Am. J. Respir. Cell Mol. Biol., Volume 19, Number 5, November, 1998 799-804

Erythromycin Inhibits ATP-Induced Intracellular Calcium Responses in Bovine Tracheal Epithelial Cells

Mitsuko Kondo, Soichiro Kanoh, Jun Tamaoki, Hideki Shirakawa, Shunichi Miyazaki, and Atsushi Nagai

First Department of Medicine and Second Department of Physiology, Tokyo Women's Medical College, Tokyo; and Third Department of Medicine, National Defense Medical College, Saitama, Japan

Erythromycin (EM) therapy is known to decrease airway secretion in chronic inflammatory airway diseases such as diffuse panbronchiolitis. Airway secretion is regulated by intracellular Ca²⁺ concentration ([Ca²⁺]_i). To elucidate the intracellular site of action of EM in airway epithelium, we examined the effect of EM on Ca²⁺ dynamics in cultured bovine tracheal epithelial cells using fura-2. EM per se did not cause any change in [Ca²⁺]_i. Adenosine triphosphate (ATP; 10⁴ M) induced a biphasic [Ca²⁺]_i increase, consisting of a transient response followed by a sustained response. Pretreatment of cells with EM had little effect on the ATP-induced transient Ca²⁺ response but substantially reduced the sustained response in a dose-dependent manner. Clarithromycin, another 14-membered ring macrolide, likewise showed the inhibitory effect, but ampicillin and cephasolin did not. Uridine triphosphate (UTP; 10⁴ M) induced a biphasic [Ca²⁺]_i increase similar to ATP, and the UTP-induced sustained Ca²⁺ response was also inhibited by EM. In Ca²⁺-deficient medium (1 mM ethyleneglycol-bis-(-aminoethyl ether)-N, N'-tetraacetic acid [EGTA]) or in the presence of La³⁺, the sustained Ca²⁺ response disappeared, suggesting that EM may inhibit Ca²⁺ influx induced by P_2u purinoceptor stimulation. In single-cell Ca²⁺ image analysis, low concentration of ATP (10⁶ M) induced Ca²⁺ oscillations, which were also inhibited by EM. The disappearance of [Ca²⁺]_i oscillations after addition of EM was similar to that after addition of EGTA. These results suggest that EM may decrease Ca²⁺-dependent airway secretion by inhibiting agonist-stimulated Ca²⁺ influx.

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