Enhanced fibroblast apoptosis and impaired wound healing in type 2 diabetes is mediated by TNF dysregulation
Chehab Pla, Loubna
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Background: A serious complication of diabetes is impaired healing, Which can lead to diminished physical activity and in some cases chronic wounds and limb amputation. Multiple factors are likely to contribute to deficient healing in diabetics. They include an altered host response that prolongs inflammation and diminishes anti-bacterial defenses, altered protease activity, a tendency for vascular abnormalities, the generation of an inadequate number of cells to accomplish rapid and robust healing, decreased growth factor production, a failure to form a sufficient amount of extracellular matrix and alterations in apoptosis that may interfere with healing by decreasing the number of cells that participate in new tissue formation. Methods: To investigate the impact of diabetes on dermal wound healing small excisional wounds were created in type 2 db/db diabetic mice and normoglycemic littermates. Impaired healing was assessed by measuring the percent fill and the gap between epithelial and connective tissue edges of the wound. To examine the role of TNF [alpha], diabetic and normoglycemic mice were treated with pegsunercept (TNF-[alpha] inhibitor) or vehicle alone, starting two days after wounding. Experiments were performed to assess the level of fibroblast apoptosis with and without TNF-[alpha] inhibitor. Results: Healing was significantly reduced on day 5 after wounding in the diabetic micc. Gap between the edges of the healing epithelium and the healing connective tissue was approximately l.7 fold larger in diabetic mice. Pegsunercept had no effect on healing at this time point. On day nine after wounding there was relatively little improvement in the diabetic wounds while the normoglycemic animals had healed extensively. Treatment with pegsunercept had a significant effect on diabetic healing at this time point. Pegsunercept also increased the percentage of the wound filled with new connective tissue by approximately 50% in the diabetic mice. On Day 9 the number of apoptotic fibroblast was 4-fold higher in the diabetic compared to the normoglycemic group. After inhibition of TNF, fibroblast apoptosis was reduced by approximately 50% in both the diabetic and non-diabetic mice (P[less than] 0.05). Fibroblast density was measured. The number of fibroblasts per mm2 was almost 2 fold higher in the normal compared to the diabetic mice (P[less than]0.05). Fibroblast density in diabetic mice treated with TNF inhibitor increased by 64% (P[less than]0.05). Conclusion: Treatment of diabetic mice with a TNF [alpha] inhibitor improves healing and this may occur through reducing fibroblasts cell death and increasing fibroblast numbers.
PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact email@example.com.Thesis (MSD)--Boston University, Goldman School of Dental Medicine, 2007 (Endodontics).Includes bibliographical references: leaves 65-86.
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