Abstract
Although in vitro studies have previously demonstrated that mitogen-activated protein kinases are important for the activation of transcription factors and the regulation of proinflammatory mediators, the function of c-Jun NH2-terminal kinase (JNK) in acute lung injury (ALI) remains to be fully elucidated. The present study aimed to investigate the effect of the JNK selective inhibitor SP600125 on lipopolysaccharide (LPS)-induced ALI. Pulmonary edema, the expression of inflammatory cytokines and pathological alterations were found to be significantly attenuated in LPS-induced ALI following treatment with SP600125 in vivo. In vitro, it was demonstrated that SP600125 administration significantly improved A549 cell viability in a dose-dependent manner using the Cell Counting kit-8 and the 5-ethynyl-2′-deoxyuridine incorporation assay. Furthermore, flow cytometric analysis demonstrated that the apoptotic rate was significantly reduced in a concentration-dependent manner following SP600125 injection. At the molecular level, SP600125 treatment dose-dependently inhibited JNK activation and upregulated claudin-4 expression in vivo and in vitro. In combination, the results from the present study indicated that the JNK inhibitor SP600125 protected against LPS-induced ALI in vivo and in vitro, possibly by upregulating the expression of claudin-4.
Highlights
Acute lung injury (ALI) is a life‐threatening clinical disease characterized by acute respiratory distress syndrome, which may be caused by several different factors, including trauma, sepsis and pneumonia [1,2]
The results from the Enzyme-linked immunosorbent assay (ELISA) demonstrated that the expression of tumor necrosis factor‐α (TNF‐α) and IL‐6 in the bronchoalveolar lavage fluid (BALF) in the LPS‐treated rats was markedly increased compared with the rats in the control group
ALI is an acute and progressive respiratory disease, which is characterized by progressive diffuse bilateral pulmonary edema and inflammation [16]
Summary
Acute lung injury (ALI) is a life‐threatening clinical disease characterized by acute respiratory distress syndrome, which may be caused by several different factors, including trauma, sepsis and pneumonia [1,2]. Clinical studies have demonstrated that elevated levels of proinflammatory cytokines in the serum of patients with ALI are associated with an increased mortality rate [5]. Lung‐protective ventilation and corticosteroids have been shown to downregulate the level of inflammatory cytokines as well as decrease the mortality rate of patients with ALI [6]. Previous studies demonstrated that signaling pathways, including the nuclear factor‐κB (NF‐κB), mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase pathways, were upregulated in animal models of ALI [7,8,9]. The c‐Jun NH2‐terminal kinase (JNK) is a member of the MAPK family, which has been implicated in the regulation of inflammatory signals and other extracellular signals to intracellular target molecules [10,11]. The therapeutic effect and associated mechanism of SP600125 was analyzed in lipopolysaccharide (LPS)‐induced ALI in vivo and in vitro
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