Mice carrying an endogenous deletion of the 3′-AU-rich region of the TNFα gene develop a Crohn's disease-like phenotype: A key role of TNFα in the pathogenesis of chronic intestinal inflammation

1998 ◽  
Vol 114 ◽  
pp. A954 ◽  
Author(s):  
F. Cominelli ◽  
D. Kontoyiannis ◽  
T.T. Pizarro ◽  
G. Kollias
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Inflammation ◽  
Rich Region ◽  
Chronic Intestinal Inflammation

scholarly journals Extracellular vesicles package dsDNA to aggravate Crohn’s disease by activating the STING pathway

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Fan Zhao ◽  
Tao Zheng ◽  
Wenbin Gong ◽  
Jie Wu ◽  
Haohao Xie ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Extracellular Vesicles ◽  
Intestinal Inflammation ◽  
Therapeutic Effects ◽  
Murine Colitis ◽  
Sting Pathway ◽  
Deficient Mice

AbstractCrohn’s disease (CD) is an intestinal immune-dysfunctional disease. Extracellular vesicles (EVs) are membrane-enclosed particles full of functional molecules, e.g., nuclear acids. Recently, EVs have been shown to participate in the development of CD by realizing intercellular communication among intestinal cells. However, the role of EVs carrying double-strand DNA (dsDNA) shed from sites of intestinal inflammation in CD has not been investigated. Here we isolated EVs from the plasma or colon lavage of murine colitis and CD patients. The level of exosomal dsDNA, including mtDNA and nDNA, significantly increased in murine colitis and active human CD, and was positively correlated with the disease activity. Moreover, the activation of the STING pathway was verified in CD. EVs from the plasma of active human CD triggered STING activation in macrophages in vitro. EVs from LPS-damaged colon epithelial cells were also shown to raise inflammation in macrophages via activating the STING pathway, but the effect disappeared after the removal of exosomal dsDNA. These findings were further confirmed in STING-deficient mice and macrophages. STING deficiency significantly ameliorated colitis. Besides, potential therapeutic effects of GW4869, an inhibitor of EVs release were assessed. The application of GW4869 successfully ameliorated murine colitis by inhibiting STING activation. In conclusion, exosomal dsDNA was found to promote intestinal inflammation via activating the STING pathway in macrophages and act as a potential mechanistic biomarker and therapeutic target of CD.

scholarly journals Comorbid Inflammatory Diseases of Digestive System and Eye

2021 ◽  
Vol 18 (1) ◽  
pp. 20-29
Author(s):  
S. A. Bulgakov ◽  
G. M. Chernakova ◽  
E. A. Kleshcheva ◽  
S. V. Simonova
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Inflammatory Bowel Diseases ◽  
Intestinal Inflammation ◽  
Ophthalmological Examination ◽  
Extraintestinal Manifestations ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases, which are often accompanied by inflammation of other organs. This article presents modern data on etiology, pathogenesis and clinical course of inflammatory bowel diseases, as well as information on extraintestinal eye manifestations of nonspecific ulcerative colitis and Crohn’s disease. The role of microbiota, genetic factors, immune system defects in pathogenesis of intestinal inflammation and extraintestinal eye manifestations is considered. The possibility the development of ophthalmopathology not only against the background of intestinal inflammation, but also as a consequence of therapeutic and surgical methods of treatment of ulcerative colitis and Crohn’s disease is noted. The peculiarities of the course of episcleritis/scleritis, keratitis, uveitis, chorioretinitis, optical neuritis for patients with inflammatory bowel diseases are considered. The presence of these complications may reflect the activity of the underlying disease, which in some cases requires correction of therapy. Anterior uveitis and episcleritis/scleritis are the most common extraintestinal manifestations of inflammatory bowel disease. Inflammation of tissues of the posterior segment of the eye and optic nerve against the background of ulcerative colitis and Crohn’s disease are less common, but are of clinical importance, as they can catastrophically damage the structures of the eye and, as a consequence, lead to complete blindness. Considering the possibility of mild clinical symptoms and asymptomatic course of inflammation in the eye envelopes, the importance of ophthalmological examination of all patients with ulcerative colitis and Crohn’s disease is emphasized. Aspects of modern therapy of ophthalmopathology and background intestinal inflammation are highlighted. Biological preparations — antagonists of pro-inflammatory cytokines — have been identified as the most promising in the treatment of inflammatory intestinal diseases and extraintestinal manifestations. The important role of proper nutrition and biologically active supplements containing omega-3 fatty acids, vitamin D, microelements, was noted as auxiliary therapy of both intestinal and extraintestinal inflammation.

