title: Dysfunction of the non-neuronal cholinergic system in the airways and blood cells of patients with cystic fibrosis.
abstract: The non-neuronal cholinergic system is widely expressed in human airways, skin and immune cells. Choline acetyltransferase (ChAT), acetylcholine and nicotine/muscarine receptors are demonstrated in epithelial surface cells, submucosal glands, airway smooth muscle fibres and immune cells. Moreover, acetylcholine is involved in the regulation of cell functions like proliferation, differentiation, migration, organization of the cytoskeleton, cell-cell contact, secretion and transport of ions and water. Cystic fibrosis (CF), the most frequent genetic disorder, is known to be caused by a mutation of the CF-gene coding for the cystic fibrosis transmembrane regulator protein (CFTR). CFTR represents a regulating transport protein for ion channels and processes involving endo- and exocytosis. Despite the identification of the genetic mutation knowledge of the underlying cellular pathways is limited. In the present experiments the cholinergic system was investigated in the peripheral blood and in the lung of CF patients undergoing lung transplantation (n=7). Acetylcholine content in bronchi and lung parenchyma of CF was reduced by 70% compared to controls (tumor-free tissue obtained from patients with lung tumor; n=13). In contrast, ChAT activity was elevated to some extent (p>0.05) in CF, and esterase activity did not differ from control. Acetylcholine content extracted from peripheral leucocytes (30 ml) was also reduced by 70% in CF (n=13) compared to healthy volunteers (n=9). Double labelling experiments with anti-CF antibodies and anti-ChAT antibodies showed a co-localization in peripheral lymphocytes, giving first evidence that CFTR may be linked with the intracellular storage/transport of non-neuronal acetylcholine. It is concluded that the non-neuronal cholinergic system is involved in the pathogenesis of CF. A reduced content of non-neuronal acetylcholine could contribute to the deleterious changes of epithelial ion and water movements in CF, because acetylcholine stimulates apical Cl(-) secretion, inhibits apical Na(+) and water absorption and therewith facilitates mucociliary clearance.
authors.affiliation: Institute of Pathology, Univ. Hospital, Johannes Gutenberg University Mainz, Langenbeckstr. 1, D-55101 Mainz, Germany. wessler@uni-mainz.de
authors.forename: Ignaz
authors.initials: I
authors.lastname: Wessler
authors.forename: Fernando
authors.initials: F
authors.lastname: Bittinger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kamin
authors.forename: Fred
authors.initials: F
authors.lastname: Zepp
authors.forename: Eckhard
authors.initials: E
authors.lastname: Meyer
authors.forename: Arno
authors.initials: A
authors.lastname: Schad
authors.forename: Charles James
authors.initials: CJ
authors.lastname: Kirkpatrick
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000097:blood / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism
chemical_list: D002795:Choline O-Acetyltransferase; D000109:Acetylcholine