Contribution of early life oxidant stress on lung development and redox regulation in rats: Implications for innate immune response to respiratory infections.
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Fetal growth restriction (FGR) is associated with reduced lung function and chronic lung disease in adulthood. Early life respiratory infections may also limit infant weight gain and contribute to poorer lung function. Maintaining oxidant/antioxidant or “redox” balance is critical for normal vascular and alveolar development and for mounting innate immune responses to respiratory pathogens. We hypothesized that redox imbalance due to exposure to oxidative stressors early in life may alter pulmonary or immune system maturation. Our prior work showed that exposure of Long Evans dams to the oxidant air pollutant, ozone, during implantation (“hit #1”) caused asymmetrical FGR. Using this FGR model, we further showed that female offspring from ozone-exposed dams (i.e., FGR-prone females) had reduced lung capacity and pathologic changes consistent with impaired angiogenesis and primary alveolarization. In the current study, control and FGR-prone offspring of both sexes were further exposed to ozone (3-times) during adolescence, a period of rapid lung growth (hit #2”). Based on 2-way ANOVA testing, “dam” exposure effects were observed in females resulting in fewer mature alveoli and thicker pulmonary arteries. In males, an adolescent or “pup” exposure effect was observed for increased ductal space, consistent with disruption of secondary alveolarization, especially in the FGR-prone males. Lung mRNA expression of vascular genes and hypoxia (Hif-1a) or redox (Nrf2, Nfkb1) sensing transcription factors revealed dam exposure effects for increased Vegfa expression in both sexes. However, in females, dam exposure effects were also associated with reduced Hif-1α and Nos3 expression likely due to fewer mature endothelial cells being present. In males, although Hif-1a expression was not affected, dam exposure effects were observed for increased Nfkb1 and Nrf2 (with corresponding increases in Trx1 and Nqo1 but not Gclc) expression. Conversely, in females no exposure effects were observed for Nfkb1 or Nrf2 expression, yet dam exposure increased Gclc expression, and significant pup exposure effects were observed for increased Nqo-1 and Ho-1 expression. Hif-1a expression was positively correlated with Ace2 expression in all groups, and moreover, dam exposure led to reduced Ace expression in males, and reduced Ace, Ace2 and Agtr1a expression in females. As expected, in controls, adolescent ozone exposure resulted in increased protein leakage into bronchoalveolar lavage fluid (an index of acute lung injury), with corresponding cytokine increases (IL-6, KCgro) and neutrophilic inflammation. Notably, FGR-prone offspring incurred comparable lung injury, however their inflammatory responses were blunted, especially in males. Across all groups, lung total antioxidant capacity (TAC) in females was higher (by 33%) than in males; and lung TAC was inversely correlated with lung injury. Offspring experiencing combined Hit#1 + Hit#2 ozone exposure showed divergent antioxidant gene expression patterns compared to offspring exposed during adolescence only, especially the males. In conclusion, underlying chronic hypoxia in FGF-prone offspring led to differences in Hif-1a signaling which, in some manner, limited responsiveness of the Nrf2/Nfkb1 inflammatory pathways. Hence, early life oxidant pollutant exposure and resultant redox dysregulation may contribute to both lung pathologic changes and to impaired innate immune response to respiratory pathogens. (Abstract does not reflect USEPA policy).