This study demonstrated that cigarette smoke exposure increases MUC5AC mRNA and mucin synthesis via a signaling pathway that involves up-regulation of EGFR and CLCA1 both in vivo and in vitro. It has been shown that cigarette smoke up-regulates EGFR expression leading to mucin production in the airway epithelium. This is the first study to show a critical role for CLCA1 in cigarette smoke-induced mucin production, which is one of the major features of COPD.
In this study, we showed that either a blocker of CLCAs, niflumic acid, or a selective EGFR tyrosine kinase inhibitor, AG-1478, are completely able to inhibit cigarette smoke-induced mucin synthesis as well as the upregulation of MUC5AC mRNA expression, and that the effect of combining both drugs is not synergistic. This indicates that both CLCA1 and EGFR are dependently affecting mucin production as a part of a single complex signaling pathway, but it does not exclude the participation of CLCAs other than CLCA1. It seems that CLCA1 is involved in the pathologic induction of mucin, while a different CLCAs are related to the baseline physiologic mucin secretion. Although niflumic acid is a known blocker of the CLCAs and has been shown to block the function of hCLCAi,- it is nonspecific to CLCA1. Therefore the contribution of its blocking of any other CLCAs cannot be accurately evaluated. In fact, despite the increasing number of discovered CLCAs both in animals and human and their seemingly important functions, understanding these channels has been limited by the absence of specific blockers and the fact that their molecular identities remain in question. Continue reading “Observation of Niflumic Acid and AG-1478 Reduce Cigarette Smoke-Induced Mucin Synthesis”