RRC ID 67884
Author Xu Y, Ito T, Fushimi S, Takahashi S, Itakura J, Kimura R, Sato M, Mino M, Yoshimura A, Matsukawa A.
Title Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice.
Journal PLoS One
Abstract BACKGROUND:Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation.
METHODS:Wild-type (WT) mice and Spred-2(-/-) mice were exposed to intratracheal LPS (50 µg in 50 µL PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/-) mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells.
RESULTS:LPS-induced acute lung inflammation was significantly exacerbated in Spred-2(-/-) mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2(-/-) mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells.
CONCLUSIONS:The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the development of LPS-induced lung inflammation by negatively regulating the ERK-MAPK pathway. Thus, Spred-2 may represent a therapeutic target for the treatment of ALI.
Volume 9(9)
Pages e108914
Published 2014-1-1
DOI 10.1371/journal.pone.0108914
PII PONE-D-14-17685
PMID 25275324
PMC PMC4183529
MeSH Acute Disease Animals Butadienes / pharmacology Cell Line Chemokine CCL2 / metabolism Chemokine CXCL2 / metabolism Disease Progression* Enzyme Activation / drug effects Epithelial Cells / drug effects Epithelial Cells / metabolism Epithelial Cells / pathology Extracellular Signal-Regulated MAP Kinases / metabolism Lipopolysaccharides Macrophages, Alveolar / drug effects Macrophages, Alveolar / metabolism Macrophages, Alveolar / pathology Mice, Inbred C57BL Mice, Knockout Nitriles / pharmacology Pneumonia / enzymology Pneumonia / metabolism* Pneumonia / pathology* Repressor Proteins / deficiency* Repressor Proteins / metabolism Tumor Necrosis Factor-alpha / metabolism
IF 2.74
Human and Animal Cells RAW 264(RCB0535)