Wound inflammation in diabetic ob/ob mice: functional coupling of prostaglandin biosynthesis to cyclooxygenase-1 activity in diabetes-impaired wound healing.
This study focused on the regulation of prostaglandin (PG) production in diabetes-impaired wound tissue. Cyclooxygenase (COX)-1 and -2 expression and activity were severely dysregulated in chronic wounds of diabetic ob/ob mice. Those wounds were characterized by a reduced expression of COX-1 and the presence of strongly elevated levels of COX-2 when compared with conditions observed in healthy animals. Resolution of the diabetic and impaired wound-healing phenotype by systemic administration of leptin into ob/ob mice increased COX-1 expression in wound margin keratinocytes and decreased COX-2 expression in inner wound areas to levels found in wild-type animals. Notably, improved wound healing was characterized by a marked increase in PGE2/PGD2 biosynthesis that colocalized with induced COX-1 in new tissue at the margin of the wound. COX-2 expression did not significantly contribute to PGE2/PGD2 production in impaired wound tissue. Accordingly, only late wound tissue from SC-560-treated (selective COX-1 inhibitor) but not celecoxib-treated (selective COX-2 inhibitor) ob/ob mice exhibited a severe loss in PGE2, PGD2, and prostacyclin at the wound site, and this change was associated with reduced keratinocyte numbers in the neo-epithelia. These data constitute strong evidence that a dysregulation of COX-1-coupled prostaglandin contributes to diabetes-impaired wound healing.
Kämpfer
Heiko
H
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der JW Goethe-Universität Frankfurt/M., Theodor-Stern-Kai 7, D-60590 Frankfurt/M., Germany.
Schmidt
Ronald
R
Geisslinger
Gerd
G
Pfeilschifter
Josef
J
Frank
Stefan
S
D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology* / Q000503:physiopathology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000473:pathology*; D020738:Leptin / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000473:pathology* / Q000503:physiopathology; D015230:Prostaglandin D2 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology; D014947:Wounds and Injuries / Q000473:pathology*
D020738:Leptin; D008565:Membrane Proteins; D011994:Recombinant Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone; D015230:Prostaglandin D2