Inhibiting lung elastase activity enables lung growth in mechanically ventilated newborn mice.

Rationale: Mechanical ventilation with O-2-rich gas (MV-O-2) offers life-saving treatment for respiratory failure, but also promotes lung injury. We previously reported that MV-O-2 of newborn mice increased lung elastase activity, causing elastin degradation and redistribution of elastic fibers from septal tips to alveolar walls. These changes were associated with transforming growth factor (TGF)-beta activation and increased apoptosis leading to defective alveolarization and lung growth arrest, as seen in neonatal chronic lung disease. Objectives: To determine if intratracheal treatment of newborn mice with the serine elastase inhibitor elafin would prevent MV-O-2-induced lung elastin degradation and the ensuing cascade of events causing lung growth arrest. Methods: Five-day-old mice were treated via tracheotomy with recombinant human elafin or vehicle (lactated-Ringer solution), followed by MV with 40% O-2 for 8-24 hours; control animals breathed 40% O-2 without MV. At study's end, lungs were harvested to assess key variables noted below. Measurements and Main Results: MV-O-2 of vehicle-treated pups increased lung elastase and matrix metalloproteinase-9 activity when compared with unventilated control animals, causing elastin degradation (urine desmosine doubled), TGF-beta activation (pSmad-2 tripled), and apoptosis (cleaved-caspase-3 increased 10-fold). Quantitative lung histology showed larger and fewer alveoli, greater inflammation, and scattered elastic fibers. Elafin blocked these MV-O-2-induced changes. Conclusions: Intratracheal elafin, by blocking lung protease activity, prevented MV-O-2-induced elastin degradation, TGF-beta activation, apoptosis, and dispersion of matrix elastin, and attenuated lung structural abnormalities noted in vehicle-treated mice after 24 hours of MV-O-2. These findings suggest that elastin breakdown contributes to defective lung growth in response to MV-O-2 and might be targeted therapeutically to prevent MV-O-2-induced lung injury.