Impact Of Early Life Ozone And Lps Exposure On Long Term Programming Of Innate Immunity

It is well documented that the respiratory system of young children, particularly within the first year of life, is highly sensitive to environmental stimuli. During infancy, postnatal growth and differentiation of pulmonary epithelium occurs in parallel with maturation of the innate and adaptive arms of the immune system. Epidemiologic data support a link between early life air pollution and microbial exposures and increased lung infection susceptibility and enhanced disease severity in children. But the mechanisms behind this increased susceptibility during early life remain poorly defined. The focus of this dissertation research is to characterize the development of innate immune responses during early life using a non-human primate model. We hypothesize that exposures to common environmental challenges such as ozone and endotoxin during infancy can result in sustained modulation of innate immune responses to pathogens, both systemically and locally within the lung. Work outlined in Chapter 2 shows that postnatal ozone exposure of the airways results in persistent attenuation of innate immune responses to a microbial challenge. Our data clearly show that the immunosuppressive effects of ozone exposure are not limited to cells within the lung. Instead, the ability of cells within the peripheral blood compartment to respond to LPS challenge is also negatively affected. Another unexpected finding in this study is that the effects of postnatal ozone exposure on the LPS-induced cytokine response is maintained within the peripheral blood compartment for at least 6 months after the exposure period. This suggests that early life environmental exposures result in the generation of a "memory" response that imprints future immune responses to a microbial challenge. Studies described in Chapter 3 further confirm the generation of this "memory" response following endotoxin (LPS) challenge. The results highlight the important role of the airway epithelium in initiating the immune response to a microbial challenge. Age had a significant impact on the ability of airway epithelium to generate a robust inflammatory response to microbial challenge. Infant airway epithelium was hypo-responsive, juvenile airway epithelium responded with a robust IL-6 protein response and adult airway epithelium responded with a strong IL-8 protein response. To further understand the potential mechanisms responsible for infant airway epithelium hyporesponsiveness, we investigated the role of innate immune signaling through toll like receptors in the airway epithelium. The results indicate that toll-like receptor signaling pathway-induced gene expression changes in the airway epithelium are age dependent. The study revealed that multiple genes in the toll-like receptor signaling pathway show differential expression in infant airway epithelium compared to adult airway epithelium. Studies described in Chapter 4 confirm the importance of understanding the effects of early life ozone and endotoxin exposures on pulmonary immunity. Our data show that epithelial cells isolated from postnatal ozone-exposed animals maintain a persistently modulated protein expression pattern for IL-6 and IL-8. This study provides additional support for the notion that airway epithelium is capable of developing "memory" following ozone exposure, such that prior exposures impact the magnitude and duration of cytokine responses to a subsequent microbial challenge. Importantly, we have been able to delineate the differential effects of ozone and endotoxin exposure on regulation of cytokine expression by epithelial cells. Collectively, these data clearly indicate the differential effects of early life ozone and endotoxin exposure and their influence on innate immune responses. More importantly, these findings provide clear evidence that the molecular pathways that respond to ozone and endotoxin exposure retain memory, such that cells within the lung and peripheral blood compartments no longer yield a robust inflammatory response to a future microbial challenge.