Mechanical ventilation of the very immature lung: mechanisms of injury and repair

2017-02-17T01:14:57Z (GMT) by Brew, Nadine
Very preterm infants often require mechanical ventilation (MV) due to respiratory insufficiency. However, respiratory support that includes MV can injure the immature lung and contribute to the development of bronchopulmonary dysplasia (BPD). Structural changes in the lungs that are associated with MV and BPD can persist, resulting in deficits in lung function in children and young adults. Multiple factors are known to contribute to the development of BPD including MV, the use of supplemental oxygen, infection and impaired nutrition, so it has been difficult to determine the effects of MV alone. Using our unique model of MV-induced lung injury in the fetal sheep we are able to investigate the effects of MV alone on the immature lung. To determine if MV-induced injury in the very immature lung persists or resolves in the absence of further ventilation, we exposed very immature fetal sheep to a brief period (2h) of MV and examined the lungs 24h and 15d later. These studies were conducted in sheep in both the saccular and early-alveolar stages of lung development. Knowledge about the susceptibility to MV-induced injury at different stages of lung development will provide important information regarding the factors contributing to BPD in preterm infants. At both stages of lung development brief, injurious MV caused severe lung injury at 24h. Lungs displayed reduced secondary septal crest density, atelectasis, disorganised extracellular matrix deposition and hemorrhage. Bronchioles had thickened, injured epithelium and often contained luminal debris. MV caused differences in lung injury manifestation between saccular and early-alveolar stage lungs. Fifteen days after MV was performed saccular and early-alveolar stage lungs spontaneously repaired and displayed no signs of injury or remodelling. In order to determine if injury and/ or repair mechanisms are active in our model of MV-induced injury 24h after brief MV mRNA and protein expression of cytokines, early response genes and a subset of putative repair genes were evaluated. Cytokine and early response gene mRNA levels were not elevated and the protein deposition of early response genes was also not increased. The mRNA expression levels of two putative repair genes, metallothionein and urokinase plasminogen activator receptor, were significantly increased. Protein deposition of metallothionien was also increased in ventilated lungs. This study has shown for the first time that 24h after MV of the very immature lung, while lungs remain severely injured and remodelled that (1) lung repair processes are likely to have commenced, (2) manifestation of acute phase lung injury has ceased, and (3) the saccular and early-alveolar stage lungs are likely to undergo repair by similar mechanisms. These findings demonstrate that the immature lung does have the capacity to repair in the absence of continued MV. Furthermore I have identified possible mechanisms of repair in the developing lung, which are worthy of further investigation.