• Wen-Jie Ji, Yong-Qiang Ma, Xin Zhou, Yi-Dan Zhang, Rui-Yi Lu, Zhao-Zeng Guo, Hai-Ying Sun, Dao-Chuan Hu, Guo-Hong Yang, Yu-Ming Li, and Lu-Qing Wei.
• Department of Respiratory and Critical Care Medicine, Pingjin Hospital, Logistics University of the Chinese People's Armed Police Forces, Tianjin, China ; Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Institute of Cardiovascular Disease and Heart Center, Pingjin Hospital, Logistics University of the Chinese People's Armed Police Forces, Tianjin, China.
• Plos One. 2013 Jan 1; 8 (11): e81090.

BackgroundRecent 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 FindingsWe 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 (20 mg/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 (2.5 mg/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 Ly6C(hi) 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/SignificanceThe 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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