The Heat Shock Protein 90 Inhibitor, AT13387, Protects the Alveolo-Capillary Barrier and Prevents HCl-Induced Chronic Lung Injury and Pulmonary Fibrosis.
The Heat Shock Protein 90 Inhibitor, AT13387, Protects the Alveolo-Capillary Barrier and Prevents HCl-Induced Chronic Lung Injury and Pulmonary Fibrosis.
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DOI：
10.3390/cells11061046
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发表时间：
2022-03-19
期刊：
影响因子：
6
通讯作者：
Catravas JD
中科院分区：
文献类型：
--
作者：
Colunga Biancatelli RML;Solopov P;Dimitropoulou C;Gregory B;Day T;Catravas JD
盐酸（HCl）暴露可引起哮喘样疾病、反应性气道功能障碍综合征和肺纤维化。热休克蛋白90 （HSP90）是一种调节多种细胞过程的分子伴侣。HSP90抑制剂正在进行癌症的临床试验，也正在各种临床前环境中研究其抗炎和抗纤维化作用。本研究研究了热休克蛋白90 （HSP90）抑制剂AT13387在体内预防HCl暴露引起的慢性肺损伤的能力及其在体外内皮屏障中的保护作用。给C57Bl/6J小鼠灌胃0.1N盐酸（2µL/g体重，气管内），24 h后开始用载药或AT13387（10或15 mg/kg， SC）治疗，3次/周；我们分析HCl后30天的组织学、功能和分子标记。此外，我们监测了暴露于HCl （0.02 N）和用载药或AT13387（2µM）处理的单层人肺微血管内皮细胞（HLMVEC）的跨内皮电阻（TER）和蛋白表达。盐酸引起持续的肺泡炎症；活化促纤维化通路（MAPK/ERK, HSP90）；胶原蛋白、纤维连接蛋白和弹性蛋白沉积增加；纤维化的组织学证据；肺功能下降，表现为压力-容积曲线下移，呼吸系统阻力（Rrs）、弹性（Ers）、组织阻尼(G)增加，以及对甲胆碱的高反应性。15 mg/kg at13387治疗可减少肺泡炎症、纤维化和NLRP3染色；阻断ERK和HSP90的激活；并能减轻胶原沉积、慢性肺损伤和气道高反应性的发展。在体外，AT13387可阻止hcc诱导的屏障功能丧失和AKT、ERK和ROCK1的激活，并恢复HSP70和cofilin的表达。HSP90抑制剂AT13387是一种很有前途的治疗慢性肺损伤的候选药物，可以在现场皮下注射，并且剂量低，无毒。
Hydrochloric acid (HCl) exposure causes asthma-like conditions, reactive airways dysfunction syndrome, and pulmonary fibrosis. Heat Shock Protein 90 (HSP90) is a molecular chaperone that regulates multiple cellular processes. HSP90 inhibitors are undergoing clinical trials for cancer and are also being studied in various pre-clinical settings for their anti-inflammatory and anti-fibrotic effects. Here we investigated the ability of the heat shock protein 90 (HSP90) inhibitor AT13387 to prevent chronic lung injury induced by exposure to HCl in vivo and its protective role in the endothelial barrier in vitro. We instilled C57Bl/6J mice with 0.1N HCl (2 µL/g body weight, intratracheally) and after 24 h began treatment with vehicle or AT13387 (10 or 15 mg/kg, SC), administered 3×/week; we analyzed histological, functional, and molecular markers 30 days after HCl. In addition, we monitored transendothelial electrical resistance (TER) and protein expression in a monolayer of human lung microvascular endothelial cells (HLMVEC) exposed to HCl (0.02 N) and treated with vehicle or AT13387 (2 µM). HCl provoked persistent alveolar inflammation; activation of profibrotic pathways (MAPK/ERK, HSP90); increased deposition of collagen, fibronectin and elastin; histological evidence of fibrosis; and a decline in lung function reflected in a downward shift in pressure–volume curves, increased respiratory system resistance (Rrs), elastance (Ers), tissue damping (G), and hyperresponsiveness to methacholine. Treatment with 15 mg/kg AT13387reduced alveolar inflammation, fibrosis, and NLRP3 staining; blocked activation of ERK and HSP90; and attenuated the deposition of collagen and the development of chronic lung injury and airway hyperreactivity. In vitro, AT13387 prevented HCl-induced loss of barrier function and AKT, ERK, and ROCK1 activation, and restored HSP70 and cofilin expression. The HSP90 inhibitor, AT13387, represents a promising drug candidate for chronic lung injury that can be administered subcutaneously in the field, and at low, non-toxic doses.
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影响因子：
4.6
作者：
Armstrong HK;Gillis JL;Johnson IRD;Nassar ZD;Moldovan M;Levrier C;Sadowski MC;Chin MY;Tomlinson Guns ES;Tarulli G;Lynn DJ;Brooks DA;Selth LA;Centenera MM;Butler LM
通讯作者：
Butler LM
影响因子：
5.6
作者：
Colunga Biancatelli RML;Solopov P;Dimitropoulou C;Catravas JD
通讯作者：
Catravas JD
影响因子：
--
作者：
Kerger BD;Fedoruk MJ
通讯作者：
Fedoruk MJ
影响因子：
4
作者：
Catravas, John D.;Snead, Connie;Dimitropoulou, Christiana;Chang, Albert S. Y.;Lucas, Rudolf;Verin, Alexander D.;Black, Stephen M.
通讯作者：
Black, Stephen M.
影响因子：
9.6
作者：
BROOKS, SM;WEISS, MA;BERNSTEIN, IL
通讯作者：
BERNSTEIN, IL