Mucosal healing in inflammatory bowel diseases: a systematic review

Neurath, Markus F.; Travis, Simon

doi:10.1136/gutjnl-2012-302830

Cited by 714 publications

(536 citation statements)

References 189 publications

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“…Many of these new therapeutic approaches have been developed on the basis of studies in IBD mouse models, genetic studies, analyses of IBD tissues and new insights into inflammatory pathways in other chronic inflammatory disorders, such as rheumatoid arthritis and psoriasis 97,117,147,148 . Some of these new agents might gain approval by FDA and the European Medicines Agency and might enable new strict end points in IBD therapy to be achieved 149,150 , including mucosal healing on endoscopy, deep remission (clin ical remission plus mucosal healing), transmural healing and histological healing, thereby raising the bar for future drugs in IBD therapy and possibly preventing severe IBD associated complications such as surgery and hospitalizations. In this context, new cytokine and signalling block ers have yielded promising results and will probably add to our future clinical armamen tarium in patients with IBD 106,115 .…”

Section: Discussionmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

530

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: Discussionmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

530

403

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“…The use of immunosuppressive and/or anti-inflammatory compounds has a limited ability to facilitate mucosal healing [40,41], and yet the disrupted mucosal barrier integrity is a key component in the pathogenesis of UC. Barrier dysfunction enables the ingress of luminal antigens and pathogens, and the continuous activation of a proinflammatory immune response in the lamina propria and the associated chronic inflammation that is the hallmark of UC.…”

Section: Discussionmentioning

confidence: 99%

Restoring Mucosal Barrier Function and Modifying Macrophage Phenotype with an Extracellular Matrix Hydrogel: Potential Therapy for Ulcerative Colitis

Keane

Dziki

Sobieski

et al. 2016

ECCOJC

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“…A recent series of clinical studies have shown that complete regeneration of the intestinal mucosa, called ''mucosal healing'', predicts long-term remission and low risk of surgical treatment in IBD patients [3]. Therefore the importance of intestinal epithelial cells (IECs) in IBD is sharply increasing, and thus gathering much attention of many researchers.…”

Section: Introductionmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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Mucosal healing in inflammatory bowel diseases: a systematic review

Cited by 714 publications

References 189 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Restoring Mucosal Barrier Function and Modifying Macrophage Phenotype with an Extracellular Matrix Hydrogel: Potential Therapy for Ulcerative Colitis

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

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