Pathogenesis of Liver-Dependent Acute Lung Injury

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DESCRIPTION (provided by applicant): There are connections between hepatic function and acute lung injury: a) ARDS in the setting of hepatic failure is almost uniformly fatal; b) hepatic dysfunction is common in patients with ARDS; and c) animal studies demonstrate release of pro-inflammatory cytokines from the liver in response to endotoxemia or hepatic ischemia. In an in situ perfused swine preparation we find that endotoxin induced lung injury only occurs when the liver is included in the circulation. We conclude that endotoxin does not injure the lung directly, but "primes" the lung for injury that is mediated by endotoxin induced release of mediators from the liver. We hypothesize that: a) Direct effects of endotoxin prime the lung for injury, but injury requires mediators released from the liver; b) Endotoxemia induces increased hepatic expression of gene(s) encoding protein(s) secreted into the circulation that mediate liver dependent lung injury, c) Bone marrow derived stem cells are critical modulators of the acute inflammatory response to endotoxemia in both the liver and the lungs and; d) Suppression of endotoxin induced acute inflammation and lung injury by bone marrow cells is primarily an effect of a subset of non-hematopoietic, mesenchymal-like stem cells. We will test these hypotheses by: 1) Determining whether endotoxin "priming" of the lung for injury is necessary for injury caused by endotoxin induced release of mediators from the liver, determining molecular responses to endotoxemia in both the lungs and liver and identifying endotoxin induced mediators produced in the liver and released into the circulation that mediate lung injury; 2) Determining effects of bone marrow derived cells on endotoxin induced inflammation (lung and liver) and release of mediators by the liver, characterizing effects of these cells on endotoxin induced molecular responses, determining whether bone marrow cells must be delivered to both the lungs and the liver to prevent lung injury, and determining whether the population of effective marrow derived cells is non-hematopoietic and mesenchymal-like; and 3) Determining in vivo the effects of access to an expanded pool of bone marrow cells on endotoxin-induced inflammation and lung injury and characterizing the populations of cells recruited to the lungs and the liver in vivo following endotoxemia in a parabiotic mouse preparation. These studies will elucidate mechanisms of acute lung inflammation and injury and identify novel potentials for therapy.