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

Abstract

Cigarette smoking produces pulmonary hypertension (PHT) through unknown mechanisms. In animal models acute smoke exposure induces cell proliferation in the small arteries adjacent to the alveolar ducts, and chronic exposure results in muscularisation of these vessels, with changes related to the development of PHT. Studies indicate that serine-elastase inhibitors can prevent experimental monocrotaline-induced PHT. This study examined whether they could also prevent cigarette smoke-induced pulmonary vascular disease.Guinea-pigs were exposed to cigarette smoke or air for 6 months. Some animals also received ZD0892, an orally active, synthetic, selective, serine-elastase inhibitor. The percentage of muscularised, small, pulmonary arteries was determined by morphometric analysis of histological sections and vascular cell proliferation by proliferating cell nuclear antigen staining.Vascular cell proliferation was markedly increased in the smoke-exposed animals and the percentage of completely muscularised small vessels was increased four-fold. Cell proliferation indices correlated with muscularisation indices. In the animals treated with ZD0892, the number of completely muscularised vessels was reduced by 50% and cell proliferation was reduced by 61%.These data suggest that smoke-induced cell proliferation leads to pulmonary arterial muscularisation. Serine-elastase inhibitors appear to be able to reduce cell proliferation and vascular remodelling. Pulmonary hypertension (PHT) frequently develops in subjects with chronic obstructive pulmonary disease (COPD) [1], and is an ominous finding, since it has been shown to be a significant predictor of mortality [2]. The mechanistic basis of PHT in smokers is not known. Although it is often stated that PHT arises as a result of loss of the vascular bed secondary to emphysematous lung destruction, clinical-pathologicalepidemiological studies, including work from the authors9 laboratory [3], indicate that this is not necessarily true. Likewise, although the idea that hypoxic vasoconstriction causes PHT in COPD formed the basis of two clinical trials, analysis of the lungs from these patients showed consistent vascular abnormalities that could not explain the varying physiological responses to exercise nor the vascular response to oxygen that was found [4]. A very recent study on patients in the National Emphysema Treatment Trial concluded that PHT was probably related to factors other than hypoxia [5].A guinea-pig model has been developed by the authors, in which pulmonary arterial pressure increases and vascular remodelling occurs after chronic exposure to cigarette smoke and prior to the development of emphysema [6]. Using this model, the authors have shown that PHT cannot be directly ascribed to either hypoxia or emphysematous lung destruction [3,6], but that there appears to be dynamic alteration of both the pulmonary vasculature and airways, resulting in both PHT and airflow obstruction as independent processes [7]. In this model, acute exposure to cigarette smo...

Smoking, Metalloproteinases, and Vascular Disease

“…56,57 Matrix metalloproteinases may also participate in cigarette smoke-induced pulmonary vascular remodeling. 58,59 An interesting potential link between the role of matrix metalloproteinases in smoking-induced emphysema and in smokinginduced vascular disease is cadmium. Cadmium, inhaled in cigarette smoke, induces lung proteolysis.…”

Tobacco Smoke Exposure in Pulmonary Arterial and Thromboembolic Pulmonary Hypertension

“…Thus, in addition to a genetic predisposition and associated disease, environmental factors may play a pathogenic role. Animal studies have shown that tobacco smoke exposure can lead to pulmonary endothelial dysfunction and plexogenic PH [4,5] , and some reports indicate that this might also be the case in humans [6,7] . In a single-center study, we recently showed a higher prevalence of smokers (former or current) in patients with pulmonary arterial hypertension (PAH) compared to chronic thromboembolic PH (CTEPH) and healthy controls from the Swiss Health Survey (SHS) 2007 [8] .…”

Efeito do inibidor de proteinase de origem vegetal CrataBL, sobre a lesão pulmonar induzida pela elastase em camundongos C57/BI6

“…Desde que as proteinases deixaram de ser consideradas apenas como proteínas de degradação enzimática e tornaram-se importantes moléculas sinalizadoras envolvidas em vários processos biológicos vitais, os inibidores da proteinase estão sendo intensamente investigados (Turk, 2006). Algumas moléculas sintéticas foram desenvolvidas para testar o papel terapêutico dos inibidores de proteinases na DPOC, tais como CP-471,474 (Selman, 2003); ZD0892 (Wright, 2003); SP-B (Guarnieri, 2010); MR889 (Luisetti, 1996); FR901277 (Benetazzo, 1999).…”