Endothelin-A receptor antagonist BQ-610 blocks cigarette smoke-induced mitogenesis in rat airways and vessels

Abstract

To ascertain whether endothelin may play a role in cigarette smoke-induced cell proliferation in the airways and arterial vasculature of the lung, we exposed groups of seven Sprague-Dawley rats to either room air (control) plus saline infusion, an intravenous infusion of the selective endothelin A antagonist BQ-610 (control BQ-610), the smoke of 10 cigarettes (smoke only), or the smoke of 10 cigarettes after intravenous BQ-610 infusion (smoke + BQ-610). Cell proliferation was quantified by determining the percentage of cell nuclei labeled by 5-bromo-2'-deoxyuridine. We separately evaluated the cells in the epithelium and wall components of the bronchioles, and endothelium and wall components of the peribronchiolar and perialveolar ductular arteries. We found that cigarette smoke produced significant cell proliferation in the airway epithelium and wall, in the peribronchiolar arterial endothelial compartment, and in both the endothelial and wall compartments of the perialveolar ductular arteries. Pretreatment with BQ-610 reduced the peribronchiolar arterial endothelial and the perialveolar ductular arterial wall proliferation to control lev- els and reduced but did not totally abrogate the smoke-in- duced proliferation of the airway epithelial, airway wall, and perialveolar ductular arterial endothelial compartments. We conclude that cigarette smoke-induced cell proliferation of the airways and pulmonary arterial vessels is at least partially mediated through stimulation of the endothelin-A receptors.

Cigarette smoke exposure causes constriction of rat lung

“…Endothelin is a known constrictor of bronchial smooth muscle, and it has previously been shown that cigarette smoke induces an endothelin A receptor-mediated associated increase in cell proliferation [12]. The present study found that pretreatment of the explants with the endothelin A inhibitor BQ610 diminished contractility in group VO, suggesting that, at least in airways that had not previously encountered cigarette smoke, endothelin was one of the mediators of constriction.…”

“…Likewise, it is possible that the smoke stimulates the release of bronchoconstrictive mediators. For example, it has been shown that endothelin receptor antagonists block smoke-induced airway and vascular cell proliferation [12]; since endothelin is also a powerful bronchoconstrictor, this finding raises the possibility that endothelin is also involved in the very acute effects of smoke on the airways.…”

A neutrophil elastase inhibitor reduces cigarette smoke-induced remodelling of lung vessels

“…Using a microdissection technique, the authors have been able to demonstrate rapid upregulation of endothelin gene expression in both the main and muscular pulmonary arteries after acute cigarette smoke exposure [23]. There is a known association between cell proliferation and endothelin production and in a previous study [11] the authors demonstrated that acute smoke-induced cell proliferation in the vasculature could be reduced or completely abrogated by BQ-610, an endothelin-a receptor antagonist. Endothelin also appears to increase the release of the neutrophil metalloprotease, gelatinase B, which in turn acts in a positive feedback loop to increase endothelin generation [24].…”

“…This acute response appears to involve or to be invoked by oxidants, which are also known to stimulate smooth muscle mitogenesis in cultures [8,9], since it can be partially, but not completely, blocked by antioxidants [10]. However, other mediators, such as endothelin, also appear to play an important role in the proliferate response [11].When guinea-pigs are chronically exposed to cigarette smoke for o4 months, vascular cell proliferation continues throughout the entire period [12], and the animals develop marked muscularisation of the arteries and arterioles adjacent to the alveolar ducts, more than tripling the percentage of these vessels in which a double elastic lamina (a marker of muscularisation) can be identified. These structural changes are accompanied by physiological evidence of PHT [6].…”

“…This acute response appears to involve or to be invoked by oxidants, which are also known to stimulate smooth muscle mitogenesis in cultures [8,9], since it can be partially, but not completely, blocked by antioxidants [10]. However, other mediators, such as endothelin, also appear to play an important role in the proliferate response [11].…”