title: Spironolactone attenuates bleomycin-induced pulmonary injury partially via modulating mononuclear phagocyte phenotype switching in circulating and alveolar compartments.
abstract: 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.
  
  
  RESULTS
  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 (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
  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.
authors.affiliation: 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.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Ji
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Ma
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Yi-Dan
authors.initials: YD
authors.lastname: Zhang
authors.forename: Rui-Yi
authors.initials: RY
authors.lastname: Lu
authors.forename: Zhao-Zeng
authors.initials: ZZ
authors.lastname: Guo
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Sun
authors.forename: Dao-Chuan
authors.initials: DC
authors.lastname: Hu
authors.forename: Guo-Hong
authors.initials: GH
authors.lastname: Yang
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Li
authors.forename: Lu-Qing
authors.initials: LQ
authors.lastname: Wei
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000950:Antigens, Ly; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053583:Interleukin-1beta; C480309:Ly6G antigen, mouse; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D013148:Spironolactone