Calprotectin or Lactoferrin: Do They Help

2016 ◽  
Vol 34 (1-2) ◽  
pp. 98-104 ◽  
Author(s):  
Emily K. Wright
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Inflammation ◽  
Gastrointestinal Symptoms ◽  
Treat To Target ◽  
Clinical Relapse ◽  
Markers Of Inflammation ◽  
Fecal Biomarkers

Background: The diagnosis and monitoring of inflammatory bowel disease (IBD) has traditionally relied on clinical assessment, serum markers of inflammation and endoscopic examination. Fecal biomarkers such as calprotectin (FC) and lactoferrin (FL) are predominantly derived from neutrophils, are easily detectable in the feces and are now established as valuable markers of intestinal inflammation. In recent years, a ‘treat to target' concept has emerged for the management of IBD. Adequate control of inflammation in IBD at a biochemical level is quickly becoming an important target in IBD management. Key Messages: Fecal biomarkers have been shown to be significantly and consistently increased in both adult and pediatric patients with IBD versus those without IBD. Fecal biomarkers are therefore useful in determining those patients with gastrointestinal symptoms who are likely to benefit from colonoscopy versus those in whom colonoscopy is likely to be normal. Fecal biomarkers correlate significantly with endoscopic disease in both Crohn's disease and ulcerative colitis. Suggested cutoffs for FC for endoscopically active disease in IBD range from 50 to 280 μg/g. Fecal biomarkers reflect the success of treatment intensification and can help predict clinical relapse. Both FC and FL are accurate in the detection of postoperative endoscopic recurrence of Crohn's disease, and FC may be clinically useful in predicting those patients with acute severe ulcerative colitis who may progress to colectomy. There are limitations to these fecal tests including a false positive rate and intra-individual variability. Conclusions: This review focuses on the role of fecal biomarkers in the diagnosis, monitoring and management of IBD and how best to interpret results. We will discuss the emerging role of these biomarkers in the IBD management landscape including FC-guided drug dosing and the development of home-based testing and e-health applications. Fecal biomarker results must always be interpreted in a clinical context. Endoscopic assessment remains the gold standard for diagnosis and monitoring of IBD.

VEGF, basic-FGF, and TGF-beta in Crohn's disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation

2001 ◽  
Vol 96 (3) ◽  
pp. 822-828 ◽  
Author(s):  
Shigeo Kanazawa ◽  
Tsukasa Tsunoda ◽  
Eishi Onuma ◽  
Toshimitsu Majima ◽  
Mitsuyasu Kagiyama ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Inflammation ◽  
Tgf Beta ◽  
Basic Fgf ◽  
Chronic Intestinal Inflammation

scholarly journals Antibodies to interleukin 12 abrogate established experimental colitis in mice.

1995 ◽  
Vol 182 (5) ◽  
pp. 1281-1290 ◽  
Author(s):  
M F Neurath ◽  
I Fuss ◽  
B L Kelsall ◽  
E Stüber ◽  
W Strober
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Murine Model ◽  
Cd4 T Cells ◽  
Intestinal Inflammation ◽  
Interleukin 12 ◽  
Trinitrobenzene Sulfonic Acid ◽  
Ifn Gamma ◽  
Chronic Intestinal Inflammation

