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Review
. 2010 Jul;7(4):284-9.
doi: 10.1513/pats.201001-002SM.

Mitigation of Chlorine Lung Injury by Increasing Cyclic AMP Levels

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Free PMC article
Review

Mitigation of Chlorine Lung Injury by Increasing Cyclic AMP Levels

Gary W Hoyle. Proc Am Thorac Soc. .
Free PMC article

Abstract

Chlorine is considered a chemical threat agent to which humans may be exposed as a result of accidental or intentional release. Chlorine is highly reactive, and inhalation of the gas causes cellular damage to the respiratory tract, inflammation, pulmonary edema, and airway hyperreactivity. Drugs that increase intracellular levels of the signaling molecule cyclic AMP (cAMP) may be useful for treatment of acute lung injury through effects on alveolar fluid clearance, inflammation, and airway reactivity. This article describes mechanisms by which cAMP regulates cellular processes affecting lung injury and discusses the basis for investigating drugs that increase cAMP levels as potential treatments for chlorine-induced lung injury. The effects of beta(2)-adrenergic agonists, which stimulate cAMP synthesis, and phosphodiesterase inhibitors, which inhibit cAMP degradation, on acute lung injury are reviewed, and the relative advantages of these approaches are compared.

Figures

Figure 1.
Figure 1.
Production and degradation of cyclic AMP (cAMP). The production of cAMP is stimulated by binding of ligand to a Gs-coupled G protein–coupled receptor, leading to activation of adenylate cyclase. Adenylate cyclase catalyzes the formation of cAMP from ATP. Phosphodiesterase (PDE) enzymes catalyze the degradation of cAMP to AMP. PDE inhibitors block degradation of cAMP, leading to increased intracellular concentrations of this mediator. Downstream effects of cAMP are mediated through protein kinase A and Epac pathways.
Figure 2.
Figure 2.
Effect of rolipram on airway hyperreactivity in chlorine-exposed mice. (A) Mice were exposed to a dose of 250 ppm-hour chlorine (8). The following day, respiratory mechanics were measured in anesthetized, mechanically ventilated mice at baseline and after inhalation of aerosolized methacholine using a FlexiVent system (SCIREQ, Montreal, PQ, Canada). The responses of chlorine-exposed and unexposed mice were significantly different (P < 0.05 by repeated measures ANOVA; n = 4 mice/group). (B) Mice were exposed to 256 ± 3 ppm-hour chlorine (mean ± SE, three exposures). Mice received rolipram (300 μg/kg) or vehicle intranasally 1 hour and then again 10–11 hours after exposure. The day after exposure, airway reactivity was measured as in A. The responses of rolipram- and vehicle-treated mice were significantly different (P < 0.05 by repeated measures ANOVA; n = 8–9 mice/group).

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