Effects of cigarette smoke and hypoxia on pulmonary circulation in the guinea pig

Abstract

Cigarette smoke (CS) and chronic hypoxia (CH) can produce pulmonary hypertension. Similarities and differences between both exposures and their interaction have not been explored. The aim of the present study was to investigate the effects of CS and CH, as single factors or in combination, on the pulmonary circulation in the guinea pig.51 guinea pigs were exposed to CS for 12 weeks and 32 were sham-exposed. 50% of the animals in each group were additionally exposed to CH for the final 2 weeks. We measured pulmonary artery pressure (Ppa), and the weight ratio between the right ventricle (RV) and left ventricle plus the septum. Pulmonary artery contractility in response to noradrenaline (NA), endothelium-dependent vasodilatation and distensibility were evaluated in organ bath chambers. The number of small intrapulmonary vessels showing immunoreactivity to smooth muscle (SM) a-actin and double elastic laminas was assessed microscopically.CS and CH induced similar increases of Ppa and RV hypertrophy (p,0.05 for both), effects that were further enhanced when both factors were combined. CH increased the contractility to NA (p,0.01) and reduced the distensibility (p,0.05) of pulmonary arteries. Animals exposed to CS showed an increased number of small vessels with positive immunoreactivity to SM a-actin (p,0.01) and those exposed to CH a greater proportion of vessels with double elastic laminas (p,0.05).We conclude that CH amplifies the detrimental effects of CS on the pulmonary circulation by altering the mechanical properties of pulmonary arteries and enhancing the remodelling of pulmonary arterioles.KEYWORDS: Chronic obstructive pulmonary disease, cigarette smoke, hypoxia, pulmonary hypertension, vascular remodelling P ulmonary hypertension is a common and serious complication of chronic obstructive pulmonary disease (COPD). It is considered to result from the effects of chronic hypoxaemia on pulmonary vessels. Indeed, acute and chronic exposure to hypoxia results in smooth muscle cell (SMC) and adventitial fibroblast proliferation [1]. Nevertheless, structural changes in the pulmonary arteries of COPD patients differ from those observed in subjects exposed to a hypoxic environment. Whereas subjects living at high altitudes show medial hypertrophy, COPD patients show prominent changes in the intima [2]. Intimal hypertrophy is present in nonhypoxaemic COPD patients and in smokers with normal lung function, suggesting that vascular changes may be triggered by cigarette smoke (CS) before hypoxaemia develops.Cigarette smoking is associated with endothelial dysfunction [3], increased expression of growth factors [4] and inflammatory cell infiltrate in pulmonary arteries [5]. These factors may induce SMC proliferation and increase pulmonary vascular resistance. The molecular mechanisms by which CS induces vascular changes remain unknown, but they might be related to oxidative damage [6].The effects of hypoxia on human lungs are difficult to characterise because it is usually related to the presence of primary lu...

Smoking Exposure Induces Human Lung Endothelial Cell Adaptation to Apoptotic Stress

“…Whereas typical plexiform lesions from idiopathic PAH are only rarely described in COPD, up to 70% of patients with COPD go on to develop PAH and pulmonary artery remodeling, features directly associated with worse prognosis and disease exacerbations (27). In addition, our results support findings in vivo of effects of smoking on pulmonary vasculature remodeling even in the absence of airspace destruction (28).…”

Sildenafil in a cigarette smoke-induced model of COPD in the guinea-pig

“…Whereas guinea-pigs exposed to CS showed increased mPAP and RV hypertrophy compared with nonexposed animals, in keeping with previous studies [22,23]; CS-exposed, sildenafil-treated animals displayed mPAP values and a RV/LV+S weight ratio similar to the nonexposed animals, confirming the vasodilator action of sildenafil in this experimental model [10][11][12]. The lack of increase in PAP was not accompanied by differences in lung vessel structure, since CS-exposed guinea-pigs treated with sildenafil showed pulmonary artery wall thickening, muscularisation of small vessels and proliferation of smooth muscle cells at similar levels to CS-exposed, untreated guinea-pigs and at significantly higher levels than in nonexposed animals.…”

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Cigarette smoke causes lung vascular barrier dysfunction via oxidative stress-mediated inhibition of RhoA and focal adhesion kinase

“…Pulmonary endothelial dysfunction and vascular remodeling are also reported in the lungs of COPD patients (12,40,62). CS is a major risk factor for COPD (53).…”

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