title: Critical role of toll-like receptor 4 in hypoxia-inducible factor 1α activation during trauma/hemorrhagic shocky induced acute lung injury after lymph infusion in mice.
abstract: AB The nuclear transcription factor hypoxia-inducible factor 1[alpha] (HIF-1α) is a key regulator of gene expression under hypoxic and inflammatory conditions. The germline-encoded pattern recognition receptor toll-like receptor 4 (TLR4) recognizes molecular motifs shared by large groups of microorganisms as well as by endogenous ligands released from stressed and/or injured tissues. We have previously demonstrated that local inhibition of HIF-1α ameliorates lung injury induced by trauma/hemorrhagic shock (T/HS) in rats. In the current study, we directly determined the role of TLR4 in HIF-1α activation during T/HS-induced acute lung injury in mice. C3H/HeJ mice that harbor a TLR4 mutation and wild-type (WT) mice were infused T/HS or trauma/sham shock (T/SS) lymph from Sprague-Dawley rats. Evans blue dye lung permeability, lung water content, myeloperoxidase levels, and lung histological analysis confirmed that TLR4-deficient mice are resistant to lung injury after T/HS lymph infusion. Lungs from WT and TLR4mut mice after T/SS lymph infusion expressed negligible levels of HIF-1α. The induction of HIF-1α in lung homogenates from TLR4mut mice after T/HS or T/HS lymph infusion was markedly reduced as compared with their WT counterparts but remained elevated as compared with TLR4mut mice after T/SS lymph infusion. Endothelial cells from TLR4mut mice and silence of TLR4 in cells from WT mice showed a remarkable reduction of HIF-1α on T/HS lymph stimulation. Blocking of nuclear factor-κB activity by SN50 or Bay 11-7085 in WT cells diminished T/HS lymph-induced HIF-1α accumulation when compared with T/SS lymph incubation. Thus, our data suggest that TLR4 activation by T/HS is necessary for T/HS-induced lung injury and an augmented pulmonary HIF-1α response, which will provide more insights into the pathogenesis of shock-induced acute lung injury and identify potential therapeutic targets.
authors: Hong
authors: H
authors: Jiang
authors: Rong
authors: R
authors: Hu
authors: Lulu
authors: L
authors: Sun
authors: Dongdong
authors: D
authors: Chai
authors: Zhendong
authors: Z
authors: Cao
authors: Qifang
authors: Q
authors: Li
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D002199:Capillary Permeability; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism*; D008196:Lymph / Q000378:metabolism*; D008297:Male; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D017354:Point Mutation; D011654:Pulmonary Edema / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4