Mechanisms of Chlorine Hypersensitivity in Asthma

University Of Alabama At Birmingham, Birmingham AL

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Abstract

An estimated 13 million Americans are affected by asthma. This patient population is at high risk during exposures to pulmonary agents and irritant chemicals, including chlorine, tear gases and various industrial agents. Even at low chlorine exposure levels, asthma patients respond with rapid airway constriction and obstruction, bronchospasm, mucus secretion and pain, leading to panic and incapacitation. Thus, asthma patients require special and rapid care. The goal of our research is to develop pharmacological approaches for the treatment of asthma patients after exposure to chlorine and other pulmonary agents. The immediate airway responses to chlorine and other irritants are initiated by chemosensory neurons innervating the airways. In asthma patients these neurons are highly sensitized to chemical stimuli. In our CounterACT research in the last year we found convincing evidence for a pre-eminent role of the ion channel TRPA1 as the primary chlorine sensor in airway sensory neurons. We found TRPA1 to be strongly activated by chlorine in primary and heterologous cells. In addition, TRPA1-deficient mice displayed greatly reduced respiratory depression in response to chlorine, indicating that TRPA1 is the major neuronal chlorine sensor in vivo. TRPA1 and other TRP ion channels are known to be sensitized by inflammatory signaling pathways activated during asthma, thereby increasing the sensitivity of airway neurons to chlorine and other chemical threats. We hypothesize that post-exposure administration of TRP channel antagonists, in combination with adrenergic agonists and antioxidants, will counteract life-threatening hypersensitivity responses in asthma patients to chlorine and other pulmonary chemical threats. To examine this hypothesis we aim to (1) compare responses of wild-type and TRP-channel deficient mice to chlorine in the background of the ovalbumin asthma model, (2) Establish pharmacological measures to counteract chlorine hypersensitivity responses and chlorine-induced tissue damage in asthma and (3) Analyze the mechanism of TRPA1 activation and sensitization by chlorine, and its reversal.