Effect of imatinib on lipopolysaccharide‑induced acute lung injury and endothelial dysfunction through P38 MAPK and NF-κB signaling pathway in vivo and in vitro

Abstract

The primary purpose of these research was to demonstrate the preventive effect of IMA on lipopolysaccharide (LPS)-induced inflammation in acute lung injury(ALI) mouse models and Human umbilical vascular endothelial cells (HUVECs). LPS stimulation for 24h to induce ALI and inflammation of cells. The pathological results of lungs was evaluated by W/D ratio, pulmonary vascular permeability measurement and immunohistochemistry of myeloperoxidase(MPO). Cell viability was measured using CCK8 assay. Expression of pro-inflammatory mediators was analyzed by RT-PCR and ELISA. The protein level was analyzed by Western blot. The structure of cell junction was detected by immunofluorescence. IMA dose-dependently improved pulmonary pathological damage induced by LPS, reduced the lung wet/dry weight ratio and MPO expression in lung tissue. IMA decreased bronchoalveolar lavage fluid (BALF) inflammatory cell count, as well as the release of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) in blood. Pretreatment with IMA in HUVECs significantly attenuated LPS-induced actin stress fiber formation and VE-cadherin disruption. In addition, IMA down-regulated the mRNA abundances of Vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), interleukin-1B (IL-1β), IL-6 and TNF-α expression, the phosphorylation of protein p-p65, p-IκBα, p-p38, p-ERK and p-JNK induced by LPS were attenuated after IMA treatment in vivo and in vitro. In summary, IMA modulate of NF-κB and MAPK signaling pathways as well as the production of pro-inflammatory cytokines to prevent cellular damage due to LPS infection. These results indicate that in the treatment of LPS-induced acute lung injury, IMA could be a potential modulator.