Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process.
Chronic bacterial airway infections are the major cause of mortality in cystic fibrosis (CF). Normal airway defenses include reflex stimulation of submucosal gland mucus secretion by sensory neurons that release substance P (SubP). CFTR is an anion channel involved in fluid secretion and mutated in CF; the role of CFTR in secretions stimulated by SubP is unknown. We used optical methods to measure SubP-mediated secretion from human submucosal glands in lung transplant tissue. Glands from control but not CF subjects responded to mucosal chili oil. Similarly, serosal SubP stimulated secretion in more than 60% of control glands but only 4% of CF glands. Secretion triggered by SubP was synergistic with vasoactive intestinal peptide and/or forskolin but not with carbachol; synergy was absent in CF glands. Pig glands demonstrated a nearly 10-fold greater response to SubP. In 10 of 11 control glands isolated by fine dissection, SubP caused cell volume loss, lumen expansion, and mucus flow, but in 3 of 4 CF glands, it induced lumen narrowing. Thus, in CF, the reduced ability of mucosal irritants to stimulate airway gland secretion via SubP may be another factor that predisposes the airways to infections.
Choi
Jae Young
JY
Stanford University, California 94305-2130, USA.
Khansaheb
Monal
M
Joo
Nam Soo
NS
Krouse
Mauri E
ME
Robbins
Robert C
RC
Weill
David
D
Wine
Jeffrey J
JJ
D000367:Age Factors; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002212:Capsicum / Q000737:chemistry; D002217:Carbachol / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D003022:Clotrimazole / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005088:Exocrine Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009093:Mucus / Q000378:metabolism*; D010938:Plant Oils / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology / Q000502:physiology*; D034421:Sus scrofa; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
C505032:CFTR protein, human; D002614:Chelating Agents; D010938:Plant Oils; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D005576:Colforsin; D013373:Substance P; D014660:Vasoactive Intestinal Peptide; D004533:Egtazic Acid; D002217:Carbachol; D003022:Clotrimazole