International Journal of Molecular Sciences

Editorial

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4 pages, 194 KiB

Open AccessEditorial

Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies

by Jesús Cosín-Roger

Int. J. Mol. Sci. 2024, 25(12), 6416; https://doi.org/10.3390/ijms25126416 - 11 Jun 2024

Viewed by 1112

Abstract

Inflammatory Bowel Disease (IBD) is a complex and challenging health problem that exerts a significant impact on the quality of life of millions of individuals worldwide [...] Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies)

Research

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17 pages, 5381 KiB

Open AccessArticle

Evaluation of the Antifibrotic Effects of Drugs Commonly Used in Inflammatory Intestinal Diseases on In Vitro Intestinal Cellular Models

by Serena Artone, Alessia Ciafarone, Francesca Rosaria Augello, Francesca Lombardi, Maria Grazia Cifone, Paola Palumbo, Benedetta Cinque and Giovanni Latella

Int. J. Mol. Sci. 2024, 25(16), 8862; https://doi.org/10.3390/ijms25168862 - 14 Aug 2024

Viewed by 1163

Abstract

The mechanism underlying intestinal fibrosis, the main complication of inflammatory bowel disease (IBD), is not yet fully understood, and there is no therapy to prevent or reverse fibrosis. We evaluated, in in vitro cellular models, the ability of different classes of drugs currently [...] Read more.

The mechanism underlying intestinal fibrosis, the main complication of inflammatory bowel disease (IBD), is not yet fully understood, and there is no therapy to prevent or reverse fibrosis. We evaluated, in in vitro cellular models, the ability of different classes of drugs currently used in IBD to counteract two pivotal processes of intestinal fibrosis, the differentiation of intestinal fibroblasts to activated myofibroblasts using CCD-18Co cells, and the epithelial-to-mesenchymal transition (EMT) of intestinal epithelial cells using Caco-2 cells (IEC), both being processes induced by transforming growth factor-β1 (TGF-β1). The drugs tested included mesalamine, azathioprine, methotrexate, prednisone, methylprednisolone, budesonide, infliximab, and adalimumab. The expression of fibrosis and EMT markers (collagen-I, α-SMA, pSmad2/3, occludin) was assessed by Western blot analysis and by immunofluorescence. Of the drugs used, only prednisone, methylprednisolone, budesonide, and adalimumab were able to antagonize the pro-fibrotic effects induced by TGF-β1 on CCD-18Co cells, reducing the fibrosis marker expression. Methylprednisolone, budesonide, and adalimumab were also able to significantly counteract the TGF-β1-induced EMT process on Caco-2 IEC by increasing occludin and decreasing α-SMA expression. This is the first study that evaluates, using in vitro cellular models, the direct antifibrotic effects of drugs currently used in IBD, highlighting which drugs have potential antifibrotic effects. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies)

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17 pages, 3712 KiB

Open AccessArticle

P2X7 Receptor Regulates Collagen Expression in Human Intestinal Fibroblasts: Relevance in Intestinal Fibrosis

by Lluis Lis-López, Cristina Bauset, Marta Seco-Cervera, Dulce Macias-Ceja, Francisco Navarro, Ángeles Álvarez, Juan Vicente Esplugues, Sara Calatayud, Maria Dolores Barrachina, Dolores Ortiz-Masià and Jesús Cosín-Roger

Int. J. Mol. Sci. 2023, 24(16), 12936; https://doi.org/10.3390/ijms241612936 - 18 Aug 2023

Cited by 4 | Viewed by 1637

Abstract

Intestinal fibrosis is a common complication that affects more than 50% of Crohn´s Disease (CD) patients. There is no pharmacological treatment against this complication, with surgery being the only option. Due to the unknown role of P2X7 in intestinal fibrosis, we aim to [...] Read more.

