Aryl Hydrocarbon Receptor (AhR) Attenuation of Subchronic Cigarette Smoke-induced Pulmonary Neutrophilia Is Associated with Retention of Nuclear RelB and Suppression of Intercellular Adhesion Molecule-1 (ICAM-1)

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Cigarette smoke is associated with chronic and enhanced pulmonary inflammation characterized by increased cytokine production and leukocyte recruitment to the lung. Although the aryl hydrocarbon receptor (AhR) is well-known to mediate toxic effects of manmade environmental contaminants, the AhR has emerged as a suppressor of acute cigarette smoke-induced neutrophilia by a mechanism involving the NF-κB protein RelB. Yet individuals who smoke often smoke for many years and vary in their cigarette consumption. As there is currently no information on the AhR prevention of lung inflammation, including neutrophilia, due to varied and prolonged exposure regimes, we exposed control andAhR−/−mice to cigarette smoke for 2 weeks (subchronic exposure) utilizing low and high exposure protocols and evaluated pulmonary inflammation. Subchronic cigarette smoke exposure significantly increased pulmonary neutrophilia dose-dependently inAhR−/−mice. Surprisingly, there was no difference between smoke-exposedAhR+/−andAhR−/−mice in the expression of cytokines associated with neutrophil recruitment. Expression of pulmonary intercellular adhesion molecule-1 (ICAM-1), an adhesion molecule involved in neutrophil migration and retention, was higher in pulmonary endothelial cells fromAhR−/−mice. Although total lung RelB expression was increased by cigarette smoke, nuclear RelB was significantly lower in subchronically exposedAhR−/−mice. Inhibition of AhR activity by CH-223191 in endothelial cells potentiated ICAM-1 expression and prevented RelB nuclear translocation but had no effect on neutrophil adhesion. These data support that genetic absence of the AhR contributes to heightened pulmonary neutrophilia in response to ongoing cigarette smoke exposure. Interindividual variations in AhR expression may enhance the susceptibility to cigarette smoke-induced diseases.

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