A role for autophagy in gut barrier disruption after alcohol and traumatic injury

Loyola University Chicago, Maywood IL

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Abstract

? DESCRIPTION (provided by applicant): Alcohol abuse remains one of the leading causes of morbidity and premature death in the world, and is a major risk factor associated with traumatic injury. Thermal injury is a major trauma that accounts for 40,000 hospitalizations annually, and over 50% of these patients have detectable blood alcohol (ethanol) levels at the time of admittance. In addition to the many complications associated directly with traumatic injury, disruptions of the gastrointestinal barrier and function frequently occur. This compromise of the gut barrier and subsequent translocation of bacteria and other pathogens can result in sepsis, multiple organ failure, and death. Our laboratory has previously shown decreases in gut epithelial cell proliferation, increases in inflammatory mediators, and bacterial translocation across the intestinal barrier when alcohol intoxication is present at the time of traumatic thermal injury. However, the mechanism by which gut inflammation and healing are perturbed following the combined insult is currently unknown. Autophagy is a highly conserved cellular process, and has been shown to be a key regulator of cellular proliferation and apoptosis, which are integral to maintaining gut homeostasis. Changes in autophagy may disrupt the inflammatory response and barrier integrity within the intestines. Thus, we hypothesize that the accumulation of autophagosomes in intestinal epithelial cells contributes to gut inflammation and barrier leakiness following combined alcohol and thermal injury. We have shown that the combined insult leads to an increase in LC3II/LC3I ratio. We have also shown that increased autophagy and inflammation markers can be rescued by treatment with the autophagy inhibitor 3- methyladenine given at the time of insult, further suggesting a role for autophagy in response to gut injury. The present study will investigate the role autophagy plays in inflammation and gut barrier leakiness following combined injury. Aim 1 will characterize the changes in autophagic flux following combined injury in intestinal epithelial cells, focusing on hallmark proteins within the autophagy signaling pathway. Aim 2 will determine if 3-MA treatment and/or LC3?-knockout suppress autophagic flux and restore tight junction protein expression and reduce acute inflammation and gut leakiness following combined injury. We expect this study will illuminate potential translational contributions to patient treatment to improve prognosis and survival following traumatic injury in the presence of alcohol intoxication.