Intestinal fibrosis is a common complication that affects more than 50% of Crohn´s Disease (CD) patients. There is no pharmacological treatment against this complication, with surgery being the only option. Due to the unknown role of P2X7 in intestinal fibrosis, we aim to analyze the relevance of this receptor in CD complications. Surgical resections from CD and non-Inflammatory Bowel Disease (IBD) patients were obtained. Intestinal fibrosis was induced with two different murine models: heterotopic transplant model and chronic-DSS colitis in wild-type and P2X7-/- mice. Human small intestine fibroblasts (HSIFs) were transfected with an siRNA against P2X7 and treated with TGF-β. A gene and protein expression of P2X7 receptor was significantly increased in CD compared to non-IBD patients. The lack of P2X7 in mice provoked an enhanced collagen deposition and increased expression of several profibrotic markers in both murine models of intestinal fibrosis. Furthermore, P2X7-/- mice exhibited a higher expression of proinflammatory cytokines and a lower expression of M2 macrophage markers. Moreover, the transient silencing of the P2X7 receptor in HSIFs significantly induced the expression of Col1a1 and potentiated the expression of Col4 and Col5a1 after TGF-β treatment. P2X7 regulates collagen expression in human intestinal fibroblasts, while the lack of this receptor aggravates intestinal fibrosis. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies)

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10 pages, 1232 KiB

Open AccessArticle

Comparative Evaluation of Four Commercially Available Immunoassays for Therapeutic Drug Monitoring of Infliximab and Adalimumab

by Florian Rissel, Yoann Cazaubon, Syrine Saffar, Romain Altwegg, Mélanie Artasone, Claire Lozano, Thierry Vincent and Alexandre Jentzer

Int. J. Mol. Sci. 2023, 24(12), 10379; https://doi.org/10.3390/ijms241210379 - 20 Jun 2023

Cited by 5 | Viewed by 1525

Abstract

Therapeutic drug monitoring (TDM) of anti-TNF-α is an important tool in clinical practice for inflammatory diseases. In this study, we have evaluated the performance of several assays for drug and antidrug antibodies (ADA) measurement in the serum. 50 sera from patients treated with [...] Read more.

Therapeutic drug monitoring (TDM) of anti-TNF-α is an important tool in clinical practice for inflammatory diseases. In this study, we have evaluated the performance of several assays for drug and antidrug antibodies (ADA) measurement in the serum. 50 sera from patients treated with infliximab (IFX) and 49 sera from patients treated with adalimumab (ADAL) were monitored with four immunoassays. We have compared Promonitor, i-Track10^®, and ez-track1 assays to our gold standard Lisa Tracker^® ELISA using Cohen’s kappa, Passing-Bablok, and Bland–Altman analysis. The qualitative analysis evaluated by Cohen’s kappa values found for IFX measurements an “almost perfect” concordance for Promonitor, “moderate” for i-Track10^® and “substantial” for ez-Track1. For ADAL, kappa values were “moderate” for all tested methods. For anti-IFX, kappa values were “almost perfect” for Promonitor, “fair” for i-Track10^®, and “substantial” for ez-Track1. For anti-ADAL, kappa values were “almost perfect” for all three assays. For quantitative analysis of drug measurements, Pearson’s r values were all above 0.9 and Lin’s concordance coefficients of all immunoassays were around 0.80. Performances of the four evaluated immunoassays were acceptable for TDM based on our laboratory experience. Nevertheless, concordance between the four methods for IFX measurement was not perfect and we recommend the use of the same assay for the follow-up of a given patient. The performances of the four immunoassays evaluated were similar and are acceptable for TDM based on our laboratory experience. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies)

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24 pages, 4955 KiB

Open AccessArticle

Targeting Lineage-Specific Transcription Factors and Cytokines of the Th17/Treg Axis by Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Attenuates TNBS-Induced Experimental Colitis

by Marta Szandruk-Bender, Benita Wiatrak, Stanisław Dzimira, Anna Merwid-Ląd, Łukasz Szczukowski, Piotr Świątek and Adam Szeląg

Int. J. Mol. Sci. 2022, 23(17), 9897; https://doi.org/10.3390/ijms23179897 - 31 Aug 2022

Cited by 6 | Viewed by 2246

Abstract

The pharmacotherapy of inflammatory bowel disease (IBD) is still not fully effective and safe. Attempts to search for new IBD drugs remain an incessant research aim. One of the novel approaches is targeting the developmental pathway molecules and effector cytokines of Th17/Treg axis. [...] Read more.

