Thirty-eight-negative-kinase-1 is a major mediator of trauma-induced intestinal injury and multi-organ failure

Einleitung:

Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier and can facilitate bacterial translocation leading to a systemic inflammatory response (SIRS) and/or multi-organ dysfunction syndromes (MODS). A variety of gastrointestinal disorders including inflammatory bowel disease has been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients putting the gut at the centre of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative-kinase-1 (TNK1) kinase whose activity is regulated merely by expression.

Ziele und Methodik:

We investigated the effect of TNK1 on intestinal integrity and its role in MODS using experimental mouse models.

Ergebnis:

TNK1 expression induced crypt-specific apoptosis leading to bacterial translocation, subsequent septic shock and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of RelA, and release of IL-6 and TNF-alpha. A TNF-alpha neutralising antibody, partially blocked development of intestinal damage. Vice-versa, gut-specific deletion of TNK1 protected the intestinal mucosa from colitis related injury and prevented cytokine release in the gut. Finally, TNK1 was found to be upregulated in the gut in a murine and porcine trauma models, and human inflammatory bowel disease.

Schlussfolgerung:

Targeting TNK1 in the intestinal epithelium may be a promising therapeutic approach in situations when the intestinal homoeostasis is disturbed.