Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity

Abstract

Previously in rats injected with the toxin monocrotaline and administered SC-39026, a serine elastase inhibitor, pulmonary hypertension was decreased in association with reduced muscularization of peripheral pulmonary arteries. To determine whether inhibition of elastolytic activity might prevent this vascular change in other conditions producing pulmonary hypertension, we administered SC-39026 to rats during a 10-day exposure to chronic hypobaric hypoxia. We also measured elastolytic activity in the central pulmonary arteries of rats using [3H]elastin substrate and determined whether there was an increase in activity either as early as 2 days or at completion of the hypoxic exposure, which could be inhibited by SC-39026. to further determine whether the mechanism of muscularization of peripheral arteries is modulated by degradation of elastin or other elastase-susceptible extracellular matrix proteins, we assessed desmosine excretion and ultrastructural alterations in elastin as well as in type IV collagen, fibronectin, and laminin. SC-39026 reduced the number of muscularized arteries and the level of pulmonary arterial pressure during exposure to chronic hypoxia. Elastolytic activity was fourfold higher in central pulmonary arteries 2 days after hypoxia when compared with values in control vessels, and the activity was inhibited by SC-39026. In small peripheral pulmonary arteries there were no significant changes with hypoxia reflected in desmosines or in the immunocytochemistry of elastase-susceptible glycoproteins, with the exception of decreased laminin. This feature was not inhibited by SC-39026. To further assess whether the protective effect of SC-39026 was related to its inhibition of elastase, an extended study was carried out using a different elastase inhibitor, alpha 1-proteinase inhibitor. An even greater reduction in hypoxia-induced pulmonary hypertension and vascular changes was observed with this elastase inhibitor and the latter included medial hypertrophy.

Neutrophil Elastase Is Produced by Pulmonary Artery Smooth Muscle Cells and Is Linked to Neointimal Lesions

“…We identified the elastase involved as neutrophil elastase (NE) produced by PA SMC, suggesting that it is the endogenous vascular elastase previously related to PAH in other experimental models. 12,16,18,19 Moreover, we showed that NE is produced in significantly greater amounts by cultured murine S100A4 versus C57 PA SMC, and by human PA SMC from IPAH versus control lungs, and we localized NE to neointimal and plexiform lesions in human lung specimens.…”

“…opathy after transplantation, 28,51 vein graft atherosclerosis 52 and fibrosis following viral myocarditis, 53,54 or pulmonary hypertension induced by hypoxia 12,14 or monocrotaline. 13,15 In five of these models, 28,50,52,54 elafin was used as the elastase inhibitor, given as an infusion, 28 by gene therapy 50,52 or in an overexpressing transgenic mouse.…”

“…7 Fragmentation of PA elastin has been observed in PAs of PAH patients, 11 and heightened activity of a serine elastase has been identified in the PA in a variety of experimental forms of PAH [12][13][14][15] and in cultured PA smooth muscle cells (SMC). 16 -19 Moreover, inhibition of this elastase can attenuate or prevent [12][13][14] and even reverse 15 experimental pulmonary vascular disease in rodents. In all rodent models where elastase inhibitors were used, the pulmonary vascular lesions were characterized by loss or increased muscularization of normally nonmuscular peripheral arteries at the alveolar wall and duct level, and medial hypertrophy of proximal muscular arteries.…”

Correlation of inhaled nitric-oxide induced reduction of pulmonary artery pressure and vascular changes

“…After the hypoxic exposure period, the rats were anaesthetised with pentobarbital sodium (45 mg?kg -1 ) given intraperitoneally. A pulmonary artery catheter (Silastic tubing, 0.31 mm inside diameter (ID) and 0.64 mm outside diameter (OD)) was inserted via the right external jugular vein into the pulmonary artery by a closed-chest technique, as described previously [8,10]. The catheter was then tunnelled subcutaneously and exteriorised in the middle region of the scapular of the rat.…”

“…To determine the relationship between the hypertensive pulmonary vascular changes and response to inhaled NO, NO inhalation was carried out in a rat model of chronic PH induced by chronic hypoxic exposure of varying durations. Quantitative morphometrical analysis was applied to determine the severity of hypertensive pulmonary vasculature [8][9][10]. Low-dose NO inhalation ¡2 parts per million (ppm) was chosen because a lower dose is favourable to minimise any possible toxicity.…”