ObjectiveTo determine whether gut-derived factors leading to organ injury and increased endothelial cell permeability would be present in the mesenteric lymph at higher levels than in the portal blood of rats subjected to hemorrhagic shock. This hypothesis was tested by examining the effect of portal blood plasma and mesenteric lymph on endothelial cell monolayers and the interruption of mesenteric lymph flow on shock-induced lung injury. Summary Background DataThe absence of detectable bacteremia or endotoxemia in the portal blood of trauma victims casts doubt on the role of the gut in the generation of multiple organ failure. Nevertheless, previous experimental work has clearly documented the connection between shock and gut injury as well as the concept of gut-induced sepsis and distant organ failure. One explanation for this apparent paradox would be that gut-derived inflammatory factors are reaching the lung and systemic circulation via the gut lymphatics rather than the portal circulation. MethodsHuman umbilical vein endothelial cell monolayers, grown in two-compartment systems, were exposed to media, shamshock, or postshock portal blood plasma or lymph, and permeability to rhodamine (1 OK) was measured. Sprague-Dawley rats were subjected to 90 minutes of sham or actual shock and shock plus lymphatic division (before and after shock). Lung permeability, pulmonary myeloperoxidase levels, alveolar apoptosis, and bronchoalveolar fluid protein content were used to quantitate lung injury. ResultsPostshock lymph increased endothelial cell monolayer permeability but not postshock plasma, sham-shock lymph/plasma, or medium. Lymphatic division before hemorrhagic shock prevented shock-induced increases in lung permeability to Evans blue dye and alveolar apoptosis and reduced pulmonary MPO levels. In contrast, division of the mesenteric lymphatics at the end of the shock period but before reperfusion ameliorated but failed to prevent increased lung permeability, alveolar apoptosis, and MPO accumulation. ConclusionsGut barrier failure after hemorrhagic shock may be involved in the pathogenesis of shock-induced distant organ injury via gut-derived factors carried in the mesenteric lymph rather than the portal circulation.Gut barrier failure, with the ensuing translocation of bacteria and endotoxin from the gut, has been proposed as a major contributor to the development of systemic infec- April 23, 1998. 518 tion and multiple organ failure (MOF) after shock.' Evidence of the association between gut injury and the subsequent development of a septic state and distant organ failure2-4 continues to increase. There are abundant clinical and experimental data that trauma and hemorrhage are associated with elevated systemic cytokine levels.7 In fact, MOF, including acute lung injury, after hemorrhagic shock appears to result from an overwhelming systemic inflammatory response driven by the release, activation, and interaction of endogenous cytokines.8'9 Thus, gut-derived cy-

The development of systemic inflammation, acute lung injury, and multiple organ failure after a major thermal injury, as well as nonthermal forms of trauma, remain relatively common causes of morbidity and mortality. During the past two decades, increasing recognition that the ischemic gut may contribute to the development of sepsis and organ failure in burn patients, as well as other critically ill patient populations, has led to new hypotheses to explain burn-induced multiple organ failure as well as highlighted the importance of early enteral nutrition. Thus, the goal of this review will be to provide a perspective on the evolution of the gut hypothesis of systemic inflammation and distant organ dysfunction.

Systematic review/guideline, level III.

Prognostic study, level III.