve terminals, activated by noxious stimulants.
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Affiliation(s)
- Lujain Aloum
- Department of Pharmacology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi 127788, United Arab Emirates; (L.A.); (E.A.)
| | - Eman Alefishat
- Department of Pharmacology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi 127788, United Arab Emirates; (L.A.); (E.A.)
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi 127788, United Arab Emirates
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, Amman 11941, Jordan
| | - Janah Shaya
- Pre-Medicine Bridge Program, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi 127788, United Arab Emirates;
| | - Georg A. Petroianu
- Department of Pharmacology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi 127788, United Arab Emirates; (L.A.); (E.A.)
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30
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Yap JMG, Ueda T, Kanemitsu Y, Takeda N, Fukumitsu K, Fukuda S, Uemura T, Tajiri T, Ohkubo H, Maeno K, Ito Y, Oguri T, Ugawa S, Niimi A. AITC inhibits fibroblast-myofibroblast transition via TRPA1-independent MAPK and NRF2/HO-1 pathways and reverses corticosteroids insensitivity in human lung fibroblasts. Respir Res 2021; 22:51. [PMID: 33579280 PMCID: PMC7881560 DOI: 10.1186/s12931-021-01636-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 01/24/2021] [Indexed: 01/17/2023] Open
Abstract
Background Little is known on the role of transient receptor potential ankyrin 1 (TRPA1) in fibroblast—myofibroblast transition (FMT) that can lead to airway remodeling which is a major problem for severe asthma and fibrosis. Thus, this study investigated the effect of TRPA1 modulators on transforming growth factor beta 1(TGF-β1) -treated lung fibroblasts. Methods MRC-5 cells were preincubated with TGF-β1 for 24 h. TRPA1 agonist or antagonist were added and further incubated for 24 h. The changes in TRPA1 and alpha-smooth muscle actin (α-SMA) expressions by stimuli were evaluated using qRT-PCR, western blot and immunohistochemical analyses. Statistical significance was determined by using one- or two-way ANOVA, followed by Bonferroni’s post hoc analysis for comparison of multiple groups and paired 2-tailed Student’s t-test between 2 groups. Results MRC-5 cells treated by TGF-β1 significantly upregulated α-SMA mRNA expressions (P < 0.01), but downregulated TRPA1 gene expression (P < 0.001). Post-treatment of TRPA1 activator, allyl isothiocyanate (AITC), after TGF-β1 significantly downregulated the α-SMA gene induction (P < 0.01 at 24 h), protein expression (P < 0.05) and immunoreactivity with stress fibers (P < 0.05). On the other hand, TRPA1 antagonist HC-030031 did not prevent this effect, and instead tended to facilitate the suppressive effect of AITC when co-stimulated. AITC significantly increased phosphorylated- extracellular signal-regulated kinase (ERK) 1/2 and heme oxygenase (HO)-1 protein expressions (P < 0.05) in TGF-β1-treated cells. Combined inhibition with ERK1/2 mitogen-activated protein kinase (MAPK) and nuclear factor erythroid 2-related factor (NRF2) almost completely reversed AITC-induced α-SMA suppression (P < 0.05). Dexamethasone was not able to inhibit the upregulated α-SMA induction by TGF-β1. However, AITC improved dexamethasone-insensitive myodifferentiation in the presence of the corticosteroid (P < 0.01). Conclusion We found that AITC exerts protective effect on TGF-β1-induced α-SMA induction by activating ERK1/2 MAPK and NRF2/HO-1 pathways in lung fibroblasts. It also overcomes corticosteroids insensitivity in TGF-β1-induced α-SMA induction. TRPA1 antagonist modulates the suppressive effect, but not prevent it. AITC and TRPA1 antagonist may be therapeutic agents in treating chronic respiratory diseases.
