Anne Hilgendorff1,4, Kakoli Parai1, Robert Ertsey1, Noopur Jain1, Edwin F. Navarro1, Joanna L. Peterson1, Rasa Tamosiuniene2, Mark R. Nicolls2, Barry C. Starcher3, Marlene Rabinovitch1 and Richard D. Bland1 American Journal of Respiratory and Critical Care Medicine Vol 184. pp. 537-546, (2011)
Rationale: Mechanical ventilation with O2-rich gas (MV-O2) offers life-saving treatment for respiratory failure, but also promotes lung injury. We previously reported that MV-O2 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)-β 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-O2–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% O2 for 8–24 hours; control animals breathed 40% O2 without MV. At study’s end, lungs were harvested to assess key variables noted below.
Measurements and Main Results: MV-O2 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-β 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-O2–induced changes.
Conclusions: Intratracheal elafin, by blocking lung protease activity, prevented MV-O2–induced elastin degradation, TGF-β activation, apoptosis, and dispersion of matrix elastin, and attenuated lung structural abnormalities noted in vehicle-treated mice after 24 hours of MV-O2. These findings suggest that elastin breakdown contributes to defective lung growth in response to MV-O2 and might be targeted therapeutically to prevent MV-O2–induced lung injury.
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