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Cathepsin S Deficiency Confers Protection from Neonatal Hyperoxia-induced Lung Injury

¹ Division of Newborn Medicine, Brigham and Women's Hospital and Children's Hospital, Boston, Massachusetts; ² Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; ³ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; ⁴ Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts; ⁵ Institute of Physiological Chemistry, Martin Luther University Halle-Wittenberg, Halle, Germany; and ⁶ Department of Biochemistry, University of Texas, Tyler, Texas

Correspondence and requests for reprints should be addressed to Sule Cataltepe, M.D., Division of Newborn Medicine, Brigham and Women's Hospital, Thorn 1019, 75 Francis Street, Boston, MA 02115. E-mail: scataltepe{at}partners.org

Rationale: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that adversely affects long-term pulmonary function as well as neurodevelopmental outcomes of preterm infants. Elastolytic proteases have been implicated in the pathogenesis of BPD. Cathepsin S (cat S) is a cysteine protease with potent elastolytic activity. Increased levels and activity of cat S have been detected in a baboon model of BPD.

Objectives: To investigate whether deficiency of cat S alters the course of hyperoxia-induced neonatal lung injury in mice.

Methods: Newborn wild-type and cat S–deficient mice were exposed to 80% oxygen for 14 days. Histologic and morphometric analysis were performed and bronchoalveolar lavage protein and cells were analyzed. Lung elastin was assessed by real-time polymerase chain reaction, in situ hybridization, desmosine analysis, and Hart's stain. Distribution of myofibroblasts was analyzed by immunofluorescence. Hydroxyproline content of lung tissues was measured.

Measurements and Main Results: Hyperoxia-exposed cat S–deficient mice were protected from growth restriction and had improved alveolarization, decreased septal wall thickness, lower number of macrophages, and lower protein concentration in bronchoalveolar lavage fluid. -Smooth muscle actin–expressing myofibroblasts accounted for at least some of the increased interstitial cellularity in hyperoxia-exposed mouse lungs and were significantly less in cat S–deficient lungs. Lung hydroxyproline content was increased in hyperoxia-exposed wild-type, but not in cat S–deficient lungs. Desmosine content was significantly reduced in both genotypes with hyperoxia.

Conclusions: Cathepsin S deficiency improves alveolarization, and attenuates macrophage influx and fibroproliferative changes in hyperoxia-induced neonatal mouse lung injury.

Key Words: cathepsin • bronchopulmonary dysplasia • hyperoxia • myofibroblast

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Cathepsin S is a lysosomal papain-like cysteine protease with elastolytic activity. Limited information is available on the in vivo role of cathepsin S in normal or diseased lung, particularly in relationship to the alterations in extracellular matrix. What This Study Adds to the Field Deficiency of cathepsin S protected newborn mice from hyperoxia-induced growth restriction, impaired alveolarization, fibroproliferation, and macrophage influx. These improvements were not accompanied by any differences in lung elastin content.

 

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