In this study, we describe a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal application of low doses of TNBS in BALB/c and SJL/J mice resulted in a chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, an illness that mimics some characteristics of Crohn's disease in humans. The colon of TNBS-treated mice on day 7 was marked by infiltration of CD4+ T cells; furthermore, in situ polymerase chain reaction studies revealed high levels of interferon (IFN)-gamma mRNA in diseased colons. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion: a 20-50-fold increase in IL-2 and IFN-gamma levels and a 5-fold decrease in IL-4 levels as compared with those of stimulated LP CD4+ T cells from control BALB/c mice. Administration of monoclonal anti-IL-12 antibodies to the TNBS-treated mice both early (at 5 d) and late (at 20 d) after induction of colitis led to a striking improvement in both the clinical and histopathological aspects of the disease and frequently abrogated the established colitis completely. Furthermore, LP CD4+ T cells isolated from anti-IL-12-treated mice failed to secrete IFN-gamma upon in vitro stimulation. In summary, the data demonstrate the pivotal role of IL-12 and IFN-gamma in a TNBS-induced murine model of chronic intestinal inflammation. Furthermore, they suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease.

scholarly journals PAR-1 Antagonism to Promote Gut Mucosa Healing in Crohn’s Disease Patients: A New Avenue for CVT120165

2021 ◽  
Vol 27 (Supplement_2) ◽  
pp. S33-S37 ◽  
Author(s):  
Jean-Paul Motta ◽  
Celine Deraison ◽  
Sylvie Le Grand ◽  
Bruno Le Grand ◽  
Nathalie Vergnolle
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Cell Activation ◽  
Intestinal Inflammation ◽  
Mucosal Damage ◽  
Mucosal Healing ◽  
New Paradigm ◽  
Bowel Diseases ◽  
Clinical Benefits ◽  
Chronic Intestinal Inflammation

Abstract A new paradigm has been added for the treatment of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. In addition to resolving symptoms and inflammatory cell activation, the objective of tissue repair and mucosal healing is also now considered a primary goal. In the search of mediators that would be responsible for delayed mucosal healing, protease-activated receptor-1 (PAR-1) has emerged as a most interesting target. Indeed, in Crohn’s disease, the endogenous PAR-1 agonist thrombin is drastically activated. Activation of PAR-1 is known to be associated with epithelial dysfunctions that hamper mucosal homeostasis. This review gathers the scientific evidences of a potential role for PAR-1 in mucosal damage and mucosal dysfunctions associated with chronic intestinal inflammation. The potential clinical benefits of PAR-1 antagonism to promote mucosal repair in CD patients are discussed. Targeted local delivery of a PAR-1 antagonist molecule such as CVT120165, a formulated version of the FDA-approved PAR-1 antagonist vorapaxar, at the mucosa of Crohn’s disease patients could be proposed as a new indication for IBD that could be rapidly tested in clinical trials.

scholarly journals Tumor Necrosis Factor’s Pathway in Crohn’s Disease: Potential for Intervention

2021 ◽  
Vol 22 (19) ◽  
pp. 10273
Author(s):  
Cristiano Pagnini ◽  
Fabio Cominelli
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Tumor Necrosis ◽  
Intestinal Inflammation ◽  
Innate Immune Responses ◽  
Chronic Disorder ◽  
Near Future ◽  
Necrosis Factor ◽  
Open Issues

Crohn’s disease (CD) is a chronic disorder characterized by full thickness patchy inflammation of the gastrointestinal tract. The pathogenesis is multifactorial and involves defective innate immune responses, microbiome alterations, and dysregulated activation of the acquired component of mucosal immunity. One of the molecular mediators that is involved at different levels in the initiation and progression of intestinal inflammation characteristic of CD is tumor necrosis factor (TNF). The present manuscript provides a comprehensive review focused on the potential role of TNF in the different phases of CD pathogenesis, particularly in light of its potential clinical implications. Currently available drugs blocking TNF are evaluated and discussed, specifically for open issues that still remain utilizing such therapy. TNF exerts a paramount role in the established phase of intestinal inflammation that characterizes CD patients, and anti-TNF biologics have definitely changed patient management, offering effective and safe options of treatment. Nonetheless, many patients still do not respond to anti-TNF therapy or experience unwanted side-effects. This could partially be due to the role that TNF plays in intestinal homeostasis that is particularly important during the early phase of the inflammatory process. In fact, emerging evidence supporting the dichotomous role of TNF and the identification of molecular markers will guide a more tailored and refined therapy for CD patients in the near future.

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