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

Nature Medicine volume 6, pages 698–702 (2000)Cite this article

Abstract

Progression of pulmonary hypertension is associated with increased serine elastase activity and the proteinase-dependent deposition of the extracellular matrix smooth muscle cell survival factor tenascin-C (refs. 1,2). Tenascin-C amplifies the response of smooth muscle cells to growth factors3, which are also liberated through matrix proteolysis4. Recent organ culture studies using hypertrophied rat pulmonary arteries have shown that elastase inhibitors suppress tenascin-C and induce smooth muscle cell apoptosis5,6. This initiates complete regression of the hypertrophied vessel wall by a coordinated loss of cellularity and extracellular matrix. We now report that elastase inhibitors can reverse advanced pulmonary vascular disease produced in rats by injecting monocrotaline, an endothelial toxin. We began oral administration of the peptidyl trifluoromethylketone serine elastase inhibitors M249314 or ZD0892 21 days after injection of monocrotaline. A 1-week treatment resulted in 92% survival, compared with 39% survival in untreated or vehicle-treated rats. Pulmonary artery pressure and muscularization were reduced by myocyte apoptosis and loss of extracellular matrix, specifically elastin and tenascin-C. After 2 weeks, pulmonary artery pressure and structure normalized, and survival was 86%, compared with 0% in untreated or vehicle-treated rats. Although concomitant treatment with various agents can reduce pulmonary hypertension7, we have documented complete regression after establishment of malignant monocrotaline-induced disease.

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Figure 1: Serine elastase inhibition induces survival by reversal of pulmonary hypertension.
Figure 2: Reversal of pulmonary arterial muscular changes by elastase inhibition.
Figure 3: Cellular mechanism responsible for reversal of pulmonary artery muscularity.

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Acknowledgements

We thank J. Klein and L. Morikawa for technical assistance, D. Osmond of the Department of Physiology, University of Toronto for systemic pressure measurements, as well as the Laboratory Animal Services staff at the Hospital for Sick Children. We also thank J. Jowlabar, J. Matthews and J. Edwards for secretarial assistance. This work was supported by grants from the Heart and Stroke Foundation of Canada grant #3170, the Medical Research Council of Canada grant #PG13920 and the Primary Pulmonary Hypertension Cure Foundation. M.R. is a research endowed chair of the Heart and Stroke Foundation. K.N.C. holds a K.M. Hunter/Medical Research Council of Canada doctoral fellowship.

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Authors and Affiliations

  1. Division of Cardiovascular Research/Departments of Pediatrics, Laboratory Medicine and Pathobiology, and Medicine, Hospital for Sick Children/University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Kyle Northcote Cowan, Adrian Heilbut, Tilman Humpl, Catherine Lam & Marlene Rabinovitch

  2. Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Shinya Ito

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  1. Kyle Northcote Cowan
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Correspondence to Marlene Rabinovitch.

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Cowan, K., Heilbut, A., Humpl, T. et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 6, 698–702 (2000). https://doi.org/10.1038/76282

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