Mechanisms underlying disruption of intestinal epithelial barrier in critical illness

Lurie Children'S Hospital Of Chicago, Chicago IL

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Abstract

Impairment of the gut barrier integrity frequently occurs under various critical surgical circumstances such as post major surgery, shock, trauma, severe thermal injury, and sepsis. The gut barrier dysfunction plays an important role in amplifying inflammatory cascade and developing multiple organ failure in critically ill patients. To date, effective therapies for the gut barrier dysfunction are still limited. Although considerable progress has been made in elucidating the pathophysiologic mechanisms that lead to impairment of the gut barrier integrity, the molecular mechanisms by which the gut barrier dysfunction develops in critical surgical illness remain largely unknown. The integrity of the gut epithelium is mainly maintained by a complex network among tight junction (TJ) -associated proteins that are disrupted in critical and severe inflammatory conditions. However, it is unclear how disruption of TJ-associated molecular complex occurs in intestinal epithelial cells under severe inflammatory condictions. In preliminary experiments, we found that the 22-kDa peripheral myelin protein (PMP22) is a novel TJ-associated tetratransmembrane protein. Our preliminary data showed that (a) sepsis and inflammatory mediators induce intestinal epithelial barrier dysfunction, which is associated with down-regulation of PMP22 gene expression in intestines; (b) IFN-? plus TNF-? markedly impair intestinal epithelial permeability that is associated with inhibiting expression of PMP22 gene in intestinal epithelial cells; (c) silencing of PMP22 causes impairment of intestinal epithelial barrier integrity; and (d) knockdown of PMP22 results in decrease in ZO-1 and occludin expression. Together, our preliminary data strongly suggest that PMP22 is a key molecule for maintaining the integrity of TJ-complex. Furthermore, it seems that decrease in PMP22 levels contributes to development of sepsis-associated the gut barrier dysfunction. Therefore, we hypothesize that pro-inflammatory mediators repress PMP22 expression in intestinal epithelial cells, which subsequently affects levels of TJ molecules and attributes to impairment of the gut barrier function in critical surgical circumstances. We will test the hypothesis using advanced technologies involved in molecular and cellular biology, mouse genetic engineering, and using clinical relevant animal models and human specimens in the three Specific Aims including (1) to examine whether and how PMP22 maintains intestinal epithelial barrier integrity, (2) to study whether septic insults target PMP22, which subsequently contributes to impairment of the gut barrier integrity and progression of multiple vital organ injury, and (3) to investigate molecular mechanisms by which septic insult-derived mediators such as IFN-? and TNF-? suppress PMP22 expression in intestinal epithelial cells. Achievement of this project will fill gaps between understandings of the role of the gut epithelial barrier-associated molecules and pathogenesis of impairment of the gut barrier integrity in critical surgical circumstances. The new knowledge generated through this research will lead to development of novel strategies for prevention of gut barrier in critical surgical conditions.