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Affiliation(s)
- Jennifer Maries Go Yap
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Takashi Ueda
- Department of Anatomy and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan
| | - Yoshihiro Kanemitsu
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
| | - Norihisa Takeda
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Kensuke Fukumitsu
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Satoshi Fukuda
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Takehiro Uemura
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Tomoko Tajiri
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Hirotsugu Ohkubo
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Ken Maeno
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Yutaka Ito
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Testsuya Oguri
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Shinya Ugawa
- Department of Anatomy and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan
| | - Akio Niimi
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
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Rizopoulos T, Assimakopoulou M. Transient receptor potential (TRP) channels in human colorectal cancer: evidence and perspectives. Histol Histopathol 2021; 36:515-526. [PMID: 33528023 DOI: 10.14670/hh-18-308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Colorectal cancer (CRC) is one of the leading causes of death in the civilized world. Transient receptor potential channels (TRPs) are a heterogeneous family of cation channels that play an important role in gastrointestinal physiology. TRPs have been linked with carcinogenesis in the colon and their role as potential therapeutic targets and prognostic biomarkers is under investigation.
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Affiliation(s)
- Theodoros Rizopoulos
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, Patras, Greece
| | - Martha Assimakopoulou
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, Patras, Greece.
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Kogure Y, Kanda H, Wang S, Hao Y, Li J, Yamamoto S, Noguchi K, Dai Y. Daikenchuto attenuates visceral pain and suppresses eosinophil infiltration in inflammatory bowel disease in murine models. JGH Open 2020; 4:1146-1154. [PMID: 33319050 PMCID: PMC7731802 DOI: 10.1002/jgh3.12410] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/07/2020] [Accepted: 08/09/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Daikenchuto (DKT), a traditional Japanese formula, comprises four herbal medicines and is used for abdominal pain. Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD) and is characterized by colonic inflammation and chronic abdominal pain. The present study aimed to investigate whether DKT suppresses colonic hypersensitivity and inflammation associated with IBD in animal models. METHODS Sprague-Dawley rats were administered 4% sodium dextran sulfate (DSS) or trinitrobenzene sulfate (TNBS) in the colon to establish UC or CD models, respectively. DKT and 5-aminosalicylic acid (5-ASA) were administered orally once a day from Days 3 to 7 after induction of colitis. On Day 7, visceral pain and inflammation were evaluated by measuring the visceromotor response (VMR) to colorectal distention (CRD) and inflammatory indicators, including histological score, length of leukocyte infiltration, MPO activity, and eosinophil count. RESULTS DSS and TNBS increased VMR to CRD and the inflammation indicators. DKT, but not 5-ASA, suppressed the VMR to CRD in DSS- and TNBS-treated rats. DKT and 5-ASA decreased the eosinophil count in both IBD models. In DSS-treated rats, 5-ASA, but not DKT, suppressed the MPO activity. In TNBS-treated rats, neither 5-ASA nor DKT suppressed MPO activity. CONCLUSION These results suggest that DKT is beneficial for abdominal pain associated with IBD. The anti-inflammatory effect of DKT on IBD may involve inhibition of eosinophils. The mechanism of anti-inflammatory effect of DKT partially differs from that of 5-ASA. Coapplication of DKT and conventional medicine may produce a positive synergy effect for IBD treatment.
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Affiliation(s)
- Yoko Kogure
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
| | - Hirosato Kanda
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
- Traditional Medicine Research CenterChinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM)KobeJapan
- Department of Anatomy and NeuroscienceHyogo College of MedicineNishinomiyaJapan
| | - Shenglan Wang
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
- School of Acupuncture‐Moxibustion and TuinaBeijing University of Chinese Medicine (BUCM)BeijingChina
| | - Yongbiao Hao
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
| | - Junxiang Li
- Division of Gastroenterology, Department of Internal MedicineDongfang Hospital of BUCMBeijingChina
| | - Satoshi Yamamoto
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
| | - Koichi Noguchi
- Department of Anatomy and NeuroscienceHyogo College of MedicineNishinomiyaJapan
| | - Yi Dai
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
- Traditional Medicine Research CenterChinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM)KobeJapan
- Department of Anatomy and NeuroscienceHyogo College of MedicineNishinomiyaJapan
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Latella G, Viscido A. Could Pirfenidone Also be Effective in Treating Intestinal Fibrosis? Cells 2020; 9:cells9081762. [PMID: 32717828 PMCID: PMC7463724 DOI: 10.3390/cells9081762] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 07/21/2020] [Indexed: 12/11/2022] Open
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A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling. Int J Mol Sci 2020; 21:ijms21114008. [PMID: 32503342 PMCID: PMC7312375 DOI: 10.3390/ijms21114008] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/30/2020] [Accepted: 05/31/2020] [Indexed: 12/24/2022] Open
Abstract
Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832—a pan-PDE inhibitor, 869—a TRPA1 modulator, and 145—a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type β1 (TGF-β1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-β pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research.
