RGD PEPTIDES PROTECTS AGAINST ACUTE LUNG INJURY IN SEPTIC MICE THROUGH WISP1-INTEGRIN β6 PATHWAY INHIBITION
RGD PEPTIDES PROTECTS AGAINST ACUTE LUNG INJURY IN SEPTIC MICE THROUGH WISP1-INTEGRIN β6 PATHWAY INHIBITION
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DOI：
10.1097/shk.0000000000000313
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发表时间：
2015-04-01
期刊：
影响因子：
3.1
通讯作者：
Li, Quan
中科院分区：
文献类型：
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作者：
Ding, Xibing;Wang, Xin;Li, Quan
急性肺损伤是脓毒症的常见后果，脓毒症是由严重感染引起的危及生命的炎症反应。在这项研究中，我们阐明了合成Arg-Gly-Asp-Ser肽（RGDs）对脓毒症小鼠模型急性肺损伤的减弱作用。我们进一步发现，RGDs的有益作用源于它们对Wisp1 （wnt1诱导的信号通路）-整合素- 6通路的负调控。采用盲肠结扎穿刺（CLP）诱导脓毒症后，将小鼠随机分为实验组和对照组，记录7天生存率，与未处理对照组相比，CLP组小鼠只有20%存活；在此治疗方案中加入rgd后，生存率显著提高至80%。组织学分析显示，CLP处理的小鼠出现急性肺损伤，而CLP和RGDs联合处理的小鼠肺损伤严重程度明显降低。RGDs的加入也显著减弱了其他常见的脓毒症相关效应，如支气管肺泡灌洗液中白细胞数量增加和肺毛细血管屏障功能下降。此外，RGDs治疗降低了血清和支气管肺泡灌洗液中炎症细胞因子（如肿瘤坏死因子α和白细胞介素6）的水平，而单独CLP治疗则增加了这些蛋白质的水平。然而，有趣的是，RGDs对脓毒症诱导后的细菌侵袭没有可检测到的影响。此外，与clp处理的小鼠相比，RGDs处理的小鼠wisp1和整合素β 6水平降低。在本研究中，我们在体内评估了Wisp1和整合素β 6之间的联系。最引人注目的是，基于共免疫沉淀分析，RGDs导致Wisp1与整合素β 6的相关性降低。这些数据表明，RGDs通过抑制wisp1 -整合素β 6通路改善脓毒症小鼠模型的急性肺损伤。
Acute lung injury is a common consequence of sepsis, a life-threatening inflammatory response caused by severe infection. In this study, we elucidate the attenuating effects of synthetic Arg-Gly-Asp-Ser peptides (RGDs) on acute lung injury in a sepsis mouse model. We further reveal that the beneficial effects of RGDs stem from their negative regulation of the Wisp1 (WNT1-inducible signaling pathway)-integrin beta 6 pathway. After inducing sepsis using cecal ligation and puncture (CLP), mice were randomized into experimental and control groups, and survival rates were recorded over 7 days, whereas only 20% of mice subjected to CLP survived when compared with untreated controls; the addition of RGDs to this treatment regimen dramatically increased the survival rate to 80%. Histological analysis revealed acute lung injury in CLP-treated mice, whereas those subjected to the combined treatment of CLP and RGDs showed a considerable decrease in lung injury severity. The addition of RGDs also dramatically attenuated other common sepsis-associated effects, such as increased white blood cell number in bronchoalveolar lavage fluid and decreased pulmonary capillary barrier function. Furthermore, treatment with RGDs decreased the serum and bronchoalveolar lavage fluid levels of inflammatory cytokines such as tumor necrosis factor alpha and interleukin 6, contrary to the CLP treatment alone that increased the levels of these proteins. Interestingly, however, RGDs had no detectable effect on bacterial invasion following sepsis induction. In addition, mice treated with RGDs showed decreased levels of wisp1 and integrin beta 6 when compared with CLP-treated mice. In the present study, a linkage between Wisp1 and integrin beta 6 was evaluated in vivo. Most strikingly, RGDs resulted in a decreased association of Wisp1 with integrin beta 6 based on coimmunoprecipitation analyses. These data suggest that RGDs ameliorate acute lung injury in a sepsis mouse model by inhibiting the Wisp1-integrin beta 6 pathway.