PGD(2) modulates fibroblast-mediated native collagen gel contraction.
Repair of tissues is a necessary step in restoring tissue function following injury consequent to inflammation. Many inflammatory mediators are capable of modulating not only the activity of "inflammatory cells" but also of modulating functions of parenchymal cells that may contribute to repair. Disordered repair is believed to contribute to tissue dysfunction in many inflammatory diseases, including bronchial asthma. The current study evaluated the ability of prostaglandin D(2) (PGD(2)) to modulate fibroblast repair using the in vitro contraction of three-dimensional native collagen gels as a model system. PGD(2) stimulated gel contraction in a concentration- and time-dependent manner. In contrast, the PGD(2) analog BW245C inhibited contraction. Both effects were blocked by a DP-receptor blocker (AH6809). Neither TP receptor blocker SQ29548 nor protein kinase (PK) A antagonist KT5720 hand an effect on PGD(2)-stimulated contraction, suggesting action through a novel prostaglandin D receptor. PKC inhibitor calphostin-C (10(-6) M) blocked the PGD(2) stimulation of gel contraction. A calcium-independent PKC-epsilon inhibitor (Ro31-8220), but not calcium-dependent PKC-alpha and -beta inhibitors, also blocked the PGD(2) effect on contraction, implying a role for a calcium-independent pathway. This study, therefore, supports a role for PGD(2) in tissue repair and remodeling. These effects of PGD(2) appear to be mediated through receptor-signal transduction pathways different from the cAMP-PKA pathways mediating the proinflammatory activity of PGD(2), creating the possibility for selective therapeutic manipulation.
Department of Respiratory Medicine, University of Tokyo, Tokyo, Japan.
Tadashi
T
Kohyama
Todd A
TA
Wyatt
Xiangde
X
Liu
Fu-Qiang
FQ
Wen
Tetsu
T
Kobayashi
Qiuhong
Q
Fang
Hui Jung
HJ
Kim
Stephen I
SI
Rennard
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002227:Carbazoles; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects* / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D005782:Gels / Q000737:chemistry; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000196:embryology; D008698:Mesylates / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D014945:Wound Healing; D014966:Xanthenes / Q000494:pharmacology; D044004:Xanthones
C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002227:Carbazoles; D004791:Enzyme Inhibitors; D004963:Estrenes; D005231:Fatty Acids, Unsaturated; D005782:Gels; D006834:Hydrazines; D007211:Indoles; D008698:Mesylates; D009281:Naphthalenes; D011448:Prostaglandin Antagonists; D011758:Pyrroles; D011760:Pyrrolidinones; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013873:Thionucleotides; D014966:Xanthenes; D044004:Xanthones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C074854:U 73343; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; C057416:KT 5720; C045749:SQ 29548; D003094:Collagen; D011493:Protein Kinase C; D010738:Type C Phospholipases; D006152:Cyclic GMP; C058819:calphostin C; D015230:Prostaglandin D2; C064758:Ro 31-8220; C036293:prostaglandin D2 receptor