title: Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models.
abstract: Accumulating evidence indicates protective actions of mineralocorticoid antagonists (MR antagonists) on cardiovascular pathology, which includes blunting vascular inflammation and myocardial fibrosis. We examined the anti-inflammatory and anti-fibrotic potential of MR antagonists in rodent respiratory models. In an ovalbumin allergic and challenged Brown Norway rat model, the total cell count in nasal lavage was 29,348 ± 5451, which was blocked by spironolactone (0.3-60 mg/kg, p.o.) and eplerenone (0.3-30 mg/kg, p.o.). We also found that MR antagonists attenuated pulmonary inflammation in the Brown Norway rat. A series of experiments were conducted to determine the actions of MR blockade in acute/chronic lung injury models. (1) Ex vivo lung slice rat experiments found that eplerenone (0.01 and 10 µM) and spironolactone (10 µM) diminished lung hydroxyproline concentrations by 55 ± 5, 122 ± 9, and 83 ± 8%. (2) In in vivo studies, MR antagonists attenuated the increases in bronchioalveolar lavage (BAL) neutrophils and macrophages caused by lung bleomycin exposure. In separate studies, bleomycin (4.0 U/kg, i.t.) increased lung levels of hydroxyproline by approximately 155%, which was blocked by spironolactone (10-60 mg/kg, p.o.). In a rat Lipopolysaccharide (LPS) model, spironolactone inhibited acute increases in BAL cytokines with moderate effects on neutrophils. Finally, we found that chronic LPS exposure significantly increased end expiratory lung and decreased lung elastance in the mouse. These functional effects of chronic LPS were improved by MR antagonists. Our results demonstrate that MR antagonists have significant pharmacological actions in the respiratory system.
authors.affiliation: Respiratory and Immunology In Vivo Pharmacology, Boston Molecular Biomarkers, Merck Research Laboratories, Boston, MA, USA.
authors.forename: Gissela B
authors.initials: GB
authors.lastname: Lieber
authors.forename: Xiomara
authors.initials: X
authors.lastname: Fernandez
authors.forename: Garfield G
authors.initials: GG
authors.lastname: Mingo
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Jia
authors.forename: Michael
authors.initials: M
authors.lastname: Caniga
authors.forename: Malgorzata A
authors.initials: MA
authors.lastname: Gil
authors.forename: Shanil
authors.initials: S
authors.lastname: Keshwani
authors.forename: Janice D
authors.initials: JD
authors.lastname: Woodhouse
authors.forename: Milenko
authors.initials: M
authors.lastname: Cicmil
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.forename: Nancy
authors.initials: N
authors.lastname: Kelly
authors.forename: Johanna
authors.initials: J
authors.lastname: Jimenez
authors.forename: Yvette
authors.initials: Y
authors.lastname: Crawley
authors.forename: John C
authors.initials: JC
authors.lastname: Anthes
authors.forename: Joel
authors.initials: J
authors.lastname: Klappenbach
authors.forename: Yu-Lu
authors.initials: YL
authors.lastname: Ma
authors.forename: Robbie L
authors.initials: RL
authors.lastname: McLeod
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D004195:Disease Models, Animal; D004548:Elasticity / Q000187:drug effects; D005355:Fibrosis; D006909:Hydroxyproline / Q000378:metabolism; D006967:Hypersensitivity / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000009:adverse effects; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012123:Pulmonary Ventilation / Q000187:drug effects; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D001761:Bleomycin; D006909:Hydroxyproline
keywords: Eplerenone; Mineralocorticoid; Pulmonary fibrosis; Pulmonary inflammation