PGE 2 desensitizes β -agonist effect on human lung fibroblast-mediated collagen gel contraction through upregulating PDE4.
In the current study, we investigated the effect of a long-acting β -agonist (salmeterol) and a phosphodiesterase 4 (PDE4) inhibitor (cilomilast) on human lung fibroblast-mediated collagen gel contraction. Higher concentrations of salmeterol (10(-7) and 10(-6) M) inhibited fibroblast-mediated collagen gel contraction. No effect was observed with cilomilast alone (up to 10(-5) M). In the presence of 10(-8) M salmeterol, however, cilomilast could significantly inhibit fibroblast-mediated collagen gel contraction in a concentration-dependent manner (10(-7) ~10(-5) M). Blockade of endogenous PGE2 by indomethacin further potentiated the inhibitory effect of salmeterol on fibroblast-mediated collagen gel contraction, but it did not affect cilomilast's effect. Pretreatment with PGE2 abolished the inhibitory effect of salmeterol, but it potentiated the inhibitory effect of cilomilast on fibroblast-mediated collagen gel contraction. Finally, indomethacin slightly inhibited PDE4C expression, while PGE2 stimulated the expression of PDE4A and -4C in human lung fibroblasts. These findings suggest that long-acting β -agonist and PDE4 inhibitor have a synergistic effect in regulating fibroblast tissue repair functions and that PGE2 can modulate the effect of β -agonist and PDE4 inhibitor at least in part through the mechanism of regulating PDE4 expression.
Department of Pulmonary and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China ; Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5910, USA.
Qiuhong
Q
Fang
Yingmin
Y
Ma
Jing
J
Wang
Joel
J
Michalski
Stephen I
SI
Rennard
Xiangde
X
Liu
D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D003094:Collagen / Q000737:chemistry*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005782:Gels; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000503:physiopathology; D000068299:Salmeterol Xinafoate; D015854:Up-Regulation
D058666:Adrenergic beta-2 Receptor Agonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003509:Cyclohexanecarboxylic Acids; D005782:Gels; D009570:Nitriles; D058988:Phosphodiesterase 4 Inhibitors; D000068299:Salmeterol Xinafoate; C433247:Cilomilast; D003094:Collagen; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015232:Dinoprostone; D000420:Albuterol; D007213:Indomethacin