Elastase activity and the pathophysiology of pulmonary hypertension

Ultrastructural assessment of the pulmonary arteries on lung biopsy tissue in children with congenital heart defects first suggested that an enzyme, having as one of its proteolytic properties the ability to degrade elastin, might be important in the pathogenesis of pulmonary hypertension. Increased elastolytic activity was present in the pulmonary arteries of experimental rats prior to the initiation of vascular changes which caused pulmonary hypertension and with their progression. A cause and effect relationship between increased elastolytic activity and pulmonary vascular disease was established in experimental rats injected with monocrotaline or exposed to hypoxia, when it was shown that administration of serine elastase inhibitors reduced the severity of the vascular changes and the pulmonary hypertension. In rats injected with the toxin monocrotaline, the progression of structural changes was retarded even when infusion of the inhibitor was delayed. Taken together, these results suggested that an elastolytic enzyme might be important in the induction of structural remodelling and might also contribute to the progression of pulmonary vascular disease. Current investigations are using molecular approaches to uncover the nature of this heightened elastolytic activity and its role in pulmonary as well as systemic vascular disease.