Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2.
The mechanism(s) involved in the development of pulmonary hypertension (PH) in COPD is still the object of investigation. Cigarette smoke (CS) may lead to remodelling of intrapulmonary vessels and dynamic changes in vascular function, at least in some smokers. A role for proteases in PH has been recently put forward. We investigated, in smoking mice, the role of protease-activated receptor (PAR)-2 in the pathogenesis of PH associated with emphysema. We demonstrated that CS exposure can modulate PAR-2 expression in mouse lung. Acute CS exposure induces in wildtype (WT) and in transgenic mice over-expressing PAR-2 (FVB(PAR-2-TgN)) a similar degree of neutrophil influx in bronchoalveolar lavage fluids. After chronic CS exposure WT and FVB(PAR-2-TgN) mice show emphysema, but only transgenic mice develop muscularisation of small intrapulmonary vessels that precedes the development of PH (~45% increase) and right ventricular hypertrophy. Smoking in FVB(PAR-2-TgN) mice results in an imbalance between vasoconstrictors (especially endothelin-1) and vasodilators (i.e. vascular endothelial growth factor, endothelial nitric oxide synthase and inducible nitric oxide synthase) and enhanced production of growth factors involved both in fibroblast-smooth muscle cell transaction (i.e. platelet-derived growth factor (PDGF) and transforming growth factor β) and vascular cell proliferation (PDGF). PAR-2 signalling can influence the production and release of many factors, which may play a role in the development of PH in smokers.
De Cunto
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G
Dept of Physiopathology & Experimental Medicine, University of Siena, Siena, Italy.
Cardini
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S
Cirino
G
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Geppetti
P
P
Lungarella
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Lucattelli
M
M
D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular; D007150:Immunohistochemistry / Q000379:methods; D008168:Lung / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D012313:RNA / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000096:biosynthesis*; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*
D044464:Receptor, PAR-2; D012313:RNA