Effects of cigarette smoke on endothelial function of pulmonary arteries in the guinea pig.
BACKGROUND
Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by altering the structure and function of pulmonary vessels at early disease stages. The objectives of this study were to evaluate the effects of long-term exposure to cigarette smoke on endothelial function and smooth muscle-cell proliferation in pulmonary arteries of guinea pigs.


METHODS
19 male Hartley guinea pigs were exposed to the smoke of 7 cigarettes/day, 5 days/week, for 3 and 6 months. 17 control guinea pigs were sham-exposed for the same periods. Endothelial function was evaluated in rings of pulmonary artery and aorta as the relaxation induced by ADP. The proliferation of smooth muscle cells and their phenotype in small pulmonary vessels were evaluated by immunohistochemical expression of alpha-actin and desmin. Vessel wall thickness, arteriolar muscularization and emphysema were assessed morphometrically. The expression of endothelial nitric oxide synthase (eNOS) was evaluated by Real Time-PCR.


RESULTS
Exposure to cigarette smoke reduced endothelium-dependent vasodilatation in pulmonary arteries (ANOVA p < 0.05) but not in the aorta. Endothelial dysfunction was apparent at 3 months of exposure and did not increase further after 6 months of exposure. Smoke-exposed animals showed proliferation of poorly differentiated smooth muscle cells in small vessels (p < 0.05) after 3 months of exposure. Prolonged exposure resulted in full muscularization of small pulmonary vessels (p < 0.05), wall thickening (p < 0.01) and increased contractility of the main pulmonary artery (p < 0.05), and enlargement of the alveolar spaces. Lung expression of eNOS was decreased in animals exposed to cigarette smoke.


CONCLUSIONS
In the guinea pig, exposure to cigarette smoke induces selective endothelial dysfunction in pulmonary arteries, smooth muscle cell proliferation in small pulmonary vessels and reduced lung expression of eNOS. These changes appear after 3 months of exposure and precede the development of pulmonary emphysema.
Ferrer
Elisabet
E
Department of Pulmonary Medicine, Hospital Clínic-IDIBAPS, Barcelona, Spain. idib501@clinic.ub.es
Peinado
Víctor Ivo
VI
Díez
Marta
M
Carrasco
Josep Lluís
JL
Musri
Melina Mara
MM
Martínez
Anna
A
Rodríguez-Roisin
Robert
R
Barberà
Joan Albert
JA
D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003893:Desmin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006168:Guinea Pigs; D007150:Immunohistochemistry; D019570:Inhalation Exposure; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D000199:Actins; D003893:Desmin; D012333:RNA, Messenger; D012906:Smoke; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D052250:Nitric Oxide Synthase Type III
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