Simvastatin improves epithelial dysfunction and airway hyperresponsiveness: from asymmetric dimethyl-arginine to asthma.
Altered arginine metabolism, the uncoupling of nitric oxide synthase (NOS) by asymmetric dimethyl-arginine (ADMA), increased oxo-nitrosative stress, and cellular injury were reported in airway epithelial cells in asthma. Statins improve vascular endothelial dysfunction by reducing ADMA and increasing endothelial NOS (eNOS), thereby reducing oxo-nitrosative stress in cardiovascular diseases. Whether statin therapy leads to similar beneficial effects in lung epithelium in asthma is unknown. The effects of simvastatin therapy after sensitization (40 mg/kg, intraperitoneally) on markers of arginine and NO metabolism and features of asthma were ascertained in a murine model of allergic asthma. The effects of simvastatin on the expression of NOS in A549 lung epithelial cells were studied in vitro. Simvastatin induced eNOS in lung epithelial cells in vitro. In acute and chronic models of asthma, simvastatin therapy was associated with significantly reduced airway inflammation, airway hyperresponsiveness, and airway remodeling. ADMA and inducible nitric oxide synthase were reduced by simvastatin, but eNOS was increased. A marked reduction of nitrotyrosine, a marker of oxo-nitrosative stress, was evident in airway epithelium. Cell injury markers such as cytosolic cytochrome c, caspases 3 and 9 and apoptotic protease activating factor 1 (Apaf-1) were also reduced. Simvastatin improves dysfunctional nitric oxide metabolism in allergically inflamed lungs. Important pleiotropic mechanisms may be responsible for the statin-induced reduction of airway inflammation, epithelial injury, and airway hyperresponsiveness.
Ahmad
Tanveer
T
Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, Institute of Genomics and Integrative Biology, Delhi 110007, India.
Mabalirajan
Ulaganathan
U
Sharma
Amit
A
Aich
Jyotirmoi
J
Makhija
Lokesh
L
Ghosh
Balaram
B
Agrawal
Anurag
A
D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D001249:Asthma / Q000097:blood / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000097:blood / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002908:Chronic Disease; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D004848:Epithelium / Q000187:drug effects* / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects; D011014:Pneumonia / Q000150:complications / Q000473:pathology; D019821:Simvastatin / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects
D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III