beta2-Agonist modulates epithelial gene expression involved in the T- and B-cell chemotaxis and induces airway sensitization in human isolated bronchi.
Regular use of beta(2)-adrenoceptor agonists may enhance non-specific airway responsiveness and inflammation. In earlier experimental studies, we showed that prolonged in vitro fenoterol exposure induced airway sensitization via perturbed epithelial regulation of bronchoconstriction. The aim of the present work was to examine the involvement of inflammatory mediator genes and proinflammatory cells and to investigate the role of the bronchial epithelium in these untoward effects. Bronchial tissues were surgically removed from 17 ex-smokers. Bronchial rings and primary cultures of bronchial epithelial cells were incubated with 0.1microM fenoterol for 15h. Levels of mRNA-expression were analyzed using a real-time quantitative reverse transcription-polymerase chain reaction array. Bronchial rings were contracted with endothelin-1 and immune cell infiltration was assessed by immunohistochemistry. Compared to paired controls, fenoterol up-regulated the mRNAs of cytokines/proteins implicated in the recruitment of T and B cells or the activation and proliferation of bronchial epithelial cells (CCL20/MIP-3alpha, FOXA2, PPAR-gamma) in isolated bronchi and in cultured epithelial cells. Fenoterol exposure significantly enhanced CD8(+)-T and differentiated CD138(+)-B-cells infiltration into the bronchi, especially the subepithelial area. Increase in CD8 or CD138 labeling-intensity strongly correlated with rise in maximal contraction to endothelin-1 induced by fenoterol exposure. In summary, our results show that fenoterol modulates the T and B cells chemotaxis possibly via the epithelial chemokine secretion in isolated bronchi from ex-smokers. They also suggest that the infiltration of resident T and B cells into the subepithelial area is associated with an increase in airway responsiveness due to fenoterol exposure.
Faisy
Christophe
C
Research Unit UPRES EA220, Université Versailles Saint-Quentin, Hôpital Foch, 40 rue Worth, 92150 Suresnes, France. christophe.faisy@egp.aphp.fr
Pinto
Francisco M
FM
Blouquit-Laye
Sabine
S
Danel
Claire
C
Naline
Emmanuel
E
Buenestado
Amparo
A
Grassin Delyle
Stanislas
S
Burgel
Pierre-Régis
PR
Chapelier
Alain
A
Advenier
Charles
C
Candenas
Maria-Luz
ML
Devillier
Philippe
P
D000318:Adrenergic beta-Agonists / Q000009:adverse effects / Q000494:pharmacology*; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000009:adverse effects / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005280:Fenoterol / Q000009:adverse effects / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016540:Smoking Cessation; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D016085:Bronchoconstrictor Agents; D016207:Cytokines; D019332:Endothelin-1; D018836:Inflammation Mediators; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D005280:Fenoterol