Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor

Progression of pulmonary hypertension is associated with increased serine e lastase activity and the proteinase-dependent deposition of the extracellul ar matrix smooth muscle cell survival factor tenascin-C (refs. 1,2). Tenasc in-C amplifies the response of smooth muscle cells to growth factors(3), wh ich are also liberated through matrix proteolysis(4). Recent organ culture studies using hypertrophied rat pulmonary arteries have shown that elastase inhibitors suppress tenascin-C and induce smooth muscle cell apoptosis(5,6 ). This initiates complete regression of the hypertrophied vessel wall by a coordinated loss of cellularity and extracellular matrix. We now report th at elastase inhibitors can reverse advanced pulmonary vascular disease prod uced in rats by injecting monocrotaline, an endothelial toxin. We began ora l administration of the peptidyl trifluoromethylketone serine elastase inhi bitors M249314 or ZD0892 21 days after injection of monocrotaline. A 1-week treatment resulted in 92% survival, compared with 39% survival in untreate d or vehicle-treated rats. Pulmonary artery pressure and muscularization we re reduced by myocyte apoptosis and loss of extracellular matrix, specifica lly elastin and tenascin-C. After 2 weeks, pulmonary artery pressure and st ructure normalized, and survival was 86%, compared with 0% in untreated or vehicle-treated rats. Although concomitant treatment with various agents ca n reduce pulmonary hypertension(7), we have documented complete regression after establishment of malignant monocrotaline-induced disease.