Published ahead of print on January 9, 2003, doi:10.1164/rccm.200210-1207OC
Am. J. Respir. Crit. Care Med., Volume 167, Number 11, June 2003, 1516-1521
A more recent version of this article appeared on June 1, 2003
Submitted on October 21, 2002
Accepted on January 8, 2003
Methylprednisolone Causes Matrix Metalloproteinase-dependent Emphysema in Adult Rats
Kang-Hyeon Choe1, Laimute Taraseviciene-Stewart1, Robertas Scerbavicius1, Lajos Gera2, Rubin M Tuder3, and Norbert F Voelkel1*
1 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA,
2 Pulmonary Hypertension Center, Division of Biochemistry, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA,
3 Division of Cardiopulmonary Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: Norbert.Veolkel{at}uchsc.edu.
Previous investigations have shown that corticosteroids affect the development and maturation of the developing lung in utero and in neonatal animals. Systemic corticosteroids are routinely used for the treatment of acute exacerbations of chronic obstructive pulmonary disease and inhaled corticosteroids are increasingly prescribed for the long-term treatment of patients with chronic obstructive pulmonary disease. Because corticosteroids can affect matrix metalloproteinases and because the concept of protease/antiprotease imbalance is an important concept regarding the pathogenesis of emphysema, we examined the effects of chronic steroid treatment on lung structure in adult rats. Rats treated with 2mg/kg of methylprednisolone daily for 1, 2 or 4 weeks had an increased mean linear intercept and a decrease of the surface-volume ratio when compared to age-matched control animals, and the animals showed by zymography increased matrix metalloproteinase-9 activity in their lungs. Rats treated concomitantly with methylprednisolone and a broad-spectrum matrix metalloproteinase inhibitor (GM6001) did not develop emphysema. We conclude that systemic treatment of adult rats with the anti-inflammatory steroid methylprednisolone increases the activity of matrix metalloproteinases in the lung and causes emphysema.
Key words: corticosteroid, matrix metalloproteinase, emphysema
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