exploits the human fibrinolytic system to drive excess collagenolysis: implications in gut healing and identification of druggable targets.

08:00 EDT 11th October 2019 | BioPortfolio

Summary of "exploits the human fibrinolytic system to drive excess collagenolysis: implications in gut healing and identification of druggable targets."

Perforations, anastomotic leak and subsequent intraabdominal sepsis are among the most common and feared complications of invasive interventions in the colon and remaining intestinal tract. During physiologic healing, tissue protease activity is finely orchestrated to maintain the strength and integrity of the submucosa collagen layer in the wound. We have previously demonstrated in both mice and humans that the commensal microbe selectively colonizes wounded colonic tissues and disrupts the healing process by amplifying collagenolytic matrix-metalloprotease activity toward excessive degradation. Here we demonstrate for the first time a novel collagenolytic virulence mechanism by which is able to bind and locally activate the human fibrinolytic protease plasminogen (PLG), a protein present in high concentrations in healing colonic tissue. -mediated PLG activation leads to supraphysiologic collagen degradation; in this study, we demonstrate this concept both and . This pathoadaptive response can be mitigated with the PLG inhibitor tranexamic acid (TXA) in a fashion that prevented clinically significant complications in validated murine models of both and mediated colonic perforation. TXA has a proven clinical safety record and is FDA approved for topical application in invasive procedures, albeit for the prevention of bleeding rather than infection. As such, the novel pharmacologic effect described in this study may be translatable to clinical trials for the prevention of infectious complications of colonic healing.


Journal Details

This article was published in the following journal.

Name: American journal of physiology. Gastrointestinal and liver physiology
ISSN: 1522-1547


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