Spironolactone attenuates bleomycin-induced pulmonary injury partially via modulating mononuclear phagocyte phenotype switching in circulating and alveolar compartments.
Spironolactone attenuates bleomycin-induced pulmonary injury partially via modulating mononuclear phagocyte phenotype switching in circulating and alveolar compartments.
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螺内酯部分通过调节循环和肺泡室中的单核吞噬细胞表型转换来减轻博来霉素引起的肺损伤
DOI：
10.1371/journal.pone.0081090
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wei LQ
中科院分区：
文献类型：
--
作者：
Ji WJ;Ma YQ;Zhou X;Zhang YD;Lu RY;Guo ZZ;Sun HY;Hu DC;Yang GH;Li YM;Wei LQ
背景最近的实验研究提供的证据表明，操纵单核吞噬细胞表型可能是一种可行的方法来改变肺损伤和纤维化的严重性和持续性。盐皮质激素受体（MR）已被报道为调节巨噬细胞极化的靶点。本研究旨在探讨MR拮抗剂在博来霉素诱导的急性肺损伤和肺纤维化中的治疗潜力。方法学/主要发现我们首先证明了MR在磁珠纯化的Ly 6 G-/CD 11b+循环单核细胞和从C57 BL/6小鼠的支气管肺泡灌洗液（BALF）中收获的肺泡巨噬细胞中的表达。然后，使用螺内酯的药理干预研究（20 mg/kg/天，经口灌胃）显示MR拮抗作用导致炎性细胞浸润、细胞因子产生减少（下调的单核细胞趋化蛋白-1，转化生长因子β1，和白细胞介素-1 β在mRNA和蛋白质水平）和胶原沉积（通过Masson三色染色降低肺总羟脯氨酸含量和胶原蛋白阳性面积）。此外，在血液、BALF和酶消化的肺组织中的系列流式细胞术分析显示，螺内酯可以部分抑制博莱霉素诱导的循环Ly 6Chi单核细胞扩增，并减少肺泡中单核吞噬细胞的交替活化（F4/80+ CD 11 c + CD 206+），而间质巨噬细胞的表型（F4/80+ CD 11 c-）在研究期间不受螺内酯的影响。结论/意义本研究提供的实验证据表明，螺内酯可以减轻博莱霉素诱导的急性肺损伤和纤维化，部分通过抑制MR介导的循环单核细胞和肺泡巨噬细胞表型转换。
Background Recent experimental studies provide evidence indicating that manipulation of the mononuclear phagocyte phenotype could be a feasible approach to alter the severity and persistence of pulmonary injury and fibrosis. Mineralocorticoid receptor (MR) has been reported as a target to regulate macrophage polarization. The present work was designed to investigate the therapeutic potential of MR antagonism in bleomycin-induced acute lung injury and fibrosis. Methodology/Principal Findings We first demonstrated the expression of MR in magnetic bead-purified Ly6G-/CD11b+ circulating monocytes and in alveolar macrophages harvested in bronchoalveolar lavage fluid (BALF) from C57BL/6 mice. Then, a pharmacological intervention study using spironolactone (20mg/kg/day by oral gavage) revealed that MR antagonism led to decreased inflammatory cell infiltration, cytokine production (downregulated monocyte chemoattractant protein-1, transforming growth factor β1, and interleukin-1β at mRNA and protein levels) and collagen deposition (decreased lung total hydroxyproline content and collagen positive area by Masson’ trichrome staining) in bleomycin treated (2.5mg/kg, via oropharyngeal instillation) male C57BL/6 mice. Moreover, serial flow cytometry analysis in blood, BALF and enzymatically digested lung tissue, revealed that spironolactone could partially inhibit bleomycin-induced circulating Ly6Chi monocyte expansion, and reduce alternative activation (F4/80+CD11c+CD206+) of mononuclear phagocyte in alveoli, whereas the phenotype of interstitial macrophage (F4/80+CD11c-) remained unaffected by spironolactone during investigation. Conclusions/Significance The present work provides the experimental evidence that spironolactone could attenuate bleomycin-induced acute pulmonary injury and fibrosis, partially via inhibition of MR-mediated circulating monocyte and alveolar macrophage phenotype switching.
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影响因子：
64.8
作者：
Li W;Moore MJ;Vasilieva N;Sui J;Wong SK;Berne MA;Somasundaran M;Sullivan JL;Luzuriaga K;Greenough TC;Choe H;Farzan M
通讯作者：
Farzan M
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1165/rcmb.2010-0137oc
发表时间：
2011-09-01
影响因子：
6.4
作者：
Kikuchi, Norihiro;Ishii, Yukio;Hizawa, Nobuyuki
通讯作者：
Hizawa, Nobuyuki
影响因子：
6
作者：
Li, Ping;Xiao, Hong D.;Fuchs, Sebastien
通讯作者：
Fuchs, Sebastien
影响因子：
82.9
作者：
Kuba K;Imai Y;Rao S;Gao H;Guo F;Guan B;Huan Y;Yang P;Zhang Y;Deng W;Bao L;Zhang B;Liu G;Wang Z;Chappell M;Liu Y;Zheng D;Leibbrandt A;Wada T;Slutsky AS;Liu D;Qin C;Jiang C;Penninger JM
通讯作者：
Penninger JM