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

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. a-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.Keywords: cathepsin; bronchopulmonary dysplasia; hyperoxia; myofibroblast Advanced perinatal care over the past decade has resulted in improved survival of very-low-birth-weight (VLBW) (birth weight , 1,500 g) infants (1). However, surviving VLBW infants have increased risk of major morbidities, particularly bronchopulmonary dysplasia (BPD). BPD has a negative impact on not only short-term and long-term pulmonary function but also on overall growth and neurodevelopment of VLBW infants (2-4). The major pathologic findings associated with BPD in surfactant-treated lungs are inflammation, disrupted alveolar development, and variable amounts of fibrosis (5). Exposure of the immature lung to hyperoxia, prolonged mechanical ventilation, and antenatal or postnatal infections are primary risk factors for BPD (6, 7). However, the molecular mechanisms that link these factors to disruption of alveolarization are not completely understood and there are currently no evidence-based strategies to prevent or treat BPD.Several studies have shown that alveolar elastin expressed by myofibroblasts is a critical component of alveolar development (8, 9). The impaired alveolar development in BPD is also accompanied by changes in deposition of elas...

Suppression of inflammatory cell trafficking and alveolar simplification by the heme oxygenase-1 product carbon monoxide

“…Murine alveolar development begins on postnatal day 5, and saccular division is completed by the 30th postnatal day (53). This result is in agreement with previous work showing that exposure to supraphysiological levels of oxygen confers hypoalveolarization (18,40,41) and is consistent with the notion that oxygen exposure may be a contributing factor in the pathogenesis of BPD.…”

“…Prolonged exposure to sublethal hyperoxia in animal models recapitulates some of the processes observed in BPD (18,40,41), such as arrested alveolar development, a paucity of ␣-actin-positive myofibroblasts at the alveolar septal tips, and a corresponding increase in the number of interstitial myofibroblasts (4,21,22,48). Importantly, rodents exhibit a saccular stage of lung development at birth that is only completed after 4 wk of postnatal alveolarization (53).…”

Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

“…Although defects in macrophage infiltration have been reported in different knock-out mice models [52][53][54][55], a comprehensive investigation into the 3D migration of macrophages has only recently begun because experimental models and suitable techniques needed to be developed first. 3D migration models in vitro, such as Matrigel invasion assays, have started to shed light on the migration modes used by macrophages, and the involvement of the different protease sub-families.…”

“…In a transplant rejection model, macrophages accumulate in the transplant as determined by intravital microscopy and this is correlated with an increase in cathepsin B activity [82]. Cathepsin S is involved in the recruitment of macrophages into the brain [52] and lungs in a model of neonatal hyperoxia-induced tissue injury [53]. In chimeric mice transplanted with cathepsin S À/À or cathepsin B À/À BM, macrophages retain the ability to infiltrate tumors but are unable to assist cancer cells to invade the surrounding healthy tissues [31].…”

Role of Cathepsin K, L and S in Blood Vessel Remodeling

“…Similarly to cathepsin K, cathepsin S shows strong collagenolytic and elastolytic activities and in contrast to cathepsin K and L, this protease is more stable and retains activity at neutral pH (Chapman et al, 1997;Taleb & Clement, 2007). Under pathological conditions, cathepsin S is upregulated in lung and blood vessel tissues and its stability at neutral pH may significantly contribute to the degradation of the extracellular matrix (Deschamps et al, 2010;Samokhin et al, 2011;Hirakawa et al, 2007;Williams et al, 2009).…”