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Muscarinic receptors mediate stimulation of collagen synthesis in human lung fibroblasts

¹ Institute of Pharmacology and Toxicology, and ² Dept of Pulmonary Diseases, Medical Polyclinic, University of Bonn, Bonn, Germany.

CORRESPONDENCE: K. Racké, Institute of Pharmacology and Toxicology, University of Bonn, Reuterstraße 2b, D-53113 Bonn, Germany. Fax: 49 228735404. E-mail: racke.kurt{at}uni-bonn.de

Keywords: Airway remodelling, collagen synthesis, lung fibroblasts, mitogen-activated protein kinase, muscarinic receptors, tiotropium

Received: October 2, 2007
Accepted April 29, 2008

Clinical observations indicate that in chronic obstructive pulmonary disease patients, the long-acting muscarinic antagonist tiotropium delays decline in airway function, suggesting that cholinergic mechanisms contribute to long-term structural changes. Human lung fibroblasts express muscarinic receptors and the present study aimed to explore their role in controlling collagen synthesis.

MRC-5, HEL-299 and primary human lung fibroblasts (phLFb) were cultured. Incorporation of [³H]-proline into cellular proteins was determined as measure of collagen synthesis.

In MRC-5 cells, the muscarinic agonist carbachol enhanced [³H]-proline incorporation in a concentration-dependent manner (effective concentration of 50%: 220 nM, increase at 10 µM by 40–55%, in a different series of experiments). Likewise, 10 µM oxotremorine caused an increase of 65%. For comparison, transforming growth factor-β1 (5 ng·mL^–1) caused an increase of 80%. Effects of carbachol on total [³H]-proline incorporation and collagenase-sensitive [³H]-proline fraction were similar. The effect of 10 µM carbachol was inhibited by tiotropium (inhibitory concentration of 50%: 110 pM), prevented by pertussis toxin and the mitogen-activated protein kinase inhibitor, PD 98059. Muscarinic agonists also enhanced [³H]-proline incorporation in a tiotropium-sensitive manner in HEL-299 cells and phLFb.

In human lung fibroblasts, muscarinic receptors exert stimulatory effects on collagen synthesis. Prolonged blockade of muscarinic-induced collagen synthesis may contribute to reported beneficial long-term effects of anticholinergics in chronic obstructive pulmonary disease.

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