Article

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

Division of Cardiothoracic Surgery, Cystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7065, USA.
AJP Lung Cellular and Molecular Physiology (impact factor: 3.66). 05/2009; 297(1):L52-63. DOI:10.1152/ajplung.90406.2008
Source: PubMed

ABSTRACT 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-kappaB 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.

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Keywords

actin cytoskeletal rearrangement
 
additional studies
 
competitive TLR4 inhibitor
 
Functional TLR4
 
gene transcription
 
hilar clamping
 
ischemia-reperfusion independent
 
lung ischemia-reperfusion injury
 
microvascular endothelial cell permeability
 
murine lung ischemia-reperfusion injury
 
murine model
 
myeloid differentiation factor 88
 
noninfectious inflammatory processes
 
novel mechanism
 
profound pulmonary edema
 
pulmonary microvascular endothelial monolayers
 
reperfusion times
 
signaling pathways
 
simulated warm ischemia
 
well-accepted role