RT Journal Article
SR Electronic
T1 Muscarinic receptors mediate stimulation of collagen synthesis in human lung fibroblasts
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 555
OP 562
DO 10.1183/09031936.00129307
VO 32
IS 3
A1 S. Haag
A1 S. Matthiesen
A1 U. R. Juergens
A1 K. Racké
YR 2008
UL http://erj.ersjournals.com/content/32/3/555.abstract
AB 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.