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Cui Y, Zhang M, Leng C, Blokzijl T, Jansen BH, Dijkstra G, Faber KN. Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts. Cells 2020; 9:cells9030775. [PMID: 32235767 PMCID: PMC7140656 DOI: 10.3390/cells9030775] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 03/16/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Intestinal fibrosis is a common complication of inflammatory bowel disease. So far, there is no safe and effective drug for intestinal fibrosis. Pirfenidone is an anti-fibrotic compound available for the treatment of idiopathic pulmonary fibrosis. Here, we explored the anti-proliferative and anti-fibrotic properties of pirfenidone on primary human intestinal fibroblasts (p-hIFs). p-hIFs were cultured in the absence and presence of pirfenidone. Cell proliferation was measured by a real-time cell analyzer (xCELLigence) and BrdU incorporation. Cell motility was monitored by live cell imaging. Cytotoxicity and cell viability were analyzed by Sytox green, Caspase-3 and Water Soluble Tetrazolium Salt-1 (WST-1) assays. Gene expression of fibrosis markers was determined by quantitative reverse transcription PCR (RT-qPCR). The mammalian target of rapamycin (mTOR) signaling was analyzed by Western blotting and type I collagen protein expression additionally by immunofluorescence microscopy. Pirfenidone dose-dependently inhibited p-hIF proliferation and motility, without inducing cell death. Pirfenidone suppressed mRNA levels of genes that contribute to extracellular matrix production, as well as basal and TGF-β1-induced collagen I protein production, which was associated with inhibition of the rapamycin-sensitive mTOR/p70S6K pathway in p-hIFs. Thus, pirfenidone inhibits the proliferation of intestinal fibroblasts and suppresses collagen I production through the TGF-β1/mTOR/p70S6K signaling pathway, which might be a novel and safe anti-fibrotic strategy to treat intestinal fibrosis.
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Affiliation(s)
- Yingying Cui
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
| | - Mengfan Zhang
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
| | - Changsen Leng
- Department of Biomedical Sciences of Cells and Systems, section Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Tjasso Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Bernadien H. Jansen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
- Correspondence: ; Tel.: +31-50-3612364
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Chen Y, Mu J, Zhu M, Mukherjee A, Zhang H. Transient Receptor Potential Channels and Inflammatory Bowel Disease. Front Immunol 2020; 11:180. [PMID: 32153564 PMCID: PMC7044176 DOI: 10.3389/fimmu.2020.00180] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/23/2020] [Indexed: 02/05/2023] Open
Abstract
The transient receptor potential (TRP) cation channels are present in abundance across the gastrointestinal (GI) tract, serving as detectors for a variety of stimuli and secondary transducers for G-protein coupled receptors. The activation of TRP channels triggers neurogenic inflammation with related neuropeptides and initiates immune reactions by extra-neuronally regulating immune cells, contributing to the GI homeostasis. However, under pathological conditions, such as inflammatory bowel disease (IBD), TRP channels are involved in intestinal inflammation. An increasing number of human and animal studies have indicated that TRP channels are correlated to the visceral hypersensitivity (VHS) and immune pathogenesis in IBD, leading to an exacerbation or amelioration of the VHS or intestinal inflammation. Thus, TRP channels are a promising target for novel therapeutic methods for IBD. In this review, we comprehensively summarize the functions of TRP channels, especially their potential roles in immunity and IBD. Additionally, we discuss the contradictory findings of prior studies and offer new insights with regard to future research.
