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

Division of Newborn Medicine, Children's Hospital, Harvard Medical School; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Departments of Pediatrics and Pathology, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri; Department of Oral and Biological Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and Institute of Physiological Chemistry, Martin Luther University Halle-Wittenberg, Halle, Germany

Correspondence and requests for reprints should be addressed to Sule Cataltepe, M.D., Division of Newborn Medicine, Children's Hospital, Enders 950, 300 Longwood Avenue, Boston, MA 02115. 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: Real-time reverse transcriptase–polymerase chain reaction, 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 colocalized 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: baboon • bronchopulmonary dysplasia • cathepsin • macrophage • protease

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