Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis

Clark, Jessica; Gan, Heng; Samocha, Alexandr J.; Fox, Amy; Buchman, Timothy G.; Coopersmith, Craig M.

doi:10.1152/ajpgi.00012.2009

Cited by 60 publications

(63 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Systemic administration of EGF limits intestinal tissue damage, thereby reducing mortality in different animal models of noninfectious and infectious inflammation and intestinal injury. [30][31][32][33][34][35][36] In our study, pretreatment of MMP7 þ / þ mice with EGF reduced LPS-induced mortality ( Figure 3b) and LPS-induced intestinal permeability ( Figure 3c). Loss of gut barrier integrity can lead to efflux of bacterial gut flora or damage-associated molecular patterns, which can further activate inflammation by stimulation of PRRs in the submucosa, in the draining lymph nodes, or elsewhere.…”

Section: Mmp7 Is Expressed and Activated In The Paneth Cells Of The Isupporting

confidence: 59%

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

et al. 2014

View full text Add to dashboard Cite

Matrix metalloproteinase 7 (MMP7) is a member of the MMP family. In the small intestine, MMP7 is responsible for activating α-defensins, which are broad-spectrum anti-microbial peptides produced by the Paneth cells. We report that MMP7(-/-) mice are resistant to LPS-induced lethality and that this resistance is correlated with reduced levels of systemic cytokines. LPS induced the upregulation and activation of MMP7 in the small intestine, degranulation of the Paneth cells, and induction of intestinal permeability in MMP7(+/+) mice. In MMP7(-/-) mice, both LPS-induced intestinal permeability and consequent bacterial translocation to the mesenteric lymph nodes were reduced. Based on gene expression analysis and evaluation of intestinal damage, we attribute the protected state of MMP7(-/-) mice to reduced intestinal inflammation. Interestingly, we found that different α-defensins, namely Crp1 (DEFA1) and Crp4 (DEFA4), can stimulate IL-6 release in macrophages and ileum explants in a TLR4 independent way. We conclude that absence of MMP7 protects mice from LPS-induced intestinal permeability and lethality, and suggest that MMP7-activated α-defensins, in addition to their previously recognized bactericidal and anti-inflammatory roles, may exhibit pro-inflammatory activities in the intestine by activating macrophages and amplifying the local inflammatory response in the gut, leading to intestinal leakage and subsequent increase in systemic inflammation.

show abstract

Section: Mmp7 Is Expressed and Activated In The Paneth Cells Of The Isupporting

confidence: 59%

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In vivo intestinal permeability was measured using the fluorescein isothiocyanate-labeled dextran (FD-4) method as described [27] with modification. Rats were administered 500 mL of FD-4 (300 mg/mL; SigmaeAldrich) by oral gavage at 18 h after CLP and sham.…”

Section: In Vivo Permeability Assaymentioning

confidence: 99%

Protective effect of pioglitazone on sepsis-induced intestinal injury in a rodent model

Gao

Jiang

Xiao

et al. 2015

Journal of Surgical Research

View full text Add to dashboard Cite

“…decreased crypt proliferation (12)(13)(14)(15)(16)(17). Notably, sepsis induces intestinal hyperpermeability (18)(19)(20)(21).…”

mentioning

confidence: 99%

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

Lorentz

Liang

Meng

et al. 2017

Mol Med

Self Cite

View full text Add to dashboard Cite

Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the perijunctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK -/-and wild-type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK -/-mice (95% versus 24%, p < 0.0001). Intestinal permeability increased in septic WT mice compared with unmanipulated mice. In contrast, permeability in septic MLCK -/-mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK -/-mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8 and 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion, as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK -/-mice; however, survival was similar between septic MLCK -/-mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

show abstract

Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis

Cited by 60 publications

References 46 publications

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

Protective effect of pioglitazone on sepsis-induced intestinal injury in a rodent model

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

Contact Info

Product

Resources

About