Toxic inhalation hazards (TIHs) are noxious gases and vapors that are harmful and often deadly when inhaled. Specific sensory receptors in the airways sense the presence of these chemicals and initiate conscious, involuntary, autonomic, inflammatory, and other responses to them (1
). Some inhaled toxicants have their primary actions in tissues outside of the lungs or hinder oxygen from reaching the alveolar sacs. Usually the only noticeable sensations by these toxicants are their smell and taste, or they are not detected at all and are only recognizable by the signs and symptoms of their toxicity (2
). Most TIHs are reactive chemical gases and vapors that can severely change the structures of the proteins, lipids, DNA, and other biomolecules, resulting in a loss of protein function, DNA mutations, and necrosis of airway epithelial cells (3
). The body defends itself against these “reactive-TIHs” with the tissue barriers presented by hair, skin, and mucous membranes, as well as by extracellular fibers, fluids, membrane, cytosolic components, and glandular secretions containing high concentrations of antioxidants, buffers, and other compounds that sequester and neutralize reactive chemicals. These include uric acid, glutathione, ascorbic acid, carotenes, lipoic acid, tocopherol, ubiquinol, ammonia, carbonic acid, phosphate, and enzymes. In certain incidences these enzymes produce more toxic metabolites (5
). In severe exposures these protective chemicals are saturated and the reactive chemicals react with lung tissues, damaging lung and its delicate alveolar sacs (8
). The airways have specialized mechanisms to protect alveoli from damage. The peripheral sensory neurons of the airways express specific acid-sensitive ion channel (ASIC) and TRP cation channels that are directly activated by reactive chemicals. The activation of these ion channels triggers signaling to the brain to perceive pain and to initiate involuntary, autonomic and motor reflexes of the glands and muscles of the airways and lungs (9
). The activated channels also induce the sensory neuronal peripheral endings to release proinflammatory factors near the site of contact with the reactive TIH (15
At trace levels, the reactive TIHs are perceived as pungent and irritating, and induce sneezing, coughing, mucus secretion, upper airway inflammation, and tearing. At higher levels, these sensory neuron–mediated sensations and responses progress to incapacitating pain, uncontrollable coughing, profuse lacrimation, and resistance to airflow by bronchospasm, mucus hypersecretion, and upper and lower airway inflammation (pneumonitis) (10
). These responses neutralize, hinder, and expel toxic materials, limiting damage to the delicate alveolar sacs. However, continued exposures can lead to exaggerated responses that compromise respiratory function (20
). Reactive TIHs can compound pre-existing conditions. For example, they are notorious for triggering attacks in individuals with asthma (irritant-induced asthma) (23
). The continual respiratory responses might be involved in the development of chronic airway diseases, including bronchitis and occupational asthma, and reactive airway dysfunction syndrome (20
). Exaggerated sensory neuronal responses may contribute to the pulmonary edema and adult respiratory distress syndrome (ARDS) seen with high concentration exposure of TIHs (30
). Therefore, not only must the airways be able to immediately detect the presence of reactive TIHs and initiate the appropriate responses to prevent exposure to the alveolar sacs, they must also deactivate this in a controlled manner to allow for normal breathing and blood flow to occur once the threat has disappeared.
Injury and inflammation alter sensory neurons to become hyperactive or hypersensitive to noxious stimuli. This phenomenon has been thoroughly characterized in pain conditions such as migraine and chronic inflammatory or neuropathic pain. It would seem likely that similar mechanisms occur in the airway sensory innervation (32
). The necrotic and damaged cells of the airway epithelium release signaling molecules, such as DNA, ATP, adenosine, uric acid, other small molecules, peptides, peptidase products, lipids, and lipid-oxidation products. These molecules act as warning signals to the nearby tissues, and initiate and modulate inflammatory responses by the surrounding cells, especially the front line immune cells (4
). These signaling molecules, cytokines, and other inflammatory mediators released during an airway injury modulate the sensitivity and expression of sensory neuronal TIH receptors (35
for TRPA1 modulators). This could result in chronic or hypersensitive neurogenic inflammatory responses in the lungs and airways and possibly lead to chronic inflammatory lung diseases or hypersensitivity conditions (37
TOXIC INHALATION HAZARDS ACTIVATING THE SENSORY NEURONAL ION CHANNEL TRPA1.
Currently, the therapy for acute exposures to reactive TIHs is their removal by dilution, washing, and chemical neutralization, the treatment of pain and inflammation with anti-inflammatory medications and analgesics, and stabilization of the airways with bronchodilators (38
). Morbidity from high-level exposures to reactive TIHs can occur after the initial structural damage. Sensory neuron–mediated inflammation may have role in pulmonary edema, pneumonitis, and other complications of ARDS implicated in fatalities from high-level exposures (30
). Occupational asthma can develop from reactive TIH exposure in workplace settings, and this is usually treated by counteracting the symptoms of airway inflammation and smooth muscle constriction. Antagonists blocking TIH receptors and or modulators of these receptors may provide novel therapeutics to alleviate the irritation and inflammation resulting from acute exposures. This may in turn abate the inflammation and pulmonary edema caused by high-level exposures and treat the chronic lung and airway diseases associated with reactive chemical inhalation.