Cathepsin K deficiency aggravates lung injury in hyperoxia-exposed newborn mice

Abstract

Cathepsin K (CatK) is a potent collagenase and elastase and may be involved in the development of neonatal bronchopulmonary dysplasia. The authors evaluated the effects of CatK deletion on neonatal lung development and response to prolonged hyperoxic challenge. CatK deficiency resulted in thinner alveolar walls than wild-type littermates on postnatal day (PN) 7. However, no morphological difference could be detected between CatK-deficient and control groups on PN 14. Exposure to 90% oxygen for 7 days after birth caused intensive CatK expression in the bronchial epithelium and alveolar macrophages of wild-type mice. Hyperoxia caused fatal respiratory distress in both groups of mice. However, whereas ∼20% of wild-type mice survived for 2 weeks in hyperoxia, all CatK-deficient mice died within the first 9 postnatal days. Hyperoxia-exposed lungs of CatK-deficient mice contained high number of macrophages and multinucleated giant cells and had increased content of reduced glutathione, indicating intensified pulmonary oxidative stress. These results suggest that CatK is involved in pulmonary development and it may be an important host-defence protease in the oxygen-stressed newborn lung.

Cathepsin K overexpression modifies lung development in newborn mice

“…Our results demonstrate that CatK overexpression enlarges distal airspaces in infant mice, but the lung development is not uniformly arrested and airspace enlargement does not result in respiratory distress in infant mice. This finding is in line with our previous study that demonstrated that CatK deficiency transiently alters postnatal lung development . Together these studies underline the importance of proteases in normal lung development.…”

“…Furthermore, CatK activity is central for macrophage function and uptake of oxidized lipids during inflammation . As also reported in our previous study, deficiency of CatK may result in production of foam cells that may further enhance oxidative stress in injured tissue . Since, CatK deficiency aggravates oxygen induced lung injury, we hypothesized that sustained or slightly elevated amount of CatK in the lung could be beneficial for lung development in hyperoxia‐exposed newborn mice.…”

“…We have recently presented that CatK expression is decreased in infants developing chronic lung disease and rats exposed to prolonged hyperoxia . Furthermore, we have demonstrated that postnatal pulmonary development is altered and hyperoxia‐induced lung injury is aggravated in CatK‐deficient mice . However, the control mechanisms of alveolar development are still incompletely understood and the unique role of CatK in injurious process of the developing lung is still unclear.…”

Remodeling of Aorta Extracellular Matrix as a Result of Transient High Oxygen Exposure in Newborn Rats: Implication for Arterial Rigidity and Hypertension Risk

“…Cathepsin S is present as small foci on the smooth muscle cells plasma membrane but not in the cytosol [66], which may explain the differences in expression observed using immunofluorescence of aortic sections but not with immunoblot of whole vessel lysate. Conversely, cathepsin K deficiency aggravates lung injury in high O 2 -exposed newborn mice [67]. Cathepsin K expression levels are significantly reduced in the lungs of premature infants with bronchopulmonary dysplasia [68]; in contrast, cathepsin K is upregulated in fibrotic adult lungs, suggesting a protective role against excessive collagen deposition in adult chronically diseased lungs [69].…”

Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

“…[41] Knaapi et al reported that CatK deficiency aggravates oxidative lung stress and results in the disruption of postnatal development of the newborn lung. [107] CatK also appears to be critically involved in metabolic and cardiovascular pathology. Studies have shown that serum insulin and glucose levels, lipid accumulation in preadipocytes, and body weight gain was significantly reduced in female CatK-deficient mice.…”