Multiphase Kinetic Modeling of Air Pollutant Effects on Protein Modification and Nitrotyrosine Formation in Epithelial Lining Fluid

Abstract

Exposure to ambient air pollution is a major risk factor for human health. Inhalation of air pollutants can enhance the formation of reactive species in the epithelial lining fluid (ELF) of the respiratory tract and can lead to oxidative stress and oxidative damage. Here, we investigate the chemical modification of proteins by reactive species from air pollution and endogenous biological sources using an extended version of the multiphase chemical kinetic model KM-SUB-ELF 2.0 with a detailed mechanism of protein modification. Fine particulate matter (PM2.5) and nitrogen dioxide (•NO2) act synergistically and increase the formation of nitrotyrosine (Ntyr), a common biomarker of oxidative stress. Ozone (O3) is found to be a burden on the antioxidant defense system but without substantial influence on the Ntyr concentration. In simulations with low levels of air pollution, the Ntyr concentration in the ELF is consistent with the range of literature values for bronchoalveolar lavage fluid from healthy individuals. With high levels of air pollution, however, we obtain strongly elevated Ntyr concentrations. Our model analysis shows how chemical reactions of air pollutants can modify proteins and thus their functionality in the human body, elucidating a molecular pathway that may explain air pollutant effects on human health.

Endogenous Nitric Oxide Can Enhance Oxidative Stress Caused by Air Pollutants and Explain Higher Susceptibility of Individuals with Inflammatory Disorders

“…The formation of such species may add to the oxidative burden posed by elevated • NO levels in diseased individuals and is supported by an earlier study that found increased • NO-dependent metabolites in the ELF of asthmatic children. 49 Hence, the downstream effects of CO 3 •– and N 2 O 3 , particularly on protein oxidation and nitration, 32 warrant further investigation.…”

“…All reaction rate coefficients have been reported previously in the literature, and none were fitted in this study. In previous studies, KM-SUB-ELF has been fitted and validated using in vitro and in vivo observations. ,,, This includes chemical assays describing the ROS production of redox-active PM 2.5 constituents, − H 2 O 2 depletion in lavage fluid of humans by catalase, and H 2 O 2 and • OH production of PM 2.5 constituents in aqueous solutions mimicking ELF. , …”

“… 4 , 28 , 29 , 32 This includes chemical assays describing the ROS production of redox-active PM 2.5 constituents, 34 − 37 H 2 O 2 depletion in lavage fluid of humans by catalase, 38 and H 2 O 2 and • OH production of PM 2.5 constituents in aqueous solutions mimicking ELF. 39 , 40 32 …”

“…The kinetic multilayer model of surface and bulk chemistry in the ELF (KM-SUB-ELF) describes the multiphase chemical interactions at the air–body interface and has been used to quantify chemical dose–response relationships between ambient air pollution and reactive oxygen species (ROS) production in the ELF. ,, Further, KM-SUB-ELF-predicted ROS concentrations have been used to connect long-term exposure to transition metals in PM 2.5 with cardiovascular mortality . The model was also used to compare O 2 •– production rates from macrophages with those from PM 2.5 constituents in the ELF to investigate the ambient and endogenous sources of H 2 O 2 in the lung and to estimate the concentration of nitrotyrosine, a biomarker for oxidative stress, in the ELF …”

“… 30 The model was also used to compare O 2 •– production rates from macrophages with those from PM 2.5 constituents in the ELF 31 to investigate the ambient and endogenous sources of H 2 O 2 in the lung 29 and to estimate the concentration of nitrotyrosine, a biomarker for oxidative stress, in the ELF. 32 …”