Chronic Exposure to Cigarette Smoke Induces Pulmonary Hypertension and Vascular Remodelling in Mice Over−Expressing Protease−Activated Receptor−2 (PAR−2)

INTRODUCTION: The mechanism(s) involved in the development of pulmonary hypertension (PH) in chronic obstructive pulmonary disease is still object of research. Recent studies indicate that cigarette smoke (CS) may have, at least in some individuals, a direct effect on the intrapulmonary vessels with up−regulation of mediators that lead to vascular structural remodelling and dynamic changes in vascular function. A role for proteases in PH has been recently put forward. In the present study, we examined the role of PAR−2 in the pathogenesis of lung vascular remodelling induced in mice by chronic exposure to CS. METHODS: Mice were exposed to the smoke of 3 cigarettes / day, 5 days / week. At various times, lungs were analysed by morphology, morphometry, immunohistochemistry and molecular biology techniques. Ventricular pressure was measured by using a miniature catheter. RESULTS: After 7 months of CS exposure, FVB mice over−expressing PAR−2 developed emphysema associated with PH (~ 45% increase in mean right ventricular pressure). A marked vascular remodelling of the middle and small intrapulmonary vessels preceded the onset of PH. No vascular changes were seen in WT mice, which develop only emphysema after chronic exposure to CS. The effect of tobacco smoke in transgenic PAR−2 mice resulted in an imbalance between vasoconstrictors (especially ET−1) and vasodilators (i.e. VEGF, eNOS and iNOS) and enhanced production of growth factors involved in fibroblast−SMC transaction (PDGF and TGFb) and vascular cell proliferation (PDGF). CONCLUSIONS: PAR−2 signalling can influence the production and the release of many of these factors, which ultimately lead to vascular remodelling and aberrant vascular physiology. The level of expression of PAR−2 may play an important role in the development of PH in human smokers