Cyclooxygenase and cytochrome P-450 pathways induced by fetal calf serum regulate wound closure in 3T6 fibroblast cultures through the effect of prostaglandin E2 and 12 and 20 hydroxyeicosatetraenoic acids.
Wound-induced injury of 3T6 fibroblast cultures initiated a repair process stimulated by fetal calf serum (FCS) that restored the integrity of cell cultures. In these experimental conditions, FCS induced arachidonic acid (AA) release and eicosanoid production. Our results show that the inhibition of the cyclooxygenase (COX) and/or cytochrome P-450 pathways significantly decreases the wound closure, whereas that of the lipoxygenase pathway does not modify the wound repair process. Both EP(1) and EP(4) receptors of prostaglandin E(2) (PGE(2)) mediate PGE(2) stimulated 3T6 fibroblast wound closure. Our data suggest that calcium and cAMP are involved in the signaling event induced by PGE(2) during the 3T6 fibroblast wound repair process. On the other hand, we show that ketoconazole, a cytochrome P-450 inhibitor, hinders the wound closure induced by FCS in wounded 3T6 fibroblast cultures. 12 and 20 Hydroxyeicosatetraenoic acids (HETEs), which are key AA metabolites synthesized by cytochrome P-450, partially revert the effects of ketoconazole on the wound repair process. Thus, the COX and cytochrome P-450 pathways of the arachidonate cascade are involved in 3T6 fibroblast wound closure.
Moreno
Juan Jose
JJ
Department of Physiology, Faculty of Pharmacy, Barcelona University, Barcelona, Spain. moreno@farmacia.far.ub.es
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology*; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology / Q000502:physiology; D008084:Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D001798:Blood Proteins; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; C545636:Ptger1 protein, mouse; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone