Intestinal growth factors: Potential use in the treatment of inflammatory bowel disease and their role in mucosal healing

Krishnan, Kumar; Arnone, Baron; Buchman, Alan L.

doi:10.1002/ibd.21316

Cited by 100 publications

(81 citation statements)

References 93 publications

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“…CD is associated with structural damage and destruction of the bowel wall (31). Epithelial regeneration is a crucial step in mucosal healing and this mechanism requires the coordinated activity of IEC, Paneth cells, and goblet cells to restore intestinal barrier function (32)(33)(34). Mice carrying both Nod1 and Nod2 deletion have decreased paracellular permeability and a higher susceptibility to dextran sulfate sodium-induced colitis, highlighting a potential role of Nod receptors in the maintenance of intestinal barrier function (35).…”

Section: Discussionmentioning

confidence: 99%

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

Zanello

Goethel

Rouquier

et al. 2016

The Journal of Immunology

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Loss of function in the NOD2 gene is associated with a higher risk of developing Crohn’s disease (CD). CD is characterized by activation of T cells and activated T cells are involved in mucosal inflammation and mucosal damage. We found that acute T cell activation with anti-CD3 mAb induced stronger small intestinal mucosal damage in NOD2−/− mice compared with wild-type mice. This enhanced mucosal damage was characterized by loss of crypt architecture, increased epithelial cell apoptosis, delayed epithelial regeneration and an accumulation of inflammatory cytokines and Th17 cells in the small intestine. Partial microbiota depletion with antibiotics did not decrease mucosal damage 1 d after anti-CD3 mAb injection, but it significantly reduced crypt damage and inflammatory cytokine secretion in NOD2−/− mice 3 d after anti-CD3 mAb injection, indicating that microbial sensing by Nod2 was important to control mucosal damage and epithelial regeneration after anti-CD3 mAb injection. To determine which cells play a key role in microbial sensing and regulation of mucosal damage, we engineered mice carrying a cell-specific deletion of Nod2 in villin and Lyz2-expressing cells. T cell activation did not worsen crypt damage in mice carrying either cell-specific deletion of Nod2 compared with wild-type mice. However, increased numbers of apoptotic epithelial cells and higher expression of TNF-α and IL-22 were observed in mice carrying a deletion of Nod2 in Lyz2-expressing cells. Taken together, our results demonstrate that microbial sensing by Nod2 is an important mechanism to regulate small intestinal mucosal damage following acute T cell activation.

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Section: Discussionmentioning

confidence: 99%

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

Zanello

Goethel

Rouquier

et al. 2016

The Journal of Immunology

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“…A more direct approach to facilitate the intrinsic epithelial repair system may be adding the growth factors to promote proliferation of the stem-progenitor population [113]. Accordingly, several growth factors have been challenged for its use in treatment of IBD patients.…”

Section: Iecs As Target Cells For the Treatment Of Ibdmentioning

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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“…To provide chemical stimulation of the PVN, three different doses of glutamate (3,6, and 12 µg in a volume of 0.3 µL 0.9% saline) were microinjected into the PVN via a cannula connected to a micro-syringe with a polyethylene tube 10 min prior to the induction of UC. The injection lasted for 2 min and the injection cannula was left in place for an additional 5 min to prevent backflow [24] .…”

Section: Chemical Stimulation or Chemical Destruction Of Brain Nucleimentioning

confidence: 99%

“…In the past decade, some advancements have been achieved in our understanding of the role of environmental factors [2] . Enteric microflora, genetic and immune factors have been implicated in the pathogenesis of UC [3][4][5][6][7] . Barbara et al advanced a challenging hypothesis that human colitis may be caused by neurogenic inflammation in the gut [8] .…”

Section: Introductionmentioning

confidence: 99%

Glutamate microinjection into the hypothalamic paraventricular nucleus attenuates ulcerative colitis in rats

Zhang

Fei

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the effects of glutamate microinjection into hypothalamic paraventricular nucleus (PVN) on ulcerative colitis (UC) in rats and to explore the relevant mechanisms. Methods: 2,4,6-Trinitrobenzenesulfonic acid (100 mg/kg in 50% ethanol) was instilled into the colon of adult male SD rats to induce UC. A colonic damage score (CDS) was used to indicate the severity of the colonic mucosal damage. The pathological changes in the colonic mucosa were evaluated using immunohistochemistry, Western blotting, biochemical analyses or ELISA. Ten minutes before UC induction, drugs were microinjected into the relevant nuclei in rat brain to produce chemical stimulation or chemical lesion.Results: Microinjection of glutamate (3, 6 and 12 µg) into the PVN dose-dependently decreased the CDS in UC rats. This protective effect was eliminated after kainic acid (0.3 µg) was microinjected into PVN or into the nucleus tractus solitarius (NTS) that caused chemical lesion of these nuclei. This protective effect was also prevented when the AVP-V 1 receptor antagonist DPVDAV (200 ng) was microinjected into the NTS. The discharge frequency of the vagus was markedly decreased following microinjection of glutamate into the PVN. Microinjection of glutamate into the PVN in UC rats significantly increased the cell proliferation and anti-oxidant levels, and decreased the apoptosis and Bax and caspase 3 expression levels and reduced the pro-inflammatory factors in the colonic mucosa. Conclusion: The activation of hypothalamic PVN exerts protective effects against UC, which is mediated by the NTS and vagus. The effects may be achieved via anti-oxidative, anti-apoptotic, and anti-inflammatory factors.

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Intestinal growth factors: Potential use in the treatment of inflammatory bowel disease and their role in mucosal healing

Abstract: There are several growth factors responsible for epithelial repair. Preliminary studies using recombinant growth factors seem promising in IBD preclinical and clinical trials.

Cited by 100 publications

References 93 publications

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

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

Glutamate microinjection into the hypothalamic paraventricular nucleus attenuates ulcerative colitis in rats

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