Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 176, Issue 8, Pages 778-785Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.200704-519OC
Keywords
cathepsin; bronchopulmonary dysplasia; hyperoxia; myofibroblast
Categories
Funding
- NHLBI NIH HHS [HL075904, HL63387, HL71885, HL04403] Funding Source: Medline
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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: Hype roxia-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. alpha-Smooth muscle actin-expressing myofibroblasts accounted for at least some of the increased interstitial cellularity in hype roxia-exposed mouse lungs and were significantly less in cat S-deficient lungs. Lung hydroxyproline content was increased in hype roxia-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.
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