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Published ahead of print on September 15, 2005, doi:10.1164/rccm.200503-425OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 3, February 2006, 318-326

A more recent version of this article appeared on February 1, 2006
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Submitted on March 17, 2005
Accepted on September 14, 2005

Imbalance Between Cysteine Proteases and Inhibitors in a Baboon Model of Bronchopulmonary Dysplasia

Ozden Altiok1, Ryuji Yasumatsu1, Gulbin Bingol-Karakoc1, Richard J Riese2, Mildred T Stahlman3, William Dwyer1, Richard A Pierce4, Dieter Bromme5, Ekkehard Weber6, and Sule Cataltepe7*

1 Division of Newborn Medicine, Harvard Medical School, Children's Hospital, Boston, MA, USA, 2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA, 3 Departments of Pediatrics and Pathology, Vanderbilt University Medical Center, Nashville, TN, USA, 4 Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, USA, 5 Department of Oral and Biological Sciences, University of British Columbia, Vancouver, Canada, 6 Martin Luther University Halle-Wittenberg, Institute of Physiological Chemistry, Halle, Germany, 7 Division of Newborn Medicine, Harvard Medical School, Children's Hospital, Boston, MA, USA; Division of Newborn Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: sule.cataltepe{at}childrens.harvard.edu.

Rationale: Bronchopulmonary dysplasia (BPD) continues to be a major morbidity in preterm infants. The lung pathology in BPD is characterized by impaired alveolar and capillary development. An imbalance between proteases and protease inhibitors in association with changes in lung elastic fibers has been implicated in the pathogenesis of BPD. Objective: To investigate the expression and activity levels of papain-like lysosomal cysteine proteases, cathepsins B, H, K, L, S, and their inhibitors, cystatins B and C, in a baboon model of BPD. Methods: Quantitative real-time RT-PCR, immunohistochemistry, immunoblotting, active site labeling of cysteine proteases, and in situ hybridization were performed. Measurements and main results: The steady state mRNA and protein levels of all cathepsins were significantly increased in the lung tissue of baboons with BPD. In contrast, the steady-state mRNA and protein levels of two major cysteine protease inhibitors, cystatin B and C, were unchanged. Correlating with these alterations, the activity of cysteine proteases in lung tissue homogenates and bronchoalveolar lavage fluid was significantly higher in the BPD group. The levels of cathepsin B, H, and S increased and cathepsin K decreased with advancing gestation. All cathepsins, except for cat K, were immunolocalized to macrophages in BPD. In addition, cathepsin H and cystatin B were co-localized in type 2 alveolar epithelial cells. Cathepsin L was detected in some bronchial epithelial, endothelial, and interstitial cells. Cathepsin K was localized to some perivascular cells by in situ hybridization. Conclusions: Cumulatively, these findings demonstrate an imbalance between cysteine proteases and their inhibitors in BPD.
Key words: Bronchopulmonary dysplasia, cathepsin, protease, macrophage, baboon




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