Cathepsin K overexpression modifies lung development in newborn mice

Abstract

Cathepsin K (CatK), contributes to the development of chronic lung disease in newborn infants, but the impact of CatK for the lungs may be multifaceted. We have previously demonstrated that low level of CatK is associated with newborn lung injury and CatK deficiency aggravates lung injury in hyperoxia-exposed newborn mice. Thus, we hypothesized that sustained/higher expression of CatK could ameliorate hyperoxia-induced injury and restrain the development of pulmonary fibrosis. We studied the lungs of newborn wild-type (WT) and CatK overexpressing transgenic mice (TG) that were exposed to hyperoxia or room air for 7 or 14 days after birth. Fourfold pulmonary overexpression of CatK did not affect the growth or lung weight in room-air bred TG mice. The distal airspaces in TG mice were, however, enlarged on postnatal days (PN) 7 and 14, the latter together with increased apoptosis, compared with WT controls. Survival rate was normal and no respiratory distress was observed in air-bred TG mice. Hyperoxia inhibited alveolarization and increased collagen accumulation in WT mice. In TG mice, hyperoxia for 1 week did not aggravate the lung injury, and the lung morphology and already enlarged alveoli remained unchanged in TG mice at PN7. Prolonged hyperoxic exposure caused significant lung injury and mortality similarly in both group of mice, and only few mice survived until PN14. In summary, CatK overexpression slightly enlarges distal airways in infant mice, but hyperoxic environment is initially better tolerated when compared to WT mice. These findings suggest multifaceted role for CatK in lung development and newborn lung injury.

Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs

“…We [ 22 ] and several other authors have reported a role of cathepsins in lung development and hyperoxia induced lung injury [ 23 , 24 ]. Hence, we also evaluated mRNA expression of all cathepsins but only found noticeable differences in cathepsin L and H expression.…”

Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia

“…Cysteine proteinases have also received attention in the context of aberrant lung alveolarization, where overexpression of cathepsin K (CTSK) in mice led to the formation of enlarged air spaces under normoxic conditions (258). Despite slightly enlarged distal air spaces in CTSK-overexpressing mice, the hyperoxic environment was initially better tolerated in comparison with wild-type mice.…”

Leveraging 3D Model Systems to Understand Viral Interactions with the Respiratory Mucosa

“…Unchecked proteolytic activity can lead to tissue damage and chronic lung disease [185][186][187], highlighting the importance of protease/antiprotease balance to maintaining lung health [188]. This balance also can influence susceptibility to viral infection as proteases tend to act as activators of viral glycoproteins [123].…”

“…Under normal conditions, cysteine proteases provide many important immune functions including inflammation control, macrophage function, class II-associated Ii peptide degradation in major histocompatibility complex class II molecules, generation of CD4+ T cells, and toll-like receptor-9 signaling [205][206][207][208][209][210]. However, cysteine proteases can cause serious damage to the extracellular matrix and tissues [185][186][187] when activated by acidic conditions [211,212]. Matrix metalloproteinases are zinc-dependent endopeptidases which primarily degrade extracellular matrix components, but also activate/deactivate signaling proteins such as cytokines.…”