Sensory Detection and Responses to Toxic Gases: Mechanisms, Health Effects, and Countermeasures

Abstract

The inhalation of reactive gases and vapors can lead to severe damage of the airways and lung, compromising the function of the respiratory system. Exposures to oxidizing, electrophilic, acidic, or basic gases frequently occur in occupational and ambient environments. Corrosive gases and vapors such as chlorine, phosgene, and chloropicrin were used as warfare agents and in terrorist acts. Chemical airway exposures are detected by the olfactory, gustatory, and nociceptive sensory systems that initiate protective physiological and behavioral responses. This review focuses on the role of airway nociceptive sensory neurons in chemical sensing and discusses the recent discovery of neuronal receptors for reactive chemicals. Using physiological, imaging, and genetic approaches, Transient Receptor Potential (TRP) ion channels in sensory neurons were shown to respond to a wide range of noxious chemical stimuli, initiating pain, respiratory depression, cough, glandular secretions, and other protective responses. TRPA1, a TRP ion channel expressed in chemosensory C-fibers, is activated by almost all oxidizing and electrophilic chemicals, including chlorine, acrolein, tear gas agents, and methyl isocyanate, the highly noxious chemical released in the Bhopal disaster. Chemicals likely activate TRPA1 through covalent protein modification. Animal studies using TRPA1 antagonists or TRPA1-deficient mice confirmed the role of TRPA1 in chemically induced respiratory reflexes, pain, and inflammation in vivo. New research shows that sensory neurons are not merely passive sensors of chemical exposures. Sensory channels such as TRPA1 are essential for maintenance of airway inflammation in asthma and may contribute to the progression of airway injury following high-level chemical exposures.

TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury

“…In chlorine-exposed mice, we used two TRPV4 inhibi- tors, GSK222069 and GSK2337429A, derived from distinct chemical classes of TRPV4 inhibitors that produced almost identical therapeutic effects. Exposures to chlorine gas or chlorine bleach aerosol occur frequently because of occupational or domestic accidents, and transportation accidents such as train derailments have led to the release of large amounts of chlorine with subsequent fatalities and injuries in the affected surrounding communities (2,3,36,41). Chlorine has also been used as a chemical weapon and in terrorist incidents, posing a significant threat to the population (3,41).…”

“…Exposures to chlorine gas or chlorine bleach aerosol occur frequently because of occupational or domestic accidents, and transportation accidents such as train derailments have led to the release of large amounts of chlorine with subsequent fatalities and injuries in the affected surrounding communities (2,3,36,41). Chlorine has also been used as a chemical weapon and in terrorist incidents, posing a significant threat to the population (3,41). We observed that TRPV4 inhibitor treatment prevented blood oxygen desaturation caused by chlorine exposures, a critical parameter associated with mortality and chronic morbidity, suggesting that inhibition of TRPV4 may provide a survival benefit and improved outcomes.…”

“…Chemical injuries caused by the inhalation of toxic gases or smoke are frequent causes of severe lung injury (3,11,41). Another form of chemical lung injury with significant morbidity and mortality is acid-induced lung injury associated with gastroesophageal reflux disease or acid aspiration during surgery (5).…”

Ascorbate and Deferoxamine Administration after Chlorine Exposure Decrease Mortality and Lung Injury in Mice

“…First, reactive Cl 2 and its reactive intermediates are known to activate inflammatory cytokine pathway and genes and inflammatory cells, which will contribute to oxidant stress both in the pulmonary and extrapulmonary spaces (21,46). In addition, activation of TRPA1 ion channels, located in a subset of airway sensory neurons by Cl 2 and HOCl, will contribute to the onset and propagation of systemic inflammation (17,47). Finally, damage to skin and ocular epithelia by Cl 2 may increase systemic oxidant load by a variety of mechanisms.…”

Nitrite therapy improves survival postexposure to chlorine gas

“…Exciting recent studies are providing insights into the postexposure mechanisms that include increased oxidative stress, neurogenic and airway inflammation, fibrosis, loss of nitric oxide (NO) signaling homeostasis, and loss of endogenous airway repair mechanisms (2, 9 -11, 15, 20, 22, 25, 26, 36). This information has led to the testing and demonstration of efficacy for antioxidant therapy (9,16,22,23,37), anti-inflammatory (using corticosteroids) treatment (5), ␤2-agonists (29), phosphodiesterase inhibitors (4), transient receptor potential channel inhibitors (1,2), and strategies that improve NO bioavailability (28,36).…”