The pharmacotherapy of inflammatory bowel disease (IBD) is still not fully effective and safe. Attempts to search for new IBD drugs remain an incessant research aim. One of the novel approaches is targeting the developmental pathway molecules and effector cytokines of Th17/Treg axis. This study aimed to elucidate the impact of new pyrrolo[3,4-d]pyridazinone derivatives, compounds 7b, 10b, or 13b, on the course of experimental colitis in rats and to assess whether these new compounds may influence Th17/Treg axis. Rats were pretreated with studied compounds intragastrically before intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid used for colitis induction. Body weight loss, disease activity index, colon index, and colon tissue damage were analyzed to evaluate the severity of colitis. The colonic levels of RORγt, STAT3, CCR6, Foxp3, IL-6, IL-10, IL-17, TNF-α, IL-23, and PGE₂ were assessed. Pretreatment with compounds 7b and 13b alleviated the severity of colitis and concomitantly counteracted the increased levels of RORγt, STAT3, CCR6, IL-6, IL-17, IL-23, TNF-α, and PGE₂. The beneficial effect of compounds 7b and 13b may be due to the decrease in the levels of Th17-specific transcription factors and cytokines. The studied compounds might therefore constitute a promising therapeutic strategy in Th17/Treg imbalance-driven inflammatory conditions such as IBD. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies)

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12 pages, 1844 KiB

Open AccessArticle

Anti-Inflammatory Effect of Topiramate in a Chronic Model of TNBS-Induced Colitis

by Inês Silva, Priscila Mendes, Sofia Guerra, Rui Pinto and Vanessa Mateus

Int. J. Mol. Sci. 2022, 23(16), 9127; https://doi.org/10.3390/ijms23169127 - 15 Aug 2022

Cited by 4 | Viewed by 2473

Abstract

Inflammatory bowel disease (IBD) is characterized by a chronic and relapsing inflammatory response in the gastrointestinal tract, resulting in severe symptoms such as abdominal pain, vomiting, diarrhea, bloody stools, and weight loss. Currently, there is no cure, and the pharmacological treatment includes drugs [...] Read more.

Inflammatory bowel disease (IBD) is characterized by a chronic and relapsing inflammatory response in the gastrointestinal tract, resulting in severe symptoms such as abdominal pain, vomiting, diarrhea, bloody stools, and weight loss. Currently, there is no cure, and the pharmacological treatment includes drugs that induce and keep the patient in remission, not reversing the underlying pathogenic mechanism. These therapies, in the long term, may cause various side effects and complications, which has increased the need to investigate new, more effective, and safer pharmacological approaches. In preclinical studies, topiramate has demonstrated a potential anti-inflammatory effect by inhibiting the production of several pro-inflammatory cytokines. This study aimed to investigate the effect of topiramate in a chronic TNBS-induced colitis model in rodents. Experimental colitis was induced by four intrarectal administrations of 1% TNBS in female CD-1 mice. Topiramate 10 and 20 mg were administered intraperitoneally for 14 days. Several parameters were evaluated, such as bodyweight, alkaline phosphatase (ALP), fecal hemoglobin, fecal calprotectin, tumor necrosis factor (TNF)-α, and interleukin (IL)-10. Topiramate reduces TNBS-induced colonic damage in a model of chronic experimental colitis and normalizes the stool consistency and anus appearance. Additionally, topiramate significantly reduced the concentration of ALP, fecal hemoglobin, fecal calprotectin, TNF-α, and IL-10, demonstrating it to be a promising pharmacological approach for the treatment of IBD in the future. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies)

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16 pages, 1476 KiB

Open AccessArticle

Serological Biomarkers of Extracellular Matrix Turnover and Neutrophil Activity Are Associated with Long-Term Use of Vedolizumab in Patients with Crohn’s Disease

by Marta S. Alexdottir, Arno R. Bourgonje, Morten A. Karsdal, Martin Pehrsson, Roberta Loveikyte, Hendrik M. van Dullemen, Marijn C. Visschedijk, Eleonora A. M. Festen, Rinse K. Weersma, Klaas Nico Faber, Gerard Dijkstra and Joachim H. Mortensen

Int. J. Mol. Sci. 2022, 23(15), 8137; https://doi.org/10.3390/ijms23158137 - 23 Jul 2022

Cited by 11 | Viewed by 2489

Abstract

Crohn’s disease (CD) is a relapsing-remitting inflammatory disease of the gastrointestinal (GI) tract characterized by increased extracellular matrix (ECM) remodeling. The introduction of the α4β7-integrin inhibitor vedolizumab (VEDO) has improved disease management, although there is a high rate of primary non-response in patients [...] Read more.

