OBJECTIVEPulmonary hypertension is a proliferative vascular disease characterized by pulmonary vascular structural remodeling. Until now, the pathogenesis of pulmonary hypertension is still not fully understood. Although considerable progress has been made, there is, to date, no cure for advanced pulmonary vascular disease. Recently, a number of studies suggest that endogenous vascular elastase (EVE) play a role in the vascular changes associated with pulmonary hypertension. The purpose of the study was to determine whether an elastase inhibitor might reverse advanced pulmonary vascular disease produced in rats by injection of monocrotaline.METHODSOne hundred and twenty male Sprague-Dawley rats were used in this study. The rats were divided into three groups: control, model and ZD-0892 groups. In the model and ZD-0892 groups, the rats were subjected to a single subcutaneous injection of monocrotaline (60 mg/kg) in the hind flank, while the rats in control group received an equivalent volume of 0.9% saline. From day 21, the rats in the ZD-0892 and model groups received twice-daily gavage tube feedings of either ZD-0892 at a dose of 240 mg/kg per day or its administration vehicle, while the rats in control group were subjected to an equivalent volume of 0.9% saline. On days 21, 28 and 35 post-injection, the elastolytic activity was measured with a fluorescence microplate reader and pulmonary artery pressure was detected via catheterization. Meanwhile, the lungs were evaluated morphologically, using the barium-gelatin perfusion technique.RESULTSThe injection of monocrotaline led to severe pulmonary hypertension in rats 21 days later and pulmonary artery elastolytic activity increased remarkably. A 1-week treatment with ZD-0892 resulted in declines in elastase activity. This was associated with significant declines in pulmonary artery pressure, decreases in muscularization of peripheral arteries and reductions in medial hypertrophy. After 2 weeks, elastase activity returned to normal level. Pulmonary artery pressure and structure were normalized.CONCLUSIONIncreased elastase activity is important in the development of vascular changes and progressive pulmonary hypertension. ZD-0892 can suppress the elastase activity and completely reverse the fatal pulmonary hypertension induced by monocrotaline in rats.

2003-07-15·American Journal of Respiratory and Critical Care Medicine1区 · 医学

α-1-Antitrypsin Ameliorates Cigarette Smoke–induced Emphysema in the Mouse

1区 · 医学

Article

作者: Xie, Changshi ; Churg, Andrew ; Wright, Joanne L. ; Wang, Rong D.

Serine elastase inhibitors have been proposed as a treatment for cigarette smoke-induced emphysema, but little is known about whether such agents actually are effective. We recently reported that a synthetic serine elastase inhibitor, ZD0892, provided some protection against emphysema in a guinea pig model. For these experiments, we used transgenic mice that expressed extremely low levels of human alpha-1-antitrypsin (A1AT) but were tolerant of exogenous human A1AT. Mice were exposed to daily cigarette smoke for up to 6 months; some animals received 20 mg of human A1AT (Prolastin) every 48 hours. Treatment with A1AT produced an approximate twofold increase in serum A1AT levels and elastase inhibitory capacity and abolished smoke-induced elevations in lavage neutrophils and matrix breakdown products (desmosine and hydroxyproline) measured from 2 to 30 days of smoke exposure. A1AT oxidized to remove antiproteolytic activity did not increase serum elastase inhibitory capacity but did prevent neutrophil influx. Treatment with A1AT for 6 months provided 63% protection against increased airspace size (emphysema) and abolished smoke-mediated increases in plasma tumor necrosis factor-alpha. We conclude that A1AT therapy ameliorates smoke-induced inflammation and matrix breakdown, possibly via an antiinflammatory mechanism related to tumor necrosis factor-alpha suppression, and provides partial protection against emphysema.

2003-07-01·European Respiratory Journal1区 · 医学

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

1区 · 医学

Article

作者: Wright, J. L. ; Churg, A. ; Farmer, S. G.

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.

100 项与 ZD-0892 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
慢性阻塞性肺疾病	临床2期	-	阿斯利康制药有限公司	-
外周血管疾病	临床1期	英国	AstraZeneca PLC	-
外周血管疾病	临床1期	-	阿斯利康制药有限公司	-
慢性阻塞性肺疾病	临床1期	英国	AstraZeneca PLC	-