Mechanistic link between diesel exhaust particles and respiratory reflexes

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 3; pp. 1074 - 1084.e9
• Main Authors: Robinson, Ryan K., Birrell, Mark A., Adcock, John J., Wortley, Michael A., Dubuis, Eric D., Chen, Shu, McGilvery, Catriona M., Hu, Sheng, Shaffer, Milo S.P., Bonvini, Sara J., Maher, Sarah A., Mudway, Ian S., Porter, Alexandra E., Carlsten, Chris, Tetley, Teresa D., Belvisi, Maria G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2018; Elsevier Limited; Mosby
• Subjects: Aged; Air Pollutants - toxicity; Air pollution; Allergy and Immunology; Animals; Ankyrins; Antioxidants; Asthma; Asthma - chemically induced; Asthma - metabolism; Asthma - pathology; Asthma - physiopathology; Bronchial Spasm - chemically induced; Bronchial Spasm - metabolism; Bronchial Spasm - pathology; Bronchial Spasm - physiopathology; Bronchospasm; Cough; Depolarization; Diesel; Epidemiology; Experiments; Female; Fibers; Gene Expression Regulation - drug effects; Guinea Pigs; Humans; Kinases; Lungs; Male; Mice; Microscopy; Middle Aged; Mitochondria; Oxidative stress; Pain perception; Particulate matter; Particulate Matter - toxicity; Pollution; Polycyclic aromatic hydrocarbons; Reactive oxygen species; Reflex - drug effects; Reflexes; Respiratory tract; sensory nerves; Sensory neurons; Signal transduction; Therapeutic applications; Trachea; transient receptor potential ion channels; Transient receptor potential proteins; vagus; Vagus nerve; Vehicle Emissions; RAR; PT; DMSO; transient receptor potential ion channels; MitoTEMPO; DLS; sensory nerves; Pollution; TRP; vagus; EDX; TTX; WT; TRPA1; AhR; DEP; IIAM; DCM; TGA; NAC; PAH; ROS; NIST; PM; TEM; oxidative stress; polycyclic aromatic hydrocarbons; Transient receptor potential; aryl hydrocarbon receptor; particulate matter; transient receptor potential (TRP) ion channels; diesel exhaust particles; reactive oxygen species; PAH’s
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.04.038

Diesel exhaust particles (DEPs) are a major component of particulate matter in Europe's largest cities, and epidemiologic evidence links exposure with respiratory symptoms and asthma exacerbations. Respiratory reflexes are responsible for symptoms and are regulated by vagal afferent nerves, which innervate the airway. It is not known how DEP exposure activates airway afferents to elicit symptoms, such as cough and bronchospasm. We sought to identify the mechanisms involved in activation of airway sensory afferents by DEPs. In this study we use in vitro and in vivo electrophysiologic techniques, including a unique model that assesses depolarization (a marker of sensory nerve activation) of human vagus. We demonstrate a direct interaction between DEP and airway C-fiber afferents. In anesthetized guinea pigs intratracheal administration of DEPs activated airway C-fibers. The organic extract (DEP-OE) and not the cleaned particles evoked depolarization of guinea pig and human vagus, and this was inhibited by a transient receptor potential ankyrin-1 antagonist and the antioxidant N-acetyl cysteine. Polycyclic aromatic hydrocarbons, major constituents of DEPs, were implicated in this process through activation of the aryl hydrocarbon receptor and subsequent mitochondrial reactive oxygen species production, which is known to activate transient receptor potential ankyrin-1 on nociceptive C-fibers. This study provides the first mechanistic insights into how exposure to urban air pollution leads to activation of guinea pig and human sensory nerves, which are responsible for respiratory symptoms. Mechanistic information will enable the development of appropriate therapeutic interventions and mitigation strategies for those susceptible subjects who are most at risk. [Display omitted]