Crohn’s disease (CD) is a relapsing-remitting inflammatory disease of the gastrointestinal (GI) tract characterized by increased extracellular matrix (ECM) remodeling. The introduction of the α4β7-integrin inhibitor vedolizumab (VEDO) has improved disease management, although there is a high rate of primary non-response in patients with CD. We studied whether ECM biomarkers of neutrophil activity and mucosal damage could predict long-term response to VEDO in patients with CD. Serum levels of human neutrophil elastase (HNE)-derived fragments of calprotectin (CPa9-HNE), and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), and VI (C6Ma3) collagen, type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n = 32) before VEDO therapy. Long-term response was defined as VEDO treatment of at least 12 months. CPa9-HNE was significantly increased at baseline in non-responders compared with responders (p < 0.05). C1M, C3M, C4M, C6Ma3, and PRO-C4 were also significantly increased at baseline in non-responders compared with responders (all p < 0.05). All biomarkers were associated with response to VEDO (all p < 0.05). To conclude, baseline levels of serum biomarkers for neutrophil activity and mucosal damage are linked to the pathology of CD, and are associated with long-term use of VEDO in patients with CD. Therefore, these biomarkers warrant further validation and could aid in therapeutic decision-making concerning vedolizumab therapy. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies)

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Review

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26 pages, 2128 KiB

Open AccessReview

CD4 T-Cell Subsets and the Pathophysiology of Inflammatory Bowel Disease

by Raquel Gomez-Bris, Angela Saez, Beatriz Herrero-Fernandez, Cristina Rius, Hector Sanchez-Martinez and Jose M. Gonzalez-Granado

Int. J. Mol. Sci. 2023, 24(3), 2696; https://doi.org/10.3390/ijms24032696 - 31 Jan 2023

Cited by 70 | Viewed by 11341

Abstract

Inflammatory bowel disease (IBD) is an umbrella term for the chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, manifesting as Crohn’s disease (CD) or ulcerative colitis (UC). IBD is characterized by exacerbated innate and adaptive immunity in the gut in association with microbiota [...] Read more.

Inflammatory bowel disease (IBD) is an umbrella term for the chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, manifesting as Crohn’s disease (CD) or ulcerative colitis (UC). IBD is characterized by exacerbated innate and adaptive immunity in the gut in association with microbiota dysbiosis and the disruption of the intestinal barrier, resulting in increased bacterial exposure. In response to signals from microorganisms and damaged tissue, innate immune cells produce inflammatory cytokines and factors that stimulate T and B cells of the adaptive immune system, and a prominent characteristic of IBD patients is the accumulation of inflammatory T-cells and their proinflammatory-associated cytokines in intestinal tissue. Upon antigen recognition and activation, CD4 T-cells differentiate towards a range of distinct phenotypes: T helper(h)1, Th2, Th9, Th17, Th22, T follicular helper (Tfh), and several types of T-regulatory cells (Treg). T-cells are generated according to and adapt to microenvironmental conditions and participate in a complex network of interactions among other immune cells that modulate the further progression of IBD. This review examines the role of the CD4 T-cells most relevant to IBD, highlighting how these cells adapt to the environment and interact with other cell populations to promote or inhibit the development of IBD. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies)

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25 pages, 2865 KiB

Open AccessReview

Pathophysiology of Inflammatory Bowel Disease: Innate Immune System

by Angela Saez, Beatriz Herrero-Fernandez, Raquel Gomez-Bris, Hector Sánchez-Martinez and Jose M. Gonzalez-Granado

Int. J. Mol. Sci. 2023, 24(2), 1526; https://doi.org/10.3390/ijms24021526 - 12 Jan 2023

Cited by 155 | Viewed by 34175

Abstract

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and [...] Read more.

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies)

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