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(R)-Albuterol Elicits Antiinflammatory Effects in Human Airway Epithelial Cells via iNOS

Department of Molecular Biomedical Sciences, College of Veterinary Medicine, and Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina

Correspondence and requests for reprints should be addressed to Kenneth B. Adler, Ph.D., North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough St., Raleigh, NC 27606. E-mail: kenneth_adler{at}ncsu.edu

Catecholamines can suppress production of inflammatory mediators in different cell types, including airway epithelium, but downstream signaling mechanisms involved in regulation of these antiinflammatory effects are largely unknown. We theorized that acute ₂-adrenergic stimulation of airway epithelial cells with albuterol could suppress the production and release of inflammatory mediators, specifically granulocyte macrophage–colony stimulating factor (GM-CSF) via a pathway involving inducible nitric oxide synthase (iNOS). Normal human bronchial epithelial (NHBE) cells in primary culture were exposed to a cytokine mixture (10 ng/ml each IFN- and IL-1) to induce iNOS expression. (R)- and (S)-enantiomers of albuterol, as well as racemic mixtures, were added with these cytokines, and effects on GM-CSF expression and production were assessed. Specific inhibitors and activators of protein kinases (PKs), ₂-adrenergic receptor antagonists, and small interfering RNAs against iNOS were used to delineate signaling pathways involved. iNOS message was significantly upregulated in a concentration-dependent manner by the active (R)-enantiomer of albuterol. (R)-albuterol also attenuated cytokine-induced increases in GM-CSF steady-state mRNA expression and protein release. The (S)-enantomer of albuterol had no effect on these parameters. PKC, specifically, the isoform, was required for iNOS message increase, but PKA and PKG were not involved in the pathway. Overall, this study identifies a novel pathway by which ₂-adrenergic agonists may exhibit antiinflammatory effects in airway epithelium and surrounding milieu.

Key Words: albuterol • asthma • cytokines • epithelium • inducible nitric oxide synthase

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