title: The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy.
abstract: Acute lung injury and acute kidney injury are severe complications in critically ill patients and synergistically increase mortality in intensive care units. Organ cross-talk between the kidney and the lung has been implicated recently as amplifying injury in each organ. Here we sought to identify a possible mechanism of acute kidney injury-induced acute lung injury using a mouse bilateral nephrectomy model. Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice were more resistant to lung injury including neutrophil infiltration, increased neutrophil elastase activity, and vascular permeability caused by bilateral nephrectomy compared with TLR4-wild-type C3H/HeN mice 6 h after surgery. High-mobility group protein B1 (HMGB1) is one agonist for TLR4. Its blood concentrations were increased significantly by bilateral nephrectomy. Blockade of HMGB1 by neutralizing antibody reduced neutrophil infiltration in TLR4-wild-type C3H/HeN but not in TLR4-mutant C3H/HeJ mice. However, HMGB1 blockade in a renal ischemia reperfusion model reduced pulmonary neutrophil infiltration independent from TLR4. Thus, an enhanced HMGB1-TLR4 pathway contributes to lung injury induced by bilateral nephrectomy and the other HMGB1-dependent pathway exists in pulmonary neutrophil infiltration caused by renal ischemia reperfusion. Targeting the HMGB1-TLR4 pathway might enable development of a new therapeutic strategy to improve the outcomes of severely ill patients with both acute lung and acute kidney injury.
authors.affiliation: 1] Department of Emergency and Critical Care Medicine, University Hospital, University of Tokyo, Tokyo, Japan [2] Department of Nephrology and Endocrinology, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.affiliation: Department of Nephrology and Endocrinology, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishizu
authors.affiliation: Department of Nephrology and Endocrinology, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Tsukamoto-Sumida
authors.affiliation: Department of Emergency and Critical Care Medicine, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hiruma
authors.affiliation: Department of Nephrology and Endocrinology, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Nephrology and Endocrinology, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Ogasawara
authors.affiliation: 1] Department of Nephrology and Endocrinology, University Hospital, University of Tokyo, Tokyo, Japan [2] 22nd Century Medical and Research Center, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hamasaki
authors.affiliation: Department of Emergency and Critical Care Medicine, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yahagi
authors.affiliation: Department of Nephrology and Endocrinology, University Hospital, University of Tokyo, Tokyo, Japan.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.affiliation: 1] Department of Nephrology and Endocrinology, University Hospital, University of Tokyo, Tokyo, Japan [2] Japan Science and Technology Agency/Japan International Cooperation Agency (JST/JICA), Science and Technology Research Partnership for Sustainable Development (SATREPS), Tokyo, Japan.
authors.forename: Eisei
authors.initials: E
authors.lastname: Noiri
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D002199:Capillary Permeability; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000293:injuries / Q000503:physiopathology; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D009154:Mutation; D009392:Nephrectomy / Q000009:adverse effects*; D020556:Neutrophil Infiltration; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4