Text

theses

Nine out of ten people are breathing polluted air worldwide. Health concerns associated with human exposures to air pollutants, such as ozone and particulate matter (PM), have become a persisting and widespread problem around the globe. Interconnected, multiscale, mechanistic models were developed to study the exposure biology of air pollution in the respiratory, cardiovascular and integumentary systems, resulting from inhalation and dermal contact exposure routes. Lung function alterations were linked with ozone inhalation using a multiscale model that considers pulmonary surfactant depletion by ozone reactions, pulmonary inflammation after ozone exposure and the expansion / contraction of the alveolar units. A computational model for cardiovascular effects of air pollution was developed and implemented for human PM exposure using heart rate variability (HRV) as the health endpoint. Specific considerations were given to PM-initiated excessive oxidative stress and pro/ anti-inflammatory signaling at cellular level, neuroendocrine-immune system interactions and systemic inflammation propagation. The skin biology after air pollutant exposure was studied by mechanistic models that respectively addressed skin surface reactions, AhR activation and cell cycle regulation in keratinocytes. Inflammatory responses are often evoked when air pollutants exert their detrimental effects in any physiological system mentioned above. Macrophage is an essential type of immune cell that plays critical roles in the regulation of inflammation. An agent-based model that spans molecular, cellular and tissue levels was developed aiming at reproducing and elucidating the dynamics of macrophage polarization under various complex activation signals, while considering system stochasticity and heterogeneity. Key factors in signaling cascades were included in this model, and critical underlying regulatory controls influencing the polarization process were explored and quantified. All models were evaluated with data of in vitro and in vivo measurements from different sources. These models formed a platform that integrates physiological, biochemical and experimental information for various organ systems to mechanistically investigate biological effects initiated by air pollutants.

ETD_11274

Ph.D.

Includes bibliographical references

ETD doctoral

doi:10.7282/t3-sfmt-n747

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