title: The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice.
abstract: In recent years, new and effective therapeutic agents for blood glucose control have been added to standard diabetes therapies: dipeptidyl peptidase-4 (DPP-4) inhibitors, which prolong the bioavailability of the endogenously secreted incretin hormone glucagon-like peptide-1 (GLP-1). Full-thickness excisional wounding was performed in wild-type (C57BL/6J) and diabetic [C57BL/6J-obese/obese (ob/ob)] mice. DPP-4 activity was inhibited by oral administration of linagliptin during healing. Wound tissue was analyzed by using histological, molecular, and biochemical techniques. In healthy mice, DPP-4 was constitutively expressed in the keratinocytes of nonwounded skin. After skin injury, DPP-4 expression declined and was lowest during the most active phase of tissue reassembly. In contrast, in ob/ob mice, we observed increasing levels of DPP-4 at late time points, when delayed tissue repair still occurs. Oral administration of the DPP-4 inhibitor linagliptin strongly reduced DPP-4 activity, stabilized active GLP-1 in chronic wounds, and improved healing in ob/ob mice. At day 10 postwounding, linagliptin-treated ob/ob mice showed largely epithelialized wounds characterized by the absence of neutrophils. In addition, DPP-4 inhibition reduced the expression of the proinflammatory markers cyclooxygenase-2 and macrophage inflammatory protein-2, but enhanced the formation of myofibroblasts in healing wounds from ob/ob mice. Our data suggest a potentially beneficial role of DPP-4 inhibition in diabetes-affected wound healing.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Klinikum der JW Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schürmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Linke
authors.forename: Kerstin
authors.initials: K
authors.lastname: Engelmann-Pilger
authors.forename: Cornelia
authors.initials: C
authors.lastname: Steinmetz
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.forename: Stefan
authors.initials: S
authors.lastname: Frank
mesh_terms: D000818:Animals; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D000069476:Linagliptin; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects* / Q000235:genetics
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D054873:Dipeptidyl-Peptidase IV Inhibitors; D019402:Macrophage Inflammatory Proteins; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D052216:Glucagon-Like Peptide 1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse