Abstract
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. α-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.
