• Int. Immunopharmacol. · Aug 2019

    PIM1 inhibitor SMI-4a attenuated lipopolysaccharide-induced acute lung injury through suppressing macrophage inflammatory responses via modulating p65 phosphorylation.

    • Jinxuan Wang, Yumeng Cao, Yuqi Liu, Xinyi Zhang, Fanceng Ji, Jinbao Li, and Yun Zou.
    • Department of Anesthesiology, Weifang Medical University, Weifang, China; Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
    • Int. Immunopharmacol. 2019 Aug 1; 73: 568-574.

    AbstractPIM kinase is involved in the cellular processes of growth, differentiation and apoptosis. However, the role of PIM1 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains largely unknown. A trend of PIM1 in the lung tissue of LPS-induced ALI at different time points was detected. Histology, wet/dry (W/D) ratio, inflammatory cells in the bronchoalveolar lavage fluid (BALF) and survival rate analyses were performed when mice received the PIM1 inhibitor SMI-4a intratracheally 3 h before LPS administration. Cytokine production in vivo and in vitro was measured after SMI-4a pretreatment. NF-κB subunit p65 expression in nuclei and phosphorylation at Ser276 in lung tissues or cells were detected by Western blot analysis. The results showed that PIM1 mRNA and protein were upregulated in the lung tissue of LPS-induced ALI. The PIM1 inhibitor SMI-4a markedly improved the survival rate after lethal LPS administration, reduced the severity of lung edema, attenuated the histologic injuries of the lung tissue and reduced the counts of infiltrated inflammatory cells in the BALF. The PIM1 inhibitor SMI-4a suppressed the production of cytokines in LPS-treated RAW264.7 cell supernatants and BALF. Furthermore, LPS administration upregulated the levels of nuclear p65 and phosphorylated p65 (p-p65) at Ser276, whereas pretreatment with the PIM1 inhibitor SMI-4a reduced p65 upregulation in the nucleus and p-p65 at Ser276. Taken together, these data indicate that the PIM1 inhibitor SMI-4a may serve as a promising therapeutic strategy for LPS-induced ALI by suppressing macrophage production of cytokines via a reduction of p65 activities.Copyright © 2019. Published by Elsevier B.V.

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