Abstract
Gut ischemia/reperfusion (I/R) injury is a common clinical problem associated with significant mortality and morbidities that result from systemic inflammation and remote organ dysfunction, typically acute lung injury. The mechanisms underlying the dissemination of gut-derived harmful mediators into the circulation are poorly understood. The objective of our study was to determine the role of mesenteric lymphatic circulation in the systemic and pulmonary inflammatory response to gut I/R. Using a murine intestinal I/R model, we evaluated whether and how blocking mesenteric lymph flow affects the inflammatory response in local tissues (gut) and remote organs (lungs). We further explored the mechanisms of post-I/R lymph-induced systemic inflammation by examining neutrophil activity and interaction with endothelial cells in vitro. Mice subjected to intestinal I/R displayed a significant inflammatory response in local tissues, evidenced by neutrophil infiltration into mucosal areas, as well as lung inflammation, evidenced by increased myeloperoxidase levels, neutrophil infiltration, and elevated microvascular permeability in the lungs. Mesenteric lymph duct ligation (MLDL) had no effect on gut injury per se, but effectively attenuated lung injury following gut I/R. Cell experiments showed that lymph fluid from post-I/R animals, but not pre-I/R, increased neutrophil surface CD11b expression and their ability to migrate across vascular endothelial monolayers. Moreover, post-I/R lymph upregulated neutrophil expression of pro-inflammatory cytokines and chemokines, which was mediated by a mechanism involving nuclear factor (NF)-κB signaling. Consistently, gut I/R activated NF-κB in lung neutrophils, which was alleviated by MLDL. In conclusion, all these data indicate that mesenteric lymph circulation contributes to neutrophil activation and lung inflammation following gut I/R injury partly through activating NF-κB.
Highlights
The gut plays a central role in the development of systemic inflammation and multiple organ dysfunction, including acute lung injury (ALI), a life-threatening condition commonly seen in critically ill patients such as those with sepsis, major trauma, shock, burn, and severe infection
The results showed that blocking C3a receptor, C5a receptor, or diamine oxidase (DAO) activity had negligible effect on post-I/R lymph elicited neutrophil activation (Supplementary Figure 4)
This study investigated the role of mesenteric lymphatic circulation in lung neutrophil infiltration and activation induced by intestinal I/R
Summary
The gut plays a central role in the development of systemic inflammation and multiple organ dysfunction, including acute lung injury (ALI), a life-threatening condition commonly seen in critically ill patients such as those with sepsis, major trauma, shock, burn, and severe infection. Accumulating evidence has implicated the mesenteric lymph in ALI following hemorrhagic shock [6], burn [7], endotoxemia [8], and severe intraperitoneal infection [9]. As all these studies were carried out in rodent models of injury that induce global homeostatic disturbance not originated from the gut, they are challenged by the difficulty in interpretation of the gut as the motor of critical illness. In order to distinguish the gut origin, we used a mouse model of intestinal I/R and tested the hypothesis that mesenteric lymphatics serve as an important conduit of gut-lung crosstalk in inflammation
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