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Affiliation(s)
- Yiding Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.,Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Jingxi Mu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.,Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Min Zhu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.,Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | | | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.,Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
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37
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Roach KM, Bradding P. Ca 2+ signalling in fibroblasts and the therapeutic potential of K Ca3.1 channel blockers in fibrotic diseases. Br J Pharmacol 2020; 177:1003-1024. [PMID: 31758702 DOI: 10.1111/bph.14939] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 10/23/2019] [Accepted: 11/13/2019] [Indexed: 12/13/2022] Open
Abstract
The role of Ca2+ signalling in fibroblasts is of great interest in fibrosis-related diseases. Intracellular free Ca2+ ([Ca2+ ]i ) is a ubiquitous secondary messenger, regulating a number of cellular functions such as secretion, metabolism, differentiation, proliferation and contraction. The intermediate conductance Ca2+ -activated K+ channel KCa 3.1 is pivotal in Ca2+ signalling and plays a central role in fibroblast processes including cell activation, migration and proliferation through the regulation of cell membrane potential. Evidence from a number of approaches demonstrates that KCa 3.1 plays an important role in the development of many fibrotic diseases, including idiopathic pulmonary, renal tubulointerstitial fibrosis and cardiovascular disease. The KCa 3.1 selective blocker senicapoc was well tolerated in clinical trials for sickle cell disease, raising the possibility of rapid translation to the clinic for people suffering from pathological fibrosis. This review after analysing all the data, concludes that targeting KCa 3.1 should be a high priority for human fibrotic disease.
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Affiliation(s)
- Katy M Roach
- Institute for Lung Health, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Peter Bradding
- Institute for Lung Health, Department of Respiratory Sciences, University of Leicester, Leicester, UK
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Virk HS, Rekas MZ, Biddle MS, Wright AKA, Sousa J, Weston CA, Chachi L, Roach KM, Bradding P. Validation of antibodies for the specific detection of human TRPA1. Sci Rep 2019; 9:18500. [PMID: 31811235 PMCID: PMC6898672 DOI: 10.1038/s41598-019-55133-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 11/22/2019] [Indexed: 12/26/2022] Open
Abstract
The transient receptor potential cation channel family member ankyrin 1 (TRPA1) is a potential target for several diseases, but detection of human TRPA1 (hTRPA1) protein in cells and tissues is problematic as rigorous antibody validation is lacking. We expressed hTRPA1 in a TRPA1-negative cell line to evaluate 5 commercially available antibodies by western blotting, immunofluorescence, immunocytochemistry and flow cytometry. The three most cited anti-TRPA1 antibodies lacked sensitivity and/or specificity, but two mouse monoclonal anti-TRPA1 antibodies detected hTRPA1 specifically in the above assays. This enabled the development of a flow cytometry assay, which demonstrated strong expression of TRPA1 in human lung myofibroblasts, human airway smooth muscle cells but not lung mast cells. The most cited anti-TRPA1 antibodies lack sensitivity and/or specificity for hTRPA1. We have identified two anti-TRPA1 antibodies which detect hTRPA1 specifically. Previously published data regarding human TRPA1 protein expression may need revisiting.
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Affiliation(s)
- H S Virk
- Department of Respiratory Sciences, University of Leicester, UK Institute of Lung Health and NIHR Leicester BRC-Respiratory, Leicester, United Kingdom.
