Mechanical ventilation with 02-rich gas (MV-O2) offers life-saving treatment for patients with respiratory failure. Such treatment, however, can cause or aggravate lung injury, leading to neonatal chronic lung disease (CLD) in infants whose lungs are incompletely developed, or to ventilator-induced lung injury (VILl) in older children and adults. Despite recent progress in the management of patients with respiratory failure, notably the use of lung protective ventilation strategies featuring low tidal volumes and peak inflation pressures, acute lung injury remains a major complication of positive-pressure MV-O2. CLD, a variant of BPD,(7) results from lengthy exposure of the developing lung to MV and 02-rich gas. CLD is the leading cause of long-term hospitalization and recurrent respiratory disorders of infants who were born prematurely. It is characterized by failed formation of alveoli and lung micro-vessels, coupled with disordered lung elastin, resulting in structural and functional abnormalities that resemble pulmonary emphysema. Elastin plays a critical role in lung development.(8) A network of elastic fibers in the lung helps to provide structural integrity and distensibility to conducting airways, while enabling expansion and contraction of alveoli, pulsation of blood vessels and elastic recoil of the surrounding matrix. Lungs of infants who died with CLD show thickened, tortuous and irregularly distributed elastic fibers in the connective tissue matrix surrounding distal airspaces.(9-12) These changes were associated with reduced secondary septation and fewer alveoli than in lungs of infants who died without CLD. Urinary excretion of desmosine, a biomarker of elastin degradation, increased during the first week of MV in infants with evolving CLD.(10) Elastin breakdown in this disease has been attributed to inflammation and an imbalance between increased elastolytic activity and deficient protease inhibitors in the lungs of afflicted infants.(13-18) In studies of preterm sheep with evolving CLD,(1) we found that MV-O2 increased lung elastase activity, resulting in lung growth arrest (Fig 1) that was linked to degradation and remodeling of matrix elastin (Fig 2). In mechanically ventilated newborn mice, elevated lung elastase activity was associated with increased TGFB signaling, impaired VEGF signaling (reduced VEGF-A and VEGFR2 proteins), increased apoptosis and scattered elastin, leading to defective formation of alveoli and lung micro-vessels.(2-4) Recently we showed that intrapulmonary treatment of neonatal mice with the serine elastase inhibitor Elafin, or with a TGFB neutralizing antibody (TGPB-Nab), prevented or mitigated the adverse pulmonary effects of prolonged (24h) MV-40%O2.
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