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Diabetes 54:1543-1551, 2005
© 2005 by the American Diabetes Association, Inc.

Wound Inflammation in Diabetic ob/ob Mice

Functional Coupling of Prostaglandin Biosynthesis to Cyclooxygenase-1 Activity in Diabetes-Impaired Wound Healing

Heiko Kämpfer1, Ronald Schmidt1, Gerd Geisslinger1, Josef Pfeilschifter1, and Stefan Frank1,2

1 Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany
2 Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia

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.

Address correspondencereprint requests to Dr. Stefan Frank, Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der JW Goethe-Universität Frankfurt/M., Theodor-Stern-Kai 7, D-60590 Frankfurt/M., Germany. E-mail: s.frank{at}em.uni-frankfurt.de

Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; LC/MS/MS, liquid chromatography tandem mass spectrometry; PG, prostaglandin; PGI2, prostacyclin


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.