IGFBP7 aggravates sepsis-induced acute lung injury by activating the ERK1/2 pathway
Abstract
Introduction. Sepsis is characterized by an infection-caused acute inflammatory response, which is usually accompanied by multiple organ failure, especially lung injury. During sepsis, a large number of endotoxins such as lipopolysaccharides (LPSs) are secreted from Gram-negative bacteria. However, the mechanisms underlying acute lung dysfunction caused by sepsis have not yet been well defined. Material and methods. To identify the mechanism of insulin-like growth factor binding protein 7 (IGFBP7) in acute lung injury during sepsis, the effects of IGFBP7 shRNA were evaluated in a model of cecal ligation puncture (CLP)-induced sepsis in mice. Histologic evaluation of the effects of IGFBP7 on CLP-induced acute lung injury was performed by H&E staining. Murine pulmonary microvascular endothelial cells (MPVECs) were transfected with shIGFBP7 or shNC before treatment with LPS to mimic the sepsis-induced lung dysfunction. The effects of CLP or LPS on IGFBP7 expression and the activation of ERK1/2 pathway were analyzed by western blot. MTT and LDH assays were used to measure the viability of MPVECs under different treatment regimes. The apoptosis rate of MPVECs in different groups was detected by flow-cytometry analysis. Results. IGFBP7 was strongly up-regulated in sepsis-induced acute lung injury in mice. IGFBP7 silencing attenuated sepsis-induced apoptosis and cytotoxicity in MPVECs. Furthermore, the activation of ERK1/2 pathway was regulated by IGFBP7 during sepsis-induced inflammation. IGFBP7 inhibition by RNA interference in MPVECs attenuated CLP-induced morphological features of lung dysfunction. The knockdown of IGFBP7 attenuated LPS-induced MPVECs’ apoptosis by the suppression of the ERK1/2 pathway. Conclusions. We demonstrated for the first time that IGFBP7 is involved in the pathogenesis of sepsis-induced acute lung injury and may serve as a therapeutic target in sepsis-induced acute lung injury.
Keywords: mouseCLP sepsisacute lung injuryMPVECsIGFBP7ERK1/2siRNAapoptosis
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