Oxidant-induced epithelial alarmin pathway mediates lung inflammation and functional decline following ultrafine carbon and ozone inhalation co-exposure
Nairrita Majumder,
William T. Goldsmith,
Vamsi K. Kodali,
Murugesan Velayutham,
Sherri A. Friend,
Valery V. Khramtsov,
Timothy R. Nurkiewicz,
Aaron Erdely,
Patti C. Zeidler-Erdely,
Vince Castranova,
Jack R. Harkema,
Eric E. Kelley,
Salik Hussain
Affiliations
Nairrita Majumder
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA; Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, USA
William T. Goldsmith
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA; Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, USA
Vamsi K. Kodali
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA; Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, USA; National Institute for Occupational Safety and Health, USA
Murugesan Velayutham
Department of Biochemistry, School of Medicine, West Virginia University, USA
Sherri A. Friend
Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, USA; National Institute for Occupational Safety and Health, USA
Valery V. Khramtsov
Department of Biochemistry, School of Medicine, West Virginia University, USA
Timothy R. Nurkiewicz
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA; Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, USA
Aaron Erdely
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA; Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, USA; National Institute for Occupational Safety and Health, USA
Patti C. Zeidler-Erdely
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA; Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, USA; National Institute for Occupational Safety and Health, USA
Vince Castranova
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA
Jack R. Harkema
Department of Pathobiology and Diagnostic Investigation, School of Veterinary Medicine, Michigan State University, USA
Eric E. Kelley
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA; Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, USA
Salik Hussain
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA; Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, USA; Corresponding author. Department of Physiology and Pharmacology, School of Medicine, West Virginia University, USA.
Environmental inhalation exposures are inherently mixed (gases and particles), yet regulations are still based on single toxicant exposures. While the impacts of individual components of environmental pollution have received substantial attention, the impact of inhalation co-exposures is poorly understood. Here, we mechanistically investigated pulmonary inflammation and lung function decline after inhalation co-exposure and individual exposures to ozone (O3) and ultrafine carbon black (CB). Environmentally/occupationally relevant lung deposition levels in mice were achieved after inhalation of stable aerosols with similar aerodynamic and mass median distributions. X-ray photoemission spectroscopy detected increased surface oxygen contents on particles in co-exposure aerosols. Compared with individual exposures, co-exposure aerosols produced greater acellular and cellular oxidants detected by electron paramagnetic resonance (EPR) spectroscopy, and in vivo immune-spin trapping (IST), as well as synergistically increased lavage neutrophils, lavage proteins and inflammation related gene/protein expression. Co-exposure induced a significantly greater respiratory function decline compared to individual exposure. A synthetic catalase-superoxide dismutase mimetic (EUK-134) significantly blunted lung inflammation and respiratory function decline confirming the role of oxidant imbalance. We identified a significant induction of epithelial alarmin (thymic stromal lymphopoietin-TSLP)-dependent interleukin-13 pathway after co-exposure, associated with increased mucin and interferon gene expression. We provided evidence of interactive outcomes after air pollution constituent co-exposure and identified a key mechanistic pathway that can potentially explain epidemiological observation of lung function decline after an acute peak of air pollution. Developing and studying the co-exposure scenario in a standardized and controlled fashion will enable a better mechanistic understanding of how environmental exposures result in adverse outcomes.