| | - M Z Rekas
- Department of Respiratory Sciences, University of Leicester, UK Institute of Lung Health and NIHR Leicester BRC-Respiratory, Leicester, United Kingdom
| | - M S Biddle
- Department of Respiratory Sciences, University of Leicester, UK Institute of Lung Health and NIHR Leicester BRC-Respiratory, Leicester, United Kingdom
| | - A K A Wright
- Department of Respiratory Sciences, University of Leicester, UK Institute of Lung Health and NIHR Leicester BRC-Respiratory, Leicester, United Kingdom
| | - J Sousa
- Department of Respiratory Sciences, University of Leicester, UK Institute of Lung Health and NIHR Leicester BRC-Respiratory, Leicester, United Kingdom
| | - C A Weston
- Department of Respiratory Sciences, University of Leicester, UK Institute of Lung Health and NIHR Leicester BRC-Respiratory, Leicester, United Kingdom
| | - L Chachi
- Department of Respiratory Sciences, University of Leicester, UK Institute of Lung Health and NIHR Leicester BRC-Respiratory, Leicester, United Kingdom
| | - K M Roach
- Department of Respiratory Sciences, University of Leicester, UK Institute of Lung Health and NIHR Leicester BRC-Respiratory, Leicester, United Kingdom
| | - P Bradding
- Department of Respiratory Sciences, University of Leicester, UK Institute of Lung Health and NIHR Leicester BRC-Respiratory, Leicester, United Kingdom
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Alaimo A, Rubert J. The Pivotal Role of TRP Channels in Homeostasis and Diseases throughout the Gastrointestinal Tract. Int J Mol Sci 2019; 20:ijms20215277. [PMID: 31652951 PMCID: PMC6862298 DOI: 10.3390/ijms20215277] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/20/2019] [Accepted: 10/22/2019] [Indexed: 12/12/2022] Open
Abstract
The transient receptor potential (TRP) channels superfamily are a large group of proteins that play crucial roles in cellular processes. For example, these cation channels act as sensors in the detection and transduction of stimuli of temperature, small molecules, voltage, pH, and mechanical constrains. Over the past decades, different members of the TRP channels have been identified in the human gastrointestinal (GI) tract playing multiple modulatory roles. Noteworthy, TRPs support critical functions related to the taste perception, mechanosensation, and pain. They also participate in the modulation of motility and secretions of the human gut. Last but not least, altered expression or activity and mutations in the TRP genes are often related to a wide range of disorders of the gut epithelium, including inflammatory bowel disease, fibrosis, visceral hyperalgesia, irritable bowel syndrome, and colorectal cancer. TRP channels could therefore be promising drug targets for the treatment of GI malignancies. This review aims at providing a comprehensive picture of the most recent advances highlighting the expression and function of TRP channels in the GI tract, and secondly, the description of the potential roles of TRPs in relevant disorders is discussed reporting our standpoint on GI tract–TRP channels interactions.
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Affiliation(s)
- Alessandro Alaimo
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Povo (Tn), Italy.
| | - Josep Rubert
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Povo (Tn), Italy.
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Giorgi S, Nikolaeva-Koleva M, Alarcón-Alarcón D, Butrón L, González-Rodríguez S. Is TRPA1 Burning Down TRPV1 as Druggable Target for the Treatment of Chronic Pain? Int J Mol Sci 2019; 20:ijms20122906. [PMID: 31197115 PMCID: PMC6627658 DOI: 10.3390/ijms20122906] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/12/2019] [Accepted: 06/13/2019] [Indexed: 12/14/2022] Open
Abstract
Over the last decades, a great array of molecular mediators have been identified as potential targets for the treatment of chronic pain. Among these mediators, transient receptor potential (TRP) channel superfamily members have been thoroughly studied. Namely, the nonselective cationic channel, transient receptor potential ankyrin subtype 1 (TRPA1), has been described as a chemical nocisensor involved in noxious cold and mechanical sensation and as rivalling TRPV1, which traditionally has been considered as the most important TRP channel involved in nociceptive transduction. However, few TRPA1-related drugs have succeeded in clinical trials. In the present review, we attempt to discuss the latest data on the topic and future directions for pharmacological intervention.
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Affiliation(s)
- Simona Giorgi
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Avda de la Univesidad s/n, Universidad Miguel Hernández, 03202 Elche, Spain.
| | - Magdalena Nikolaeva-Koleva
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Avda de la Univesidad s/n, Universidad Miguel Hernández, 03202 Elche, Spain.
- AntalGenics, SL. Ed. Quorum III, Parque Científico Universidad Miguel Hernández, Avda de la Universidad s/n, 03202 Elche, Spain.
| | - David Alarcón-Alarcón
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Avda de la Univesidad s/n, Universidad Miguel Hernández, 03202 Elche, Spain.
| | - Laura Butrón
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Avda de la Univesidad s/n, Universidad Miguel Hernández, 03202 Elche, Spain.
| | - Sara González-Rodríguez
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Avda de la Univesidad s/n, Universidad Miguel Hernández, 03202 Elche, Spain.
