Mechanical ventilation with high pressures and supraphysiologic concentrations of oxygen is often needed to treat critically ill infants, but it can be quite toxic to the lung. This toxicity can lead to cell death by two distinct modes: apoptosis or necrosis. Apoptosis is often a scheduled and physiologically regulated event, while necrosis is the result of unscheduled, acute injury (often accompanied by inflammation). We have previously shown that in vivo, hyperoxia can cause significant cell death in the lung by apoptosis. TLV is a technique that may be associated with less lung injury and better physiological outcomes compared to CV. To examine whether TLV causes less lung injury and apoptosis compared to CV, we studied 2 groups of premature lambs delivered at 110 and 120 days gestation. Animals were ventilated with 100% O2 and TLV (Liquivent, Alliance Pharm., Hoechst-Marion-Roussel) or CV from birth for up to 4h. Unventilated, gestational matched controls were also studied. Standard physiologic and histologic parameters were analyzed. We also utilized the in situ TUNEL assay, which labels 3′-OH ends of DNA cut by endonucleases that are activated during apoptosis, to evaluate the amount of apoptosis occurring in the lung. Similar to previous reports, the TLV group had better gas exchange and less histologic evidence of lung injury compared to animals receiving CV. Approximately 5% of lung cells were apoptotic in both experimental groups, while gestational matched controls showed virtually no apoptosis. However, the pattern of apoptosis seen with both modes of ventilation was distinctly different. CV was associated with the presence of apoptotic cells within the lumen of immature air spaces, often with these cells completely occluding the lumen. In contrast, during TLV apoptosis was limited to a small number of epithelial cells lining the airspaces, with only a few cells found within the lumen. Although the specific cell types have not yet been identified, these observations suggest that the severity of lung injury might be related to a variety of factors including cell specific apoptosis, rather than apoptosis per se. Supported by a research grant from the March of Dimes(1-FY96-0752).
