Abstract
BackgroundAcute 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.MethodsWild-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.ResultsLPS-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.ConclusionsThe 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.
Highlights
Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain major causes of morbidity and mortality in critically ill patients [1]
We demonstrate for the first time that Sprouty-related EVH1-domain-containing protein (Spred)-2 controls the development of LPS-induced lung inflammation by negatively regulating the extracellular signal-regulated kinase (ERK)-Mitogen-activated protein kinase (MAPK) pathway
In WT mice, levels of TNF-a, CXCL2, CCL2 and IL10 were not statistically different between DMSO/LPS and U0126/LPS groups. These results suggest that the enhanced leukocyte infiltration and cytokine responses observed in Spred-22/2 mice are largely dependent on enhanced Ras-ERKMAPK activity
Summary
Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain major causes of morbidity and mortality in critically ill patients [1]. ALI/ARDS are characterized by massive leukocyte infiltration into the lung, which causes acute respiratory failure associated with severe inflammation and diffuse alveolar damage [2]. Acute respiratory failure is the consequence of a complex interaction of epithelial cells, endothelial cells and leukocytes with soluble factors, such as the bacterial endotoxin lipopolysaccharide (LPS) and endogenous cytokines [3,4,5]. Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. 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
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