Abstract
Mesenteric ischemia and reperfusion (I/R) injury can ensue from a variety of vascular diseases and represents a major cause of morbidity and mortality in intensive care units. It causes an inflammatory response associated with local gut dysfunction and remote organ injury. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of metabolic homeostasis. The catalytic α1 subunit is highly expressed in the intestine and vascular system. In loss-of-function studies, we investigated the biological role of AMPKα1 in affecting the gastrointestinal barrier function. Male knock-out (KO) mice with a systemic deficiency of AMPKα1 and wild-type (WT) mice were subjected to a 30 min occlusion of the superior mesenteric artery. Four hours after reperfusion, AMPKα1 KO mice exhibited exaggerated histological gut injury and impairment of intestinal permeability associated with marked tissue lipid peroxidation and a lower apical expression of the junction proteins occludin and E-cadherin when compared to WT mice. Lung injury with neutrophil sequestration was higher in AMPKα1 KO mice than WT mice and paralleled with higher plasma levels of syndecan-1, a biomarker of endothelial injury. Thus, the data demonstrate that AMPKα1 is an important requisite for epithelial and endothelial integrity and has a protective role in remote organ injury after acute ischemic events.
Highlights
Mesenteric ischemia is an extremely morbid condition, with mortality in the range of 60–80%, despite advances in diagnosis time and perioperative care
As the condition progresses during ischemia and reperfusion (I/R) injury, the loss of the mucosal barrier function and the systemic inflammatory response can lead to distant organ damage resulting in multiple organ dysfunction syndrome (MODS) [2,3]
Since an impaired intestinal barrier function is one of the key pathological factors of serious complications and negative outcomes after gut I/R injury [2,3], we investigated the biological role of AMPKα1 on affecting the epithelial expression of occludin and E-cadherin
Summary
Mesenteric ischemia is an extremely morbid condition, with mortality in the range of 60–80%, despite advances in diagnosis time and perioperative care. Mesenteric ischemia can be caused by several circumstances, most commonly either an embolic event, thrombotic event or a low-flow state of the intestinal vasculature due to systemic hypotension, major cardiovascular surgery or trauma [1,2]. As the condition progresses during ischemia and reperfusion (I/R) injury, the loss of the mucosal barrier function and the systemic inflammatory response can lead to distant organ damage resulting in multiple organ dysfunction syndrome (MODS) [2,3]. Of these distant organs, the lung appears to be the earliest remote organ affected by this pathogenic process [4]
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