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TRPA1 Promotes Cardiac Myofibroblast Transdifferentiation after Myocardial Infarction Injury via the Calcineurin-NFAT-DYRK1A Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:6408352. [PMID: 31217840 PMCID: PMC6537015 DOI: 10.1155/2019/6408352] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 03/05/2019] [Accepted: 03/27/2019] [Indexed: 12/18/2022]
Abstract
Cardiac fibroblasts (CFs) are a critical cell population responsible for myocardial extracellular matrix homeostasis. After stimulation by myocardial infarction (MI), CFs transdifferentiate into cardiac myofibroblasts (CMFs) and play a fundamental role in the fibrotic healing response. Transient receptor potential ankyrin 1 (TRPA1) channels are cationic ion channels with a high fractional Ca2+ current, and they are known to influence cardiac function after MI injury; however, the molecular mechanisms regulating CMF transdifferentiation remain poorly understood. TRPA1 knockout mice, their wild-type littermates, and mice pretreated with the TRPA1 agonist cinnamaldehyde (CA) were subjected to MI injury and monitored for survival, cardiac function, and fibrotic remodeling. TRPA1 can drive myofibroblast transdifferentiation initiated 1 week after MI injury. In addition, we explored the underlying mechanisms via in vitro experiments through gene transfection alone or in combination with inhibitor treatment. TRPA1 overexpression fully activated CMF transformation, while CFs lacking TRPA1 were refractory to transforming growth factor β- (TGF-β-) induced transdifferentiation. TGF-β enhanced TRPA1 expression, which promoted the Ca2+-responsive activation of calcineurin (CaN). Moreover, dual-specificity tyrosine-regulated kinase-1a (DYRK1A) regulated CaN-mediated NFAT nuclear translocation and TRPA1-dependent transdifferentiation. These findings suggest a potential therapeutic role for TRPA1 in the regulation of CMF transdifferentiation in response to MI injury and indicate a comprehensive pathway driving CMF formation in conjunction with TGF-β, Ca2+ influx, CaN, NFATc3, and DYRK1A.
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Yang Y, Wang S, Kobayashi K, Hao Y, Kanda H, Kondo T, Kogure Y, Yamanaka H, Yamamoto S, Li J, Miwa H, Noguchi K, Dai Y. TRPA1-expressing lamina propria mesenchymal cells regulate colonic motility. JCI Insight 2019; 4:122402. [PMID: 31045572 DOI: 10.1172/jci.insight.122402] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 04/02/2019] [Indexed: 12/19/2022] Open
Abstract
The physiological process of defecation is directly controlled by colorectal motility. The transient receptor potential ankyrin 1 (TRPA1) channel is expressed in small intestine enterochromaffin cells and is involved in gastrointestinal motility via serotonin release. In the colorectum, however, enterochromaffin cell localization is largely distinct from that in the small intestine. Here, we investigated the role of lower gastrointestinal tract TRPA1 in modulating colorectal motility. We found that in colonic tissue, TRPA1 is predominantly expressed in mesenchymal cells of the lamina propria, which are clearly distinct from those in the small intestine. These cells coexpressed COX1 and microsomal prostaglandin E synthase-1. Intracolonic administration of TRPA1 agonists induced colonic contraction, which was suppressed by a prostaglandin E2 (PGE2) receptor 1 antagonist. TRPA1 activation induced calcium influx and PGE2 release from cultured human fibroblastic cells. In dextran sulfate sodium-treated animals, both TRPA1 and its endogenous agonist were dramatically increased in the colonic lamina propria, accompanied by abnormal colorectal contractions. Abnormal colorectal contractions were significantly prevented by pharmacological and genetic inhibition of TRPA1. In conclusion, in the lower gastrointestinal tract, mesenchymal TRPA1 activation results in PGE2 release and consequently promotes colorectal contraction, representing what we believe is a novel physiological and inflammatory bowel disease-associated mechanism of gastrointestinal motility.
