Wound Inflammation in Diabetic ob/ob Mice

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

  1. Heiko Kämpfer1,
  2. Ronald Schmidt1,
  3. Gerd Geisslinger1,
  4. Josef Pfeilschifter1 and
  5. Stefan Frank12
  1. 1Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany
  2. 2Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia
  1. 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

Abstract

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.

Footnotes

    • Accepted February 11, 2005.
    • Received November 10, 2004.
| Table of Contents