Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice
Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice
复制标题
罗氟司特通过抑制小鼠炎症来逆转多种微生物脓毒症引起的肝损伤
DOI：
10.1038/labinvest.2017.59
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发表时间：
2017-09-01
影响因子：
5
通讯作者：
Xu, Jiangping
中科院分区：
文献类型：
--
作者：
Feng, Hongfang;Chen, Jiajia;Xu, Jiangping
Sepsis is a life-threatening syndrome accompanied by an overwhelming inflammatory response and organ dysfunction. Selective targeting of phosphodiesterase 4 (PDE4) is currently being investigated as an effective therapeutic approach for inflammation-associated diseases. Roflumilast is a selective PDE4 inhibitor, used for the treatment of severe chronic obstructive pulmonary disease in clinic. However, its role in the treatment of sepsis-induced liver damage remains unclear. In the present study, we evaluated the effects of roflumilast in mice with cecal ligation and puncture-induced sepsis, and investigated the underlying mechanism. We found that roflumilast treatment improved survival in septic mice by reducing bacterial load locally and systemically, inhibiting the expression of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor alpha, and alleviating liver injury. These effects were associated with the inhibition of nuclear translocation of nuclear factor-kappa B (NF-kappa B), as well as degradation of NF-kappa B inhibitory protein alpha. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) was also markedly inhibited by roflumilast. Moreover, roflumilast significantly suppressed the activation of signal transducer and activator of transcription 3 (STAT3) and its upstream Janus kinase 1 and Janus kinase 2. Taken together, these results indicate that roflumilast prevents polymicrobial sepsis likely by suppressing NF-kappa B, p38 MAPK, and STAT3 pathways.