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Affiliation(s)
- Yanjing Yang
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Shenglan Wang
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine (BUCM), Beijing, China
| | - Kimiko Kobayashi
- Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Yongbiao Hao
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Division of Gastroenterology, Department of Internal Medicine, HCM, Nishinomiya, Hyogo, Japan
| | - Hirosato Kanda
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Takashi Kondo
- Division of Gastroenterology, Department of Internal Medicine, HCM, Nishinomiya, Hyogo, Japan
| | - Yoko Kogure
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan
| | - Hiroki Yamanaka
- Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Satoshi Yamamoto
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan
| | - Junxiang Li
- Division of Gastroenterology, Department of Internal Medicine, Dongfang Hospital of BUCM, Beijing, China
| | - Hiroto Miwa
- Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,Division of Gastroenterology, Department of Internal Medicine, HCM, Nishinomiya, Hyogo, Japan
| | - Koichi Noguchi
- Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
| | - Yi Dai
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences (HUHS), Kobe, Hyogo, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Hyogo, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine (HCM), Nishinomiya, Hyogo, Japan
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Csekő K, Beckers B, Keszthelyi D, Helyes Z. Role of TRPV1 and TRPA1 Ion Channels in Inflammatory Bowel Diseases: Potential Therapeutic Targets? Pharmaceuticals (Basel) 2019; 12:E48. [PMID: 30935063 PMCID: PMC6630403 DOI: 10.3390/ph12020048] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 03/26/2019] [Accepted: 03/27/2019] [Indexed: 12/20/2022] Open
Abstract
Inflammatory bowel diseases (IBD) have long been recognized to be accompanied by pain resulting in high morbidity. Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) ion channels located predominantly on the capsaicin-sensitive sensory neurons play a complex role in hyperalgesia and neurogenic inflammation. This review provides an overview of their expression and role in intestinal inflammation, in particular colitis, that appears to be virtually inconsistent based on the thorough investigations of the last twenty years. However, preclinical results with pharmacological interventions, as well as scarcely available human studies, more convincingly point out the potential therapeutic value of TRPV1 and TRPA1 antagonists in colitis and visceral hypersensitivity providing future therapeutical perspectives through a complex, unique mechanism of action for drug development in IBD.
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Affiliation(s)
- Kata Csekő
- Department of Pharmacology and Pharmacotherapy, Medical School and Molecular Pharmacology Research Group, Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary.
| | - Bram Beckers
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center (MUMC+), 6202 AZ Maastricht, The Netherlands.
- NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University, 6202 AZ Maastricht, The Netherlands.
| | - Daniel Keszthelyi
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center (MUMC+), 6202 AZ Maastricht, The Netherlands.
- NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University, 6202 AZ Maastricht, The Netherlands.
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School and Molecular Pharmacology Research Group, Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary.
- PharmInVivo Ltd., H-7629 Pécs, Hungary.
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Pirfenidone inhibits epithelial-mesenchymal transition and pulmonary fibrosis in the rat silicosis model. Toxicol Lett 2019; 300:59-66. [DOI: 10.1016/j.toxlet.2018.10.019] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 09/04/2018] [Accepted: 10/17/2018] [Indexed: 12/24/2022]
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Inoue R, Kurahara LH, Hiraishi K. TRP channels in cardiac and intestinal fibrosis. Semin Cell Dev Biol 2018; 94:40-49. [PMID: 30445149 DOI: 10.1016/j.semcdb.2018.11.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 11/05/2018] [Accepted: 11/09/2018] [Indexed: 02/06/2023]
Abstract
It is now widely accepted that advanced fibrosis underlies many chronic inflammatory disorders and is the main cause of morbidity and mortality of the modern world. The pathogenic mechanism of advanced fibrosis involves diverse and intricate interplays between numerous extracellular and intracellular signaling molecules, among which the non-trivial roles of a stress-responsive Ca2+/Na+-permeable cation channel superfamily, the transient receptor potential (TRP) protein, are receiving growing attention. Available evidence suggests that several TRP channels such as TRPC3, TRPC6, TRPV1, TRPV3, TRPV4, TRPA1, TRPM6 and TRPM7 may play central roles in the progression and/or prevention of fibroproliferative disorders in vital visceral organs such as lung, heart, liver, kidney, and bowel as well as brain, blood vessels and skin, and may contribute to both acute and chronic inflammatory processes involved therein. This short paper overviews the current knowledge accumulated in this rapidly growing field, with particular focus on cardiac and intestinal fibrosis, which are tightly associated with the pathogenesis of atrial fibrillation and inflammatory bowel diseases such as Crohn's disease.
