Effect of epithelial denudation, inflammatory mediators and mast cell activation on the sensitivity of isolated human airways to methacholine.
In asthmatics, both the continuous release of mast cell-derived inflammatory mediators and damage of the airway epithelium may be related to the degree of bronchial responsiveness. We therefore evaluated the effect of inflammatory mediators and mast cell activation on the cholinergic responsiveness of strips of human bronchioles with and without epithelium. Cumulative concentration-response curves to methacholine were generated from strips with or without epithelium before, during and after incubation with threshold doses of either methacholine (3 x 10(-7) M, controls), histamine (3 x 10(-7) M), the thromboxane A2 analogue, U46619 (10(-9) M), prostaglandin (PG) D2 (3 x 10(-7) M), PGF2 alpha (3 x 10(-7) M), leukotriene (LT) C4 (10(-9) M), or anti-human immunoglobulin E (24.4 +/- 4.0 micrograms.ml-1). Strips without epithelium were 1.6 times more sensitive to methacholine than strips with epithelium (-log EC50:5.76 +/- 0.04 vs. 5.97 +/- 0.04, P less than 0.0001). The average contraction in response to identical doses of anti-IgE in strips without epithelium was 3 times greater than the contraction in strips with epithelium (P less than 0.05). Threshold concentrations of histamine, U44619 and PGD2 caused a similar non-parallel leftward shift of the concentration-response curve of strips with or without epithelium to methacholine (P less than 0.05). Together, epithelial denudation and low levels of mediators caused a 4.0- to 9.1-fold increase in sensitivity based on the -log EC10 and a 1.8- to 3.0-fold increase in sensitivity based on the -log EC50.(ABSTRACT TRUNCATED AT 250 WORDS)
Jongejan
R
R
Department of Pediatrics, Erasmus University, Rotterdam, The Netherlands.
De Jongste
J
J
Raatgeep
R
R
Stijnen
T
T
Bonta
I
I
Kerrebijn
K
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000368:Aged; D000369:Aged, 80 and over; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage; D015237:Dinoprost / Q000494:pharmacology; D004848:Epithelium / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000503:physiopathology*; D007073:Immunoglobulin E / Q000008:administration & dosage / Q000276:immunology; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology*; D016210:Methacholine Chloride / Q000494:pharmacology*; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D015230:Prostaglandin D2 / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013189:SRS-A / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D011450:Prostaglandin Endoperoxides, Synthetic; D013189:SRS-A; C026408:anti-IgE antibodies; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006632:Histamine; D015237:Dinoprost; D015230:Prostaglandin D2