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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083019-04
Application #
7805421
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2007-07-18
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$382,500
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Bustos, Martha L; Huleihel, Luai; Meyer, Ernest M et al. (2013) Activation of human mesenchymal stem cells impacts their therapeutic abilities in lung injury by increasing interleukin (IL)-10 and IL-1RN levels. Stem Cells Transl Med 2:884-95
Rojas, Mauricio; Parker, Richard E; Thorn, Natalie et al. (2013) Infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an ex-vivo perfused swine model. Stem Cell Res Ther 4:26
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Siore, Amsel M; Parker, Richard E; Cuppels, Chris et al. (2012) The role of mitochondrial oxidation in endotoxin-induced liver-dependent swine pulmonary edema. Pulm Pharmacol Ther 25:407-12