Wound Inflammation in Diabetic<i>ob</i>/<i>ob</i>Mice

Kämpfer, Heiko; Schmidt, Ronald; Geißlinger, Gerd; Pfeilschifter, Josef; Frank, Stefan

doi:10.2337/diabetes.54.5.1543

Cited by 60 publications

(49 citation statements)

References 44 publications

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“…45 However, overproduction of ROS leads to excessive oxidative stress and results in cellular dysfunction and functional alterations of DNA, lipids, and proteins. 17,45,46 The high glucose concentration in diabetic hyperglycemia is a critical initiating factor for ROS generation. 47 In this regard, db/db macrophages generated much more ROS than db/ϩ macrophages, which is consistent with a previous report.…”

Section: Discussionmentioning

confidence: 99%

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Tian

Lü

Shah

et al. 2011

The American Journal of Pathology

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Impaired macrophage functions imposed by diabetic complications and the suppressed formation of 14S, 2 1 R -d i h y d r o x y d o c o s a -4 Z , 7Z , 1 0 Z , 1 2 E , 1 6 Z , 19Z-hexaenoic acid (14S,21R-diHDHA) in wounds contribute significantly to deficient wound healing in diabetics, but how are macrophage functions and 14S,21R-diHDHA formation associated? We studied 14S,21R-diHDHA generation from macrophages using liquid chromatography/mass spectrometry. The role in macrophage-mediated wound healing functions was determined using a murine splinted excisional wound healing model and in vitro assays. 14S,21R-diHDHA acts as a macrophage-generated autacoid, and its attenuated formation in macrophages of diabetic db/db mice was accompanied by impairment of macrophage prohealing functions. 14S,21R-diHDHA restored db/db macrophage-impaired prohealing functions by promoting wound re-epithelialization, formulation of granulation tissue, and vascularization. Additionally, 12/15-lipoxygenase-deficient macrophages, which are unable to produce 14S,21R-diHDHA, exhibited impaired prohealing functions, which also were restored by 14S,21R-diHDHA treatment. The molecular mechanism for 14S,21R-diHDHA-induced recovery of impaired prohealing functions of db/db macrophages involves enhancing their secretion of vascular endothelial growth factor and platelet-derived growth factor BB, decreasing hyperglycemia-induced generation of reactive oxygen species, and increasing IL-10 expression under inflammatory stimulation. Taken together, these results indicate that deficiency of 14S,21R-diHDHA formation by diabetic macrophages contributes to their impaired prohealing functions. Our findings provide mechanistic insights into wound healing in diabetics and suggest the possibility of using autologous macrophages/monocytes, treated with 14S,21R-diHDHA, or related compounds, to promote diabetes-impaired wound healing. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Tian

Lü

Shah

et al. 2011

The American Journal of Pathology

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“…Wound M were the major source of Cox-2 expression in the wounds of ob/ob mice (Kä mpfer et al, 2005). Cox-2 represents a marker for classically activated proinflammatory M1-type M, but not for their alternatively activated M2-type M counterparts (Mosser and Edwards, 2008).…”

Section: Discussionmentioning

confidence: 99%

The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Attenuates Inflammation and Accelerates Epithelialization in Wounds of Diabetic ob/ob Mice

Schürmann

Linke²,

Engelmann-Pilger³

et al. 2012

J Pharmacol Exp Ther

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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.

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“…32 Indeed, also the Cox-2 enzyme was markedly dysregulated, at both the mRNA (Figure 10, A and B) and protein ( Figure 10C) level. Notably, Cox-2 protein, elevated in particular during late acute repair (day 7), was mainly expressed in wound margin keratinocytes ( Figure 10D), which appeared to be the main cellular source of the enzyme in DTox-treated mice despite its localization in remaining wound macrophages in control mice ( Figure 10D, left panels).…”

Section: Impaired Wounds In Dtox-treated Mice Exhibit a Severely Distmentioning

confidence: 99%

A Transgenic Mouse Model of Inducible Macrophage Depletion

Goren

Allmann

Yogev

et al. 2009

The American Journal of Pathology

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321

151

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Whether the wound macrophage is a key regulatory inflammatory cell type in skin repair has been a matter of debate. A transgenic mouse model mediating inducible macrophage depletion during skin repair has not been used to date to address this question. Here, we specifically rendered the monocyte/macrophage leukocyte lineage sensitive to diphtheria toxin by expressing the lysozyme M promoter-driven, Cremediated excision of a transcriptional STOP cassette from the simian DT receptor gene in mice (lysM-Cre/ DTR). Application of diphtheria toxin to lysM-Cre/ DTR mice led to a rapid reduction in both skin tissue and wound macrophage numbers at sites of injury. Macrophage-depleted mice revealed a severely impaired wound morphology and delayed healing. In the absence of macrophages, wounds were re-populated by large numbers of neutrophils. Accordingly, macrophage-reduced wound tissues exhibited the increased and prolonged persistence of macrophage inflammatory protein-2, macrophage chemoattractant protein-1, interleukin-1␤, and cyclooxygenase-2, paralleled by unaltered levels of bioactive transforming growth factor-␤1. Altered expression patterns of vascular endothelial growth factor on macrophage reduction were associated with a disturbed neo-vascularization at the wound site. Impaired wounds revealed a loss of myofibroblast differentiation and wound contraction. Our data in the use of lysM-Cre/ DTR mice emphasize the pivotal function of wound macrophages in the integration of inflammation and cellular movements at the wound site to enable efficient skin repair.

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Wound Inflammation in Diabeticob/obMice

Cited by 60 publications

References 44 publications

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Attenuates Inflammation and Accelerates Epithelialization in Wounds of Diabetic ob/ob Mice

A Transgenic Mouse Model of Inducible Macrophage Depletion

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