title: Plasminogen activator inhibitor type-1 deficiency exaggerates LPS-induced acute lung injury through enhancing Toll-like receptor 4 signaling pathway.
abstract: Mice lacking plasminogen activator inhibitor-1 (PAI-1) did not affect lung injury induced by gram-positive bacteria pneumococcal pneumonia but worsened lung injury induced by gram-negative bacteria Klebsiella. The exact mechanisms have not been completely elucidated. In this study, we examined the signaling pathway of Toll-like receptor 4 (TLR4) with/without PAI-1 in acute lung injury (ALI) induced by lipopolysaccharides (LPS) in mice. PAI-1 knockout mice (n=60) and wild-type mice (n=60) were exposed to LPS intratracheal instillation. Different groups of mice were then sacrificed at 0 and 8 h after LPS instillation. PAI-1-/- mice showed increased excess lung water and elevated cytokines production and release. In addition, expression of TLR4 was up-regulated and the phosphorylation activation of extracellular regulating kinase (ERK) and c-Jun N-terminal kinase (JNK) were also increased in PAI-1 knockout mice compared to wild-type mice. Inversely, interleukin (IL)-1 receptor-associated kinase-M (IRAK-M) and suppressor of cytokine signaling 1 (SOCS1) were both significantly reduced in PAI-1-/-mice after LPS challenge. PAI-1 deletion increased lung injury induced by LPS through up-regulation of TLR4, ERK and C-JNK and down-regulation of TLR4 negative regulators.
authors.affiliation: aDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Hua
authors.forename: Weiying
authors.initials: W
authors.lastname: Ren
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007442:Intubation, Intratracheal; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases