Marked increases in mucociliary clearance produced by synergistic secretory agonists or inhibition of the epithelial sodium channel.
Mucociliary clearance (MCC) is a critical host innate defense mechanism in airways, and it is impaired in cystic fibrosis (CF) and other obstructive lung diseases. Epithelial fluid secretion and absorption modify MCC velocity (MCCV). We tested the hypotheses that inhibiting fluid absorption accelerates MCCV, whereas inhibiting fluid secretion decelerates it. In airways, ENaC is mainly responsible for fluid absorption, while anion channels, including CFTR and Ca2+-activated chloride channels mediate anion/fluid secretion. MCCV was increased by the cAMP-elevating agonists, forskolin or isoproterenol (10 μM) and by the Ca2+-elevating agonist, carbachol (0.3 μM). The CFTR-selective inhibitor, CFTRinh-172, modestly reduced MCCV-increases induced by forskolin or isoproterenol but not increases induced by carbachol. The ENaC inhibitor benzamil increased basal MCCV as well as MCCV increases produced by forskolin or carbachol. MCC velocity was most dramatically accelerated by the synergistic combination of forskolin and carbachol, which produced near-maximal clearance rates regardless of prior treatment with CFTR or ENaC inhibitors. In CF airways, where CFTR-mediated secretion (and possibly synergistic MCC) is lost, ENaC inhibition via exogenous agents may provide therapeutic benefit, as has long been proposed.
The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, CA 94305-2130, USA.
Nam Soo
NS
Joo
The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, CA 94305-2130, USA.|Department of Otolaryngology-Head and Neck Surgery, Hanyang University School of Medicine, Seoul, Korea.
Jin Hyeok
JH
Jeong
The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, CA 94305-2130, USA.|Department of Otorhinolaryngology, Yonsei University, Seoul, Korea.
Hyung-Ju
HJ
Cho
The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, CA 94305-2130, USA.
Jeffrey J
JJ
Wine
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004357:Drug Synergism; D062686:Epithelial Sodium Channel Blockers / Q000494:pharmacology*; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005289:Ferrets; D017136:Ion Transport; D007545:Isoproterenol / Q000494:pharmacology*; D009079:Mucociliary Clearance / Q000187:drug effects*; D015854:Up-Regulation
D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; C013407:benzamil; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D000584:Amiloride; D002217:Carbachol; D007545:Isoproterenol