Pulmonary fibroblasts, an emerging target for anti-obstructive drugs.
Fibrotic alterations are part of the airway re-modelling processes observed in asthma and chronic obstructive pulmonary disease. There is increasing evidence that in addition to acute bronchodilatory effects, classical anti-obstructive drugs such as muscarinic antagonists and beta-adrenoceptor agonists may also modulate long-term re-modelling processes. The present review aims to summarise muscarinic and beta-adrenergic effects on pulmonary fibroblasts. Recent experimental evidence demonstrated muscarinic stimulatory effects on pulmonary fibroblasts, and long-term blockade of these pro-fibrotic effects may contribute to the beneficial effects of muscarinic antagonists, as observed particularly for the long-acting muscarinic antagonist tiotropium. On the other hand, beta-adrenoceptor agonists, via activation of adenylyl cyclase, can also exert various inhibitory effects on pulmonary fibroblasts, and these anti-fibrotic effects are mimicked by other agents that cause an increase in intracellular cyclic adenosine monophosphate (cAMP), such as phosphodiesterase inhibitors or EP2 prostanoid receptor agonists. In addition, the role of the extracellular signal-regulated kinase-mitogen-activated protein kinase pathway, protein kinase A and exchange protein activated by cAMP (Epac) and potential interactions between these cellular signalling pathways are discussed.
Racké
Kurt
K
Institute of Pharmacology and Toxicology, University of Bonn, Reuterstrabe 2b, 53113, Bonn, Germany. racke.kurt@uni-bonn.de
Haag
Susanne
S
Bahulayan
Amit
A
Warnken
Mareille
M
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D003094:Collagen; D000242:Cyclic AMP; D000262:Adenylyl Cyclases