ＴＮＦ‐αとＩＦＮ‐γの副鼻腔線毛運動への影響 塩酸アンブロキソールの併用効果

Abstract

A number of recent reports have demonstrated that proinflammatory cytokines play an important role in the regulation of the mucociliary clearance system in the upper respiratory airway. In this study, we focused on the in vitro effect of TNF-alpha and IFN-gamma on the ciliary beat frequency (CBF) of cultured human sinus epithelial cells. Sinus mucosal explants were successfully cultured on poly-L-lysine coated dishes with abundant outgrowth of ciliated cells. CBF measurement was carried out by photoelectric method at specific predetermined sites of 7 to 14 day cultured specimens. TNF-alpha at a concentration of 10ng/ml decreased CBF in a time dependent manner with a maximal decrease of 21.3% (p<0.01). A 13.9% decrease in CBF was also observed 24 hours after treatment with IFN-gamma alone (10ng/ml, p<0.01). Morphological investigation by scanning electron microscopy (SEM) revealed that epithelial desquamation and loss of the cilated cells after treatment with TNF-alpha, which was compatible with results from CBF measurements. We further examined actions of ambroxol hydrochloride, a mucolytic agent with cilioregulatory and antioxidant effects, in cytokine-induced cilioinhibition. Ambroxol at concentrations of 10-4M and 10-5M both increased CBF by 8.1% (p<0.01) and 13.5% (p<0.01), respectively. The cilioinhibitory effects of TNF-aplha and IFN-gamma were canceled by treating specimens with 10-4M of ambroxol. We speculate that regulatory effects of these proinflammatory cytokines on human sinus mucosa involve the modulation of CBF by nitric oxide (NO) as a second messenger. In addition, cilioinhibition by TNF-alpha may be partly due to cytotoxic phenomenon caused by excess generation of reactive oxygen species inside the epithelial cells.