神经药理及新药发现学科徐江平教授课题组于近日在Laboratory Investigation上发表了题为“Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice”的研究论文。
罗氟司特为已上市的磷酸二酯酶- 4（PDE - 4）抑制剂，是新型COPD的治疗药物。脓毒血症是由感染引起的全身炎症反应综合征，该疾病的治疗是一个极为棘手的问题，临床上缺乏特异性治疗方法。该论文采用盲肠结扎穿刺的方法建立脓毒血症小鼠模型，观察了罗氟司特对脓毒血症小鼠存活率、体内细菌量、相关炎症因子水平、组织器官病理改变的作用，并对其作用机制进行了初步探索。结果发现，罗氟司特能够提高脓毒血症小鼠的存活率，减少腹腔、血液及脏器内菌落数量，降低炎症因子水平，缓解肝脏的形态学损伤及转氨酶水平。其机制可能与罗氟司特特异性抑制炎症细胞内PDE4，激活cAMP/CREB信号通路，抑制NF-κB的核转位，进而减少炎症因子（如IL-6 及 TNF-α）的转录，进一步减少炎症因子受体活化后激活JAK-STAT3信号通路，减少细胞核内STAT3的水平有关。
此论文受到国家自然科学基金面上项目、国家自然科学基金青年基金等基金资助。2014级硕士研究生冯红芳为本论文的第一作者，徐江平教授为该论文的通讯作者。Lab Invest 为大类：医学 2区；小类： 病理学 2区、医学：研究与实验 2区，IF=4.857。
Feng H, Chen J, Wang H, Cheng Y, Zou Z, Zhong Q, Xu J. Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice. Lab Invest. 2017 Jun 26. doi: 10.1038/labinvest.2017.59. [Epub ahead of print]
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-κB), as well as degradation of NF-κB 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-κB, p38 MAPK, and STAT3 pathways.