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Affiliation(s)
- Ryuji Inoue
- Department of Physiology, Fukuoka University School of medicine, Nanakuma 7-451, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Lin-Hai Kurahara
- Department of Physiology, Fukuoka University School of medicine, Nanakuma 7-451, Jonan-ku, Fukuoka 814-0180, Japan
| | - Keizo Hiraishi
- Department of Physiology, Fukuoka University School of medicine, Nanakuma 7-451, Jonan-ku, Fukuoka 814-0180, Japan
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Hiraishi K, Kurahara LH, Sumiyoshi M, Hu YP, Koga K, Onitsuka M, Kojima D, Yue L, Takedatsu H, Jian YW, Inoue R. Daikenchuto (Da-Jian-Zhong-Tang) ameliorates intestinal fibrosis by activating myofibroblast transient receptor potential ankyrin 1 channel. World J Gastroenterol 2018; 24:4036-4053. [PMID: 30254408 PMCID: PMC6148431 DOI: 10.3748/wjg.v24.i35.4036] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/06/2018] [Accepted: 07/21/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto (DKT) associated with transient receptor potential ankyrin 1 (TRPA1) channels in intestinal myofibroblasts.
METHODS Inflammatory and fibrotic changes were detected in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) chronic colitis model of wild-type and TRPA1-knockout (TRPA1-KO) mice via pathological staining and immunoblotting analysis. Ca2+ imaging experiments examined the effects of DKT and its components/ingredients on intestinal myofibroblast (InMyoFib) cell TRPA1 channel function. Pro-fibrotic factors and transforming growth factor (TGF)-β1-associated signaling were tested in an InMyoFib cell line by qPCR and immunoblotting experiments. Samples from non-stenotic and stenotic regions of the intestines of patients with Crohn’s disease (CD) were used for pathological analysis.
RESULTS Chronic treatment with TNBS caused more severe inflammation and fibrotic changes in TRPA1-KO than in wild-type mice. A one-week enema administration of DKT reduced fibrotic lesions in wild-type but not in TRPA1-KO mice. The active ingredients of DKT, i.e., hydroxy α-sanshool and 6-shogaol, induced Ca2+ influxes in InMyoFib, and this was antagonized by co-treatment with a selective TRPA1 channel blocker, HC-030031. DKT counteracted TGF-β1-induced expression of Type I collagen and α-smooth muscle actin (α-SMA), which were accompanied by a reduction in the phosphorylation of Smad-2 and p38-mitogen-activated protein kinase (p38-MAPK) and the expression of myocardin. Importantly, 24-h incubation with a DKT active component Japanese Pepper increased the mRNA and protein expression levels of TRPA1 in InMyoFibs, which in turn negatively regulated collagen synthesis. In the stenotic regions of the intestines of CD patients, TRPA1 expression was significantly enhanced.
CONCLUSION The effects of DKT on the expression and activation of the TRPA1 channel could be advantageous for suppressing intestinal fibrosis, and benefit inflammatory bowel disease treatment.
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Affiliation(s)
- Keizo Hiraishi
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
| | - Lin-Hai Kurahara
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
| | - Miho Sumiyoshi
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
| | - Yao-Peng Hu
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
| | - Kaori Koga
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka 8140180, Japan
| | - Miki Onitsuka
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka 8140180, Japan
| | - Daibo Kojima
- Department of Gastroenterological Surgery, Faculty of Medicine, Fukuoka University, Fukuoka 8140180, Japan
| | - Lixia Yue
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, United States
| | - Hidetoshi Takedatsu
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, Fukuoka 8140180, Japan
| | - Yu-Wen Jian
- College of Letters and Science, University of California, Davis, CA 95616, United States
| | - Ryuji Inoue
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
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Affiliation(s)
- Simon Andrew Hirota
- Correspondence Address correspondence to: Simon Andrew Hirota, PhD, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive, NW HS1845, Calgary, Alberta, Canada T2N4N1.Department of Physiology and PharmacologyUniversity of Calgary3330 Hospital Drive, NW HS1845CalgaryAlbertaCanada T2N4N1
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