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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/L52    most recent 90406.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Zanotti, G. Articles by Egan, T. M. PubMed PubMed Citation Articles by Zanotti, G. Articles by Egan, T. M.

Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema

¹Division of Cardiothoracic Surgery, ²Division of Pulmonary and Critical Care Medicine, Cystic Fibrosis Pulmonary Research and Treatment Center, ³Carolina Cardiovascular Biology Center, ⁴Department of Pathology and Laboratory Medicine, and ⁵Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Submitted 31 July 2008 ; accepted in final form 16 April 2009

Toll-like receptors (TLRs) of the innate immune system contribute to noninfectious inflammatory processes. We employed a murine model of hilar clamping (1 h) with reperfusion times between 15 min and 3 h in TLR4-sufficient (C3H/OuJ) and TLR4-deficient (C3H/HeJ) anesthetized mice with additional studies in chimeric and myeloid differentiation factor 88 (MyD88)- and TLR4-deficient mice to determine the role of TLR4 in lung ischemia-reperfusion injury. Human pulmonary microvascular endothelial monolayers were subjected to simulated warm ischemia and reperfusion with and without CRX-526, a competitive TLR4 inhibitor. Functional TLR4 solely on pulmonary parenchymal cells, not bone marrow-derived cells, mediates early lung edema following ischemia-reperfusion independent of MyD88. Activation of MAPKs and NF-B was significantly blunted and/or delayed in lungs of TLR4-deficient mice as a consequence of ischemia-reperfusion injury, but edema development appeared to be independent of activation of these signaling pathways. Pretreatment with a competitive TLR4 inhibitor prevented edema in vivo and reduced actin cytoskeletal rearrangement and gap formation in pulmonary microvascular endothelial monolayers subjected to simulated warm ischemia and reperfusion. In addition to its well-accepted role to alter gene transcription, functioning TLR4 on pulmonary parenchymal cells plays a key role in very early and profound pulmonary edema in murine lung ischemia-reperfusion injury. This may be due to a novel mechanism: regulation of endothelial cell cytoskeleton affecting microvascular endothelial cell permeability.

microvascular permeability; endothelial cell; pulmonary edema

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