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.
MeSH terms
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Acute Lung Injury / chemically induced
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Acute Lung Injury / immunology
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Acute Lung Injury / metabolism*
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Acute Lung Injury / pathology
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Animals
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Blotting, Western
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Bronchoalveolar Lavage Fluid / chemistry
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Cytokines / biosynthesis
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Down-Regulation
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / immunology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression
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Interleukin-1 Receptor-Associated Kinases / genetics
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Interleukin-1 Receptor-Associated Kinases / immunology
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Interleukin-1 Receptor-Associated Kinases / metabolism
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Intubation, Intratracheal
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / immunology
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lipopolysaccharides / adverse effects
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Lipopolysaccharides / pharmacology
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Lung / immunology
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Lung / metabolism*
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Lung / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Plasminogen Activator Inhibitor 1* / deficiency
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Plasminogen Activator Inhibitor 1* / genetics
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Plasminogen Activator Inhibitor 1* / immunology
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Signal Transduction* / genetics
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Signal Transduction* / immunology
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / immunology
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Suppressor of Cytokine Signaling Proteins / metabolism
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism*
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Up-Regulation
Substances
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Cytokines
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Lipopolysaccharides
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Plasminogen Activator Inhibitor 1
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Socs1 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Toll-Like Receptor 4
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Interleukin-1 Receptor-Associated Kinases
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases