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      The importance of inflammation control for the treatment of chronic diabetic wounds

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          Abstract

          Diabetic chronic wounds cause massive levels of patient suffering and economic problems worldwide. The state of chronic inflammation arises in response to a complex combination of diabetes mellitus‐related pathophysiologies. Advanced treatment options are available; however, many wounds still fail to heal, exacerbating morbidity and mortality. This review describes the chronic inflammation pathophysiologies in diabetic ulcers and treatment options that may help address this dysfunction either directly or indirectly. We suggest that treatments to reduce inflammation within these complex wounds may help trigger healing.

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          Most cited references147

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          WITHDRAWN: Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition

          To provide global estimates of diabetes prevalence for 2019 and projections for 2030 and 2045.
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            Diabetic Foot Ulcers and Their Recurrence.

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              Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.

              Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.
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                Author and article information

                Contributors
                janice.tsui@ucl.ac.uk
                Journal
                Int Wound J
                Int Wound J
                10.1111/(ISSN)1742-481X
                IWJ
                International Wound Journal
                Blackwell Publishing Ltd (Oxford, UK )
                1742-4801
                1742-481X
                23 December 2022
                August 2023
                : 20
                : 6 ( doiID: 10.1111/iwj.v20.6 )
                : 2346-2359
                Affiliations
                [ 1 ] Royal Veterinary College Department of Pathobiology and Population Sciences London UK
                [ 2 ] UCL Centre for Biomaterials in Surgical Reconstruction and Regeneration, Department of Surgical Biotechnology, UCL Division of Surgery and Interventional Science University College London London UK
                Author notes
                [*] [* ] Correspondence

                Professor Janice Tsui, Division of Surgery and Interventional Science, University College London, Pond Street, London.

                Email: janice.tsui@ 123456ucl.ac.uk

                Article
                IWJ14048
                10.1111/iwj.14048
                10333011
                36564054
                7bd26471-70d1-4e8f-875d-7ab53cf8c7d5
                © 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 November 2022
                : 21 March 2022
                : 28 November 2022
                Page count
                Figures: 3, Tables: 0, Pages: 14, Words: 10064
                Funding
                Funded by: Biotechnology and Biological Sciences Research Council , doi 10.13039/501100000268;
                Award ID: 1764829
                Funded by: Engineering and Physical Sciences Research Council , doi 10.13039/501100000266;
                Award ID: EP/L020904/1
                Award ID: EP/R02961X/1
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                August 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.1 mode:remove_FC converted:10.07.2023

                Emergency medicine & Trauma
                chronic wounds,diabetes,diabetic ulcers,inflammation,wound healing
                Emergency medicine & Trauma
                chronic wounds, diabetes, diabetic ulcers, inflammation, wound healing

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