Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis

Nighot, Prashant K.; Al–Sadi, Rana; Rawat, Manmeet; Guo, Shuzhen; Watterson, D. Martin; Thomas, Y.

doi:10.1152/ajpgi.00256.2015

Cited by 107 publications

(96 citation statements)

References 65 publications

(72 reference statements)

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Section: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 91%

“…In this context, expression of MMP9 was found to be increased in IBD, particularly in patients with ulcerative colitis 74 . Functional data in experimental models of inflammation have suggested an important role of MMP9 in impairing colonic epi thelial permeability and augmenting inflammation via activation of myosin light chain kinase (MLCK) 74 . Furthermore, MMP9 favoured angiogenesis and created a proteolytic environment in the inflamed gut of a mouse model of colitis that stimulated the influx of myeloid cells into the colonic epithelium and the prod uction of TNF 75,76 .…”

Section: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 91%

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Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

512

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: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 91%

Section: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 91%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

512

403

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“…Previous studies from our laboratory and other groups have also demonstrated a central role of MLCK in modulating intestinal TJ barrier function or intestinal permeability [30,31,44–46]. These studies indicated that an increase in MLCK expression leads to MLCK-catalyzed phosphorylation of myosin light chain, contraction of peri-junctional actin/ myosin filaments, and contractile tension-generated mechanical opening of the TJ barrier and an increase in intestinal permeability [31].…”

Section: Discussionmentioning

confidence: 83%

Intestinal barrier dysfunction in human necrotizing enterocolitis

Moore

Nighot

Reyes

et al. 2016

Journal of Pediatric Surgery

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Background Intestinal barrier dysfunction has been implicated in necrotizing enterocolitis (NEC), but has not been directly measured in human NEC. Methods Small intestines removed during surgery were immediately mounted in an Ussing chamber. mRNA expression of tight junction (TJ) proteins was measured with RT-PCR. Results Fifteen infants were included, 5 with NEC and 10 with other diagnoses. Average transepithelial resistance (TER) was 11.61 ± 1.65 Ω/cm2 in NEC specimens, 23.36 ± 1.48 Ω/cm2 at resection margin, and 46.48 ± 5.65 Ω/cm2 in controls. Average flux of permeability marker mannitol was 0.23 ± 0.06 μMol/cm2 per h in NEC, 0.04 ± 0.01 μMol/cm2 per h at resection margin, and 0.017 ± 0.004 μMol/cm2 per h in control tissue (p < 0.05). RT-PCR analysis showed marked decrease in mRNA expression of a TJ protein occludin in NEC affected tissue (p < 0.03 vs. control). Additionally, mRNA expression of myosin light chain kinase (MLCK), an important regulator of TJ permeability, was increased in NEC specimens. Conclusion These studies show for the first time that NEC intestinal tissue have increased intestinal permeability, even at grossly healthy-appearing resection areas. The increase in intestinal permeability in NEC appeared to be related in part to a decrease in occludin and an increase in MLCK expression. Level of evidence Level 2.

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“…In MMP-9 knock-out mice, DSS-induced colitis and the associated increase of intestinal permeability are attenuated [93]. Accordingly, selective inhibition of MMP-9 reduces disease severity in mice [94].…”

Section: Role Of Neutrophil-derived Moleculesmentioning

confidence: 99%

The Dual Role of Neutrophils in Inflammatory Bowel Diseases

Wéra

Lancellotti

Oury

2016

JCM

230

189

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Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are characterised by aberrant immunological responses leading to chronic inflammation without tissue regeneration. These two diseases are considered distinct entities, and there is some evidence that neutrophil behaviour, above all other aspects of immunity, clearly separate them. Neutrophils are the first immune cells recruited to the site of inflammation, and their action is crucial to limit invasion by microorganisms. Furthermore, they play an essential role in proper resolution of inflammation. When these processes are not tightly regulated, they can trigger positive feedback amplification loops that promote neutrophil activation, leading to significant tissue damage and evolution toward chronic disease. Defective chemotaxis, as observed in Crohn’s disease, can also contribute to the disease through impaired microbe elimination. In addition, through NET production, neutrophils may be involved in thrombo-embolic events frequently observed in IBD patients. While the role of neutrophils has been studied in different animal models of IBD for many years, their contribution to the pathogenesis of IBD remains poorly understood, and no molecules targeting neutrophils are used and validated for the treatment of these pathologies. Therefore, it is crucial to improve our understanding of their mode of action in these particular conditions in order to provide new therapeutic avenues for IBD.

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Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis

Abstract: Nighot P, Al-Sadi R, Rawat M, Guo S, Watterson DM, Ma T. Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis.

Cited by 107 publications

References 65 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Intestinal barrier dysfunction in human necrotizing enterocolitis

The Dual Role of Neutrophils in Inflammatory Bowel Diseases

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