Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Rationale Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. Objectives: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. Methods: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-beta) was preemptively blocked in mice exposed to hyperoxia using TGF-beta-neutralizing antibodies. lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxi1 promoters fused upstream of the firefly luciferase gene. Measurements and Main Results: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygen-injured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-beta signaling drove aberrant lox, but not loxi1 or lox/2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. Conclusions: lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-beta signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD.