Early life oxidant pollutant exposure induces lung redox and RAAS dysregulation: implications for innate immune responses

Abstract

The potential for early life air pollutant exposure to result in later onset respiratory disease in children and adults is an emerging public health concern. Fetal growth restriction (FGR) and childhood respiratory infections are associated with impaired lung function in adulthood, and later in life, death from chronic obstructive pulmonary disease (COPD). We previously showed that early gestational exposure of rats to the oxidant air pollutant, ozone, resulted in asymmetrical FGR and lung developmental delays. Herein, we investigate effects of early gestational, periadolescent, and combined ozone exposure on offspring health, lung injury, antioxidant reserve, and innate immune responses. Results revealed similar ozone effects in all offspring irrespective of exposure timing in terms of minor weight loss, reduced body temperature (1.5–2.0°C), and moderate lung injury. Lung injury was inversely correlated with lung antioxidant capacity. Progeny of ozone-exposed dams (i.e., FGR-prone offspring) showed greater variability in ventilatory responses (EF50, Penh) and increased Penh correlated with greater lung injury. FGR-prone offspring had more variable, often blunted immunoinflammatory responses to subsequent ozone exposure. Enhanced expression for antioxidant (Nrf2-related or ARE) genes were observed in FGR-prone males, whereas decreased expression for hypoxia (Hif-related or HRE) and RAAS genes (Ace, Agtr1, and Ace2) was observed in FGR-prone females, potentially suggesting that cross talk between redox transcription factors, Hif/RAAS, NF-κB, and Nrf2 led to differential responses. Collectively, these findings indicate that early life oxidant air pollutant exposure and resultant redox and RAAS dysregulation may impact both lung development and innate immune responses in a sex-dependent manner, effects that may increase vulnerability to respiratory infections.