Establishment of diffuse alveolar damage induced by hyperoxia exposure in mice and elucidation of its pathogenesis

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Under mechanical ventilation with high-inspired oxygen concentration, diffuse alveolar damage (DAD) was found to take place in some patients.To clarify the molecular pathophysiology of this condition we investigated the gene expression changes induced by hyperoxia exposure in mouse lung using cDNA microarrays. It revealed that 5 genes in 4277 genes analyzed were up-regulated, and 30 genes among those were down-regulated.Subsequently, we confirmed the time course of some selected genes using real-time quantitative polymerase chain reaction (real-time qPCR). It showed that mRNA levels of cysteine rich protein 61 (CYR61) and connective tissue growth factor (CTGF) were significantly up-regulated, while those of surfactant-associated protein C (SFTPC), cytochrome P450, 2F2 (CYP2F2), lysozyme (LYZS), P lysozyme structural (LZP-S), and genes of tight junction (Claudin 1, Claudin 18, Occludin, ZO-1) were significantly down-regulated. Increasing levels of mRNAs, each encoding CYR61 and CTGF, suggests a serious risk of fibrosing alveolitis. Decrease in levels of mRNAs for SFTPC, CYP2F2, LYZS, LZP-S, and genes of tight junction suggests alveolar dysfunction, disruption of the immune system, and exudation to alveolar space.Moreover we confirmed apoptotic conditions, such as significant up-regulations of mRNA levels in Galectin-3 and Myc using real-time qPCR. Hyperoxic condition probably yielded reactive oxygen species (ROS), which resulted in a malignant cycle of ROS production by Myc overexpression.