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Published ahead of print on May 5, 2005, doi:10.1164/rccm.200502-296OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 3, August 2005, 358-363

A more recent version of this article appeared on August 1, 2005
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Submitted on February 23, 2005
Accepted on May 2, 2005

Inhaled Iloprost Reverses Vascular Remodeling in Chronic Experimental Pulmonary Hypertension

Ralph Theo Schermuly1*, Huseyin Yilmaz1, Hossein Ardeschir A Ghofrani1, Kathrin Woyda1, Soni Pullamsetti1, Andreas Schulz2, Tobias Gessler1, Rio Dumitrascu1, Norbert Weissmann1, Friedrich Grimminger1, and Werner Seeger1

1 Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany, 2 Schering Deutschland AG, Berlin, Germany

* To whom correspondence should be addressed. E-mail: ralph.schermuly{at}innere.med.uni-giessen.de.

Rationale: Inhaled iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled iloprost on changes to pulmonary vascular structure that occur in PAH. Objectives: The present study was designed to investigate chronic anti-remodeling effects of inhaled iloprost in monocrotaline (MCT)-induced pulmonary arterial hypertension in rats. Methods: Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with iloprost a dose of 6 µg.kg-1.day-1, or underwent sham nebulization with saline. Results: After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with iloprost, but not in sham treated controls. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization and the medial wall thickness of intra-acinar pulmonary arteries regressed in response to iloprost. Furthermore, the MCT-induced increase in matrix metalloproteinase 2 and 9 activities and tenascin-C expression was suppressed. Conclusions: We conclude that the inhalation of iloprost reverses pulmonary arterial hypertension and vascular structural remodeling in monocrotaline treated rats. This regimen suggests the possibility of an anti-remodeling therapy in pulmonary arterial hypertension.
Key words: Iloprost, pulmonary hypertension, inhalation, monocrotaline, remodeling




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