Despite its life-saving potential, mechanical ventilation is associated with significant preventable lung injury. In an effort to better understand the mechanisms of ventilator-induced lung injury (VILI), I profiled changes in lung gene and inflammatory mediator expressions in vivo using adult and newborn rat models of volutrauma and then identified the intracellular signaling for developmentally conserved mediators using an in vitro stretch system. Results of these studies demonstrate that the lung responds to high-tidal volume (HV) ventilation with a robust pro-inflammatory response that occurs prior to the onset of physiologic injury. Newborn lungs are less susceptible to the injurious effects of high-tidal volume then adult lungs. A distinct set of early response mediators (genes, proteins, lipids) represents a developmentally conserved mechanism through which lung cells respond to HV ventilation. Specifically, the Egr1, MIP-2 and Cox-2 mRNA responses to stretch are developmentally conserved as are the PGI2 and TXB 2 eicosanoid responses. Mechanistically, these mediators are controlled by distinct and overlapping signaling pathways that are all hierarchically integrated at a stretch-induced influx of extracellular calcium.