Deficient prostaglandin E2 production by bronchial fibroblasts of asthmatic patients, with special reference to aspirin-induced asthma.
BACKGROUND
Regulation of prostaglandin synthesis and the activation of human airway fibroblasts associated with the remodeling of the bronchi play an important role in asthma.


OBJECTIVE
We sought to assess the cyclooxygenase pathways in airway fibroblasts of patients with bronchial asthma.


METHODS
Generation of prostaglandin E(2) (PGE(2)) and pros-taglandin D(2) (PGD(2)) by bronchial fibroblasts was measured by means of mass spectrometry in culture supernatants, and cyclooxgenases expression was estimated by means of RT-PCR and immunoblotting. The cells were isolated from 3 groups of subjects: nonasthmatic patients (n = 10), patients with aspirin-tolerant asthma (ATA, n = 9), and patients with aspirin-intolerant asthma (AIA, n = 7).


RESULTS
The cytomix (LPS, 5 square g/mL; IL-1 square, 5 ng/mL; and TNF- square, 10 ng/mL; 18 hours) stimulated the production of prostaglandins. Asthmatic patients were characterized by low capacity to produce PGE(2) after cytomix stimulation. In the nonasthmatic patient group the mean PGE(2) production was 32 +/- 33 ng/mL (35-fold of the basic production), in the ATA group it was 16 +/- 18 ng/mL (16-fold), and in the AIA group it was only 5.3 +/- 3.6 ng/mL (4-fold). The mean concentration of PGD(2) for nonasthmatic patients, patients with ATA, and patients with AIA was 0.18 +/- 0.16 ng/mL (4.7-fold of the basic production), 0.18 +/- 0.14 ng/mL (4.2-fold), and 0.235 +/- 0.19 ng/mL (1.9-fold), respectively. The observed difference was not due to insufficient cyclooxygenase 2 expression because all groups had similar levels of its mRNA and protein. The patients with AIA had low expression levels of cyclooxygenase 1 protein but not of its mRNA. The PGE(2)/PGD(2) concentration ratio increased after cytomix stimulation in all groups but was significantly less in patients with AIA than in patients with ATA.


CONCLUSIONS
Our results point to a deficient PGE(2) production under proinflammatory conditions in asthmatic airways. This could weaken local defensive mechanisms and promote cysteinyl leukotriene overproduction.
Department of Medicine, Jagellonian University Medical School, Krakow, Poland.
Malgorzata
M
Pierzchalska
Zsuzsanna
Z
Szabó
Marek
M
Sanak
Jerzy
J
Soja
Andrzej
A
Szczeklik
D000328:Adult; D000368:Aged; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000139:chemically induced* / Q000378:metabolism*; D001980:Bronchi / Q000378:metabolism*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis
D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001241:Aspirin; D015230:Prostaglandin D2; D007213:Indomethacin