The ARDS Network low tidal volume study,1 which studied the effect of lower tidal volume, plateau pressure-limited ventilation compared with more conventional tidal volumes in 861 patients, has provided considerable data on several biological markers of VALI. In an analysis4 of samples from patients in this clinical trial, higher baseline plasma levels of IL-6, IL-8, and IL-10 were each associated with an increased risk of death in all patients independent of the ventilation protocol to which they were randomized. In the low tidal volume group, plasma levels of IL-6 decreased by 26% and IL-8 levels decreased by 12%, but levels of IL-10 did not change by the third study day. In 703 of the 861 patients enrolled in the study, IL-6 was measured on both day 0 and day 3. The odds ratio for mortality for plasma IL-6 level on day 3 of the study was 3.7 (95% confidence interval [CI], 2.7 to 5.7) per 10-fold increase in plasma IL-6 level. It is noteworthy that IL-6 and IL-8 levels did vary with clinical risk factor for ARDS and that factors such as infection could increase levels of these mediators. However, the authors4 calculated that the proportion of treatment effect in the low tidal volume group captured by day 3 IL-6 level was 30% (95% CI, 8 to 88%), suggesting that IL-6 may be a surrogate marker for mortality reduction attributable to low tidal volume ventilation. From these clinical studies, it appears that low tidal volume ventilation may lead to a more rapid attenuation of the inflammatory response as measured by changes in plasma and BAL cytokines. Another analysis42 of plasma samples from 565 patients in the ARDS Clinical Trials Network low tidal volume study found that higher plasma surfactant protein (SP)-D levels at baseline were associated with an increased risk of death and that the low tidal volume strategy was further associated with a significant decrease in SP-D by study day 3. Because SP-D is specific to alveolar epithelial cells, this result may indicate reduced alveolar epithelial cell injury or decreased alveolar epithelial permeability to protein in the patients treated with the low tidal volume ventilation strategy. Plasma SP-A levels did not correlate with outcome or with ventilation strategy in that study; however, a previous report44 suggested that increased plasma SP-A levels are associated with fewer ventilator-free days and higher mortality in ARDS and ALI patients independent of tidal volume.