Mustard Gas Exposure Actuates SMAD2/3 Signaling to Promote Myofibroblast Generation in the Cornea.
Mustard Gas Exposure Actuates SMAD2/3 Signaling to Promote Myofibroblast Generation in the Cornea.
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DOI：
10.3390/cells12111533
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发表时间：
2023-06-02
期刊：
影响因子：
6
通讯作者：
Mohan, Rajiv R. R.
中科院分区：
文献类型：
--
作者：
Sinha, Nishant R. R.;Tripathi, Ratnakar;Balne, Praveen K. K.;Suleiman, Laila;Simkins, Katherine;Chaurasia, Shyam S. S.;Mohan, Rajiv R. R.
硫芥子气（SM）是一种起泡剂和烷基化剂，自第一次世界大战以来，在许多大规模伤亡事件中用作化学武器。据报告，90%以上的受辐射受害者眼睛受伤。SM引起的失明的潜在机制仍然难以捉摸。本研究测试了SM诱导的角膜纤维化的发生是由于在体内兔眼中通过SMAD 2/3信号通路从驻留成纤维细胞产生肌成纤维细胞和在体外从供体角膜分离的原代人角膜成纤维细胞（hCSF）。将54只新西兰白色家兔分为3组（未处理组、溶剂组、SM-蒸汽处理组）。SM-Vapor组在MRI Global机构以200 mg-min/m3暴露于SM 8 min。在第3天、第7天和第14天收集兔角膜用于免疫组织化学、RNA和蛋白裂解物。SM引起兔角膜中SMAD 2/3、pSMAD和SMA表达在第3天、第7天和第14天显著增加。对于机制研究，用氮芥（NM）或NM + SIS 3（SMAD 3特异性抑制剂）处理hCSF，并在30 m、8 h、24 h、48 h和72 h收集。NM显著增加TGFβ、pSMAD 3和SMAD 2/3水平。相反，通过SIS 3处理抑制SMAD 2/3信号传导显著降低了hCSF中SMAD 2/3、pSMAD 3和SMASMA的表达。我们得出的结论是，SMAD 2/3信号传导似乎在芥子气暴露后角膜肌成纤维细胞形成中发挥着至关重要的作用。
Sulfur mustard gas (SM) is a vesicating and alkylating agent used as a chemical weapon in many mass-casualty incidents since World War I. Ocular injuries were reported in >90% of exposed victims. The mechanisms underlying SM-induced blindness remain elusive. This study tested the hypothesis that SM-induced corneal fibrosis occurs due to the generation of myofibroblasts from resident fibroblasts via the SMAD2/3 signaling pathway in rabbit eyes in vivo and primary human corneal fibroblasts (hCSFs) isolated from donor corneas in vitro. Fifty-four New Zealand White Rabbits were divided into three groups (Naïve, Vehicle, SM-Vapor treated). The SM-Vapor group was exposed to SM at 200 mg-min/m3 for 8 min at the MRI Global facility. Rabbit corneas were collected on day 3, day 7, and day 14 for immunohistochemistry, RNA, and protein lysates. SM caused a significant increase in SMAD2/3, pSMAD, and ɑSMA expression on day 3, day 7, and day 14 in rabbit corneas. For mechanistic studies, hCSFs were treated with nitrogen mustard (NM) or NM + SIS3 (SMAD3-specific inhibitor) and collected at 30 m, 8 h, 24 h, 48 h, and 72 h. NM significantly increased TGFβ, pSMAD3, and SMAD2/3 levels. On the contrary, inhibition of SMAD2/3 signaling by SIS3 treatment significantly reduced SMAD2/3, pSMAD3, and ɑSMA expression in hCSFs. We conclude that SMAD2/3 signaling appears to play a vital role in myofibroblast formation in the cornea following mustard gas exposure.
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影响因子：
4.6
作者：
Gonzalez-Andrades M;Alonso-Pastor L;Mauris J;Cruzat A;Dohlman CH;Argüeso P
通讯作者：
Argüeso P
影响因子：
17.8
作者：
Ljubimov AV;Saghizadeh M
通讯作者：
Saghizadeh M
影响因子：
5.2
作者：
Gupta, Suneel;Fink, Michael K.;Martin, Lynn M.;Sinha, Prashant R.;Rodier, Jason T.;Sinha, Nishant R.;Hesemann, Nathan P.;Chaurasia, Shyam S.;Mohan, Rajiv R.
通讯作者：
Mohan, Rajiv R.
影响因子：
1.6
作者：
Marlo TL;Giuliano EA;Tripathi R;Sharma A;Mohan RR
通讯作者：
Mohan RR
影响因子：
5.2
作者：
Balne, Praveen K.;Sinha, Nishant R.;Hofmann, Alexandria C.;Martin, Lynn M.;Mohan, Rajiv R.
通讯作者：
Mohan, Rajiv R.