Injury and repair in the very immature lung following brief mechanical ventilation

Abstract

Mechanical ventilation (MV) of very premature infants contributes to lung injury and bronchopulmonary dysplasia (BPD), the effects of which can be long-lasting. Little is currently known about the ability of the very immature lung to recover from ventilator-induced lung injury. Our objective was to determine the ability of the injured very immature lung to repair in the absence of continued ventilation and to identify potential mechanisms. At 125 days gestational age (days GA, 0.85 of term), fetal sheep were partially exposed by hysterotomy under anesthesia and aseptic conditions; they were intubated and ventilated for 2 h with an injurious MV protocol and then returned to the uterus to continue development. Necropsy was performed at either 1 day (short-term group, 126 days GA, n = 6) or 15 days (long-term group, 140 days GA, n = 5) after MV; controls were unventilated ( n = 7–8). At 1 day after MV, lungs displayed signs of injury, including hemorrhage, disorganized elastin and collagen deposition in the distal airspaces, altered morphology, significantly reduced secondary septal crest density, and decreased airspace. Bronchioles had thickened epithelium with evidence of injury and sloughing. Relative mRNA levels of early response genes ( connective tissue growth factor, cysteine-rich 61, and early growth response-1) and proinflammatory cytokines [ interleukins ( IL)- 1β, IL-6, IL-8, tumor necrosis factor-α, and transforming growth factor-β] were not different between groups 1 day after MV. At 15 days after MV, lung structure was normal with no evidence of injury. We conclude that 2 h of MV induces severe injury in the very immature lung and that these lungs have the capacity to repair spontaneously in the absence of further ventilation.