RATIONALE: the potential role of statins in treating chronic obstructive pulmonary disease (COPD) is controversial, and it is unclear what anatomic COPD lesions statins affect. OBJECTIVES: to determine whether an intervention of simvastatin could alter cigarette smoke-induced pulmonary hypertension. METHODS: we exposed guinea pigs to cigarette smoke for 6 months. In half the animals, simvastatin therapy was initiated after 3 months of smoke exposure. Pulmonary arterial systolic pressures were monitored weekly with a radiotelemetric catheter; additional physiologic and morphologic measurements were made at sacrifice after 6 months. Precision-cut lung explants were assessed for evidence of endothelial dysfunction, and in situ vascular nitric oxide generation was measured with 4,5-diaminofluorescein diacetate. MEASUREMENTS AND MAIN RESULTS: cigarette smoke increased the pulmonary arterial systolic pressure after approximately 4 weeks. Simvastatin returned the pressure to control levels within 4 weeks of starting treatment, and ameliorated smoke-induced small arterial remodeling as well as emphysema measured both physiologically and morphometrically at 6 months, but did not prevent smoke-induced small airway remodeling either physiologically or morphologically. In precision-cut lung slices simvastatin reversed small arterial endothelial dysfunction, and partially reversed smoke-induced loss of vascular nitric oxide generation. CONCLUSIONS: simvastatin, as an intervention therapy, reverses the pulmonary vascular effects of cigarette smoke, including pulmonary hypertension, and prevents smoke-induced emphysema, but does not prevent small airway remodeling. This is the first demonstration that an intervention can reverse a COPD-associated cigarette smoke-induced anatomic abnormality. The study also shows the importance of examining all three anatomic lung compartments when assessing the effects of a potential drug intervention in patients with COPD.
RATIONALE: the potential role of statins in treating chronic obstructive pulmonary disease (COPD) is controversial, and it is unclear what anatomic COPD lesions statins affect. OBJECTIVES: to determine whether an intervention of simvastatin could alter cigarette smoke-induced pulmonary hypertension. METHODS: we exposed guinea pigs to cigarette smoke for 6 months. In half the animals, simvastatin therapy was initiated after 3 months of smoke exposure. Pulmonary arterial systolic pressures were monitored weekly with a radiotelemetric catheter; additional physiologic and morphologic measurements were made at sacrifice after 6 months. Precision-cut lung explants were assessed for evidence of endothelial dysfunction, and in situ vascular nitric oxide generation was measured with 4,5-diaminofluorescein diacetate. MEASUREMENTS AND MAIN RESULTS: cigarette smoke increased the pulmonary arterial systolic pressure after approximately 4 weeks. Simvastatin returned the pressure to control levels within 4 weeks of starting treatment, and ameliorated smoke-induced small arterial remodeling as well as emphysema measured both physiologically and morphometrically at 6 months, but did not prevent smoke-induced small airway remodeling either physiologically or morphologically. In precision-cut lung slices simvastatin reversed small arterial endothelial dysfunction, and partially reversed smoke-induced loss of vascular nitric oxide generation. CONCLUSIONS:simvastatin, as an intervention therapy, reverses the pulmonary vascular effects of cigarette smoke, including pulmonary hypertension, and prevents smoke-induced emphysema, but does not prevent small airway remodeling. This is the first demonstration that an intervention can reverse a COPD-associated cigarette smoke-induced anatomic abnormality. The study also shows the importance of examining all three anatomic lung compartments when assessing the effects of a potential drug intervention in patients with COPD.
Authors: Scott M Gordon; Benjamin McKenzie; Georgina Kemeh; Maureen Sampson; Shira Perl; Neal S Young; Michael B Fessler; Alan T Remaley Journal: Mol Cell Proteomics Date: 2015-10-19 Impact factor: 5.911
Authors: J Michael Wells; George R Washko; MeiLan K Han; Naseer Abbas; Hrudaya Nath; A James Mamary; Elizabeth Regan; William C Bailey; Fernando J Martinez; Elizabeth Westfall; Terri H Beaty; Douglas Curran-Everett; Jeffrey L Curtis; John E Hokanson; David A Lynch; Barry J Make; James D Crapo; Edwin K Silverman; Russell P Bowler; Mark T Dransfield Journal: N Engl J Med Date: 2012-09-03 Impact factor: 91.245
Authors: Steven M Kawut; Emilia Bagiella; David J Lederer; Daichi Shimbo; Evelyn M Horn; Kari E Roberts; Nicholas S Hill; R Graham Barr; Erika B Rosenzweig; Wendy Post; Russell P Tracy; Harold I Palevsky; Paul M Hassoun; Reda E Girgis Journal: Circulation Date: 2011-05-18 Impact factor: 29.690
Authors: Behzad Yeganeh; Emilia Wiechec; Sudharsana R Ande; Pawan Sharma; Adel Rezaei Moghadam; Martin Post; Darren H Freed; Mohammad Hashemi; Shahla Shojaei; Amir A Zeki; Saeid Ghavami Journal: Pharmacol Ther Date: 2014-02-26 Impact factor: 12.310