| First Author | Zhong Y | Year | 2022 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 322 |
| Issue | 2 | Pages | L204-L223 |
| PubMed ID | 34878944 | Mgi Jnum | J:317458 |
| Mgi Id | MGI:6850210 | Doi | 10.1152/ajplung.00158.2021 |
| Citation | Zhong Y, et al. (2021) Lysyl oxidase regulation and protein aldehydes in the injured newborn lung. Am J Physiol Lung Cell Mol Physiol |
| abstractText | During newborn lung injury, excessive activity of lysyl oxidases (LOXs) disrupts extracellular matrix (ECM) formation. Previous studies indicate that TGFbeta activation in the O2-injured mouse pup lung increases lysyl oxidase (LOX) expression. But how TGFbeta regulates this, and whether the LOXs generate excess pulmonary aldehydes are unknown. First, we determined that O2-mediated lung injury increases LOX protein expression in TGFbeta-stimulated pup lung interstitial fibroblasts. This regulation appeared to be direct; this is because TGFbeta treatment also increased LOX protein expression in isolated pup lung fibroblasts. Then using a fibroblast cell line, we determined that TGFbeta stimulates LOX expression at a transcriptional level via Smad2/3-dependent signaling. LOX is translated as a pro-protein that requires secretion and extracellular cleavage before assuming amine oxidase activity and, in some cells, reuptake with nuclear localization. We found that pro-LOX is processed in the newborn mouse pup lung. Also, O2-mediated injury was determined to increase pro-LOX secretion and nuclear LOX immunoreactivity particularly in areas populated with interstitial fibroblasts and exhibiting malformed ECM. Then, using molecular probes, we detected increased aldehyde levels in vivo in O2-injured pup lungs, which mapped to areas of increased pro-LOX secretion in lung sections. Increased activity of LOXs plays a critical role in the aldehyde generation; an inhibitor of LOXs prevented the elevation of aldehydes in the O2-injured pup lung. These results reveal new mechanisms of TGFbeta and LOX in newborn lung disease and suggest that aldehyde-reactive probes might have utility in sensing the activation of LOXs in vivo during lung. |
