Role of toll-like receptor-4 in lung ischemia-reperfusion injury.
BACKGROUND
Toll-like receptor-4 has been implicated in modulating ischemia-reperfusion injury in cardiac, hepatic, renal, and cerebral models. However, its role in lung ischemia-reperfusion injury is unknown. We hypothesize that toll-like receptor-4 has a key role in initiating the inflammatory cascade in lung ischemia-reperfusion injury.


METHODS
We used toll-like receptor-4 specific short interference RNA to achieve toll-like receptor-4 knockdown in rats prior to undergoing ischemia and reperfusion. Lungs were explanted and studied for protein expression and markers of lung injury. Additional animals were evaluated for cellular uptake of toll-like receptor-4 short interference RNA. Toll-like receptor-4 short interference RNA localized to the alveolar macrophage.


RESULTS
In animals pretreated with toll-like receptor-4 short interference RNA, toll-like receptor-4 expression and mitogen-activated protein kinase phosphorylation were suppressed. Markers of lung injury including permeability index, myeloperoxidase content, and bronchoalveolar lavage inflammatory cell counts were all reduced with toll-like receptor-4 knockdown.


CONCLUSIONS
Toll-like receptor-4 is critical in the development of lung ischemia-reperfusion injury and its activation in the alveolar macrophage may be the initiating step.
Department of Surgery, Division of Thoracic Surgery, University of Washington, Seattle, Washington.
Heather E
HE
Merry
Department of Surgery, Division of Thoracic Surgery, University of Washington, Seattle, Washington.
Patrick
P
Phelan
Department of Surgery, Division of Thoracic Surgery, University of Washington, Seattle, Washington.
Mathew R
MR
Doak
Department of Surgery, Division of Thoracic Surgery, University of Washington, Seattle, Washington.
Minqing
M
Zhao
Department of Surgery, Division of Thoracic Surgery, University of Washington, Seattle, Washington.
Billanna
B
Hwang
Department of Surgery, Division of Thoracic Surgery, University of Washington, Seattle, Washington. Electronic address: msmmd@u.washington.edu.
Michael S
MS
Mulligan
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D012016:Reference Values; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism*
D015415:Biomarkers; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D009195:Peroxidase