Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2

Abstract

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 b) 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.

Risk factors and mortality associated with an elevated tricuspid regurgitant jet velocity measured by Doppler-echocardiography in thalassemia: a Thalassemia Clinical Research Network report

“…The association of a smoking history with a high TRV is not surprising, given that it is a well-established risk factor for cardiovascular and lung disease associated with PH in both animal models 45 and human studies. 46 The association of PH with splenectomy and a hypercoagulable state also has been well described in the literature.…”

PAR-2 Inhibition Reverses Experimental Pulmonary Hypertension

“…PAR-2 overexpression induced pulmonary vascular remodeling and right heart hypertrophy in mice exposed to cigarette smoke, suggesting that PAR-2 may contribute to the development of pulmonary hypertension in smokers. 28 The interaction between inflammatory and structural cells in the development and progression of PH is becoming increasingly apparent. 29 In accordance with previously published reports, 30 -34 we detected increased number of mast cells in the lungs of IPAH patients, mice exposed to hypoxia, and monocrotaline-treated rats.…”

Response to pulmonary vasodilator treatment in a former smoker with combined interstitial lung disease complicated by pulmonary hypertension: Case report and review of the literature

“…Smoking in mice results in an imbalance between vasoconstrictors (especially endothelin-1) and vasodilators (such as vascular endothelial growth factor or nitric oxide) and an enhanced production of growth factors involved in the interaction between fibroblasts and smooth muscle cells, as well as in the proliferation of vascular cells (platelet-derived growth factor and transforming growth factor-b). 9 In this context, emphysema, pulmonary fibrosis, and PH may belong to the spectrum of cigarette smoke-induced lung disease. An important role was also advocated for local inflammation, predominated by T-lymphocytes, especially CD8 þ , and by the secretion of autocrine and paracrine proinflammatory molecules, which could also represent local mediators of medial hypertrophy, exaggerated hypoxia-induced vasoconstriction, and irreversible vascular remodeling.…”