Statin reverses smoke-induced pulmonary hypertension and prevents emphysema but not airway remodeling.
BACKGROUND
the potential role of statins in treating chronic obstructive pulmonary disease (COPD) is controversial, and it is unclear what anatomic COPD lesions statins affect.


OBJECTIVE
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.


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.
Wright
Joanne L
JL
Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5 Canada. jlwright@interchange.ubc.ca
Zhou
Steven
S
Preobrazhenska
Olena
O
Marshall
Caroline
C
Sin
Don D
DD
Laher
Ismail
I
Golbidi
Saeid
S
Churg
Andrew M
AM
D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D004195:Disease Models, Animal; D006168:Guinea Pigs; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D011379:Prognosis; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000209:etiology / Q000517:prevention & control*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D012907:Smoking / Q000009:adverse effects; D014661:Vasoconstriction / Q000187:drug effects
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin