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      Transition from inflammation to proliferation: a critical step during wound healing

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          Abstract

          The ability to rapidly restore the integrity of a broken skin barrier is critical and is the ultimate goal of therapies for hard-to-heal-ulcers. Unfortunately effective treatments to enhance healing and reduce scarring are still lacking. A deeper understanding of the physiology of normal repair and of the pathology of delayed healing is a prerequisite for the development of more effective therapeutic interventions. Transition from the inflammatory to the proliferative phase is a key step during healing and accumulating evidence associates a compromised transition with wound healing disorders. Thus, targeting factors that impact this phase transition may offer a rationale for therapeutic development. This review summarizes mechanisms regulating the inflammation–proliferation transition at cellular and molecular levels. We propose that identification of such mechanisms will reveal promising targets for development of more effective therapies.

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          Wound healing--aiming for perfect skin regeneration.

          P. Martin (1997)
          The healing of an adult skin wound is a complex process requiring the collaborative efforts of many different tissues and cell lineages. The behavior of each of the contributing cell types during the phases of proliferation, migration, matrix synthesis, and contraction, as well as the growth factor and matrix signals present at a wound site, are now roughly understood. Details of how these signals control wound cell activities are beginning to emerge, and studies of healing in embryos have begun to show how the normal adult repair process might be readjusted to make it less like patching up and more like regeneration.
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            How matrix metalloproteinases regulate cell behavior.

            The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.
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              Inflammation in wound repair: molecular and cellular mechanisms.

              In post-natal life the inflammatory response is an inevitable consequence of tissue injury. Experimental studies established the dogma that inflammation is essential to the establishment of cutaneous homeostasis following injury, and in recent years information about specific subsets of inflammatory cell lineages and the cytokine network orchestrating inflammation associated with tissue repair has increased. Recently, this dogma has been challenged, and reports have raised questions on the validity of the essential prerequisite of inflammation for efficient tissue repair. Indeed, in experimental models of repair, inflammation has been shown to delay healing and to result in increased scarring. Furthermore, chronic inflammation, a hallmark of the non-healing wound, predisposes tissue to cancer development. Thus, a more detailed understanding in mechanisms controlling the inflammatory response during repair and how inflammation directs the outcome of the healing process will serve as a significant milestone in the therapy of pathological tissue repair. In this paper, we review cellular and molecular mechanisms controlling inflammation in cutaneous tissue repair and provide a rationale for targeting the inflammatory phase in order to modulate the outcome of the healing response.
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                Author and article information

                Contributors
                +46 8 51772158 , ning.xu@ki.se
                Journal
                Cell Mol Life Sci
                Cell. Mol. Life Sci
                Cellular and Molecular Life Sciences
                Springer International Publishing (Cham )
                1420-682X
                1420-9071
                14 May 2016
                14 May 2016
                2016
                : 73
                : 20
                : 3861-3885
                Affiliations
                [1 ]Unit of Dermatology and Venereology, Molecular Dermatology Research Group, Department of Medicine, Center for Molecular Medicine (CMM), L8:02, Karolinska Institutet, SE-171 76 Stockholm, Sweden
                [2 ]Unit of Dermatology and Venereology, Karolinska University Hospital, Solna, Sweden
                Author information
                http://orcid.org/0000-0003-4868-3798
                Article
                2268
                10.1007/s00018-016-2268-0
                5021733
                27180275
                6725dc79-11e9-4cb3-bab8-cee0b1f6c0f6
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 1 February 2016
                : 22 April 2016
                : 6 May 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;
                Award ID: K2014-85X-22500-01-3
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007459, Ragnar Söderbergs stiftelse;
                Funded by: Hedlunds Foundation
                Funded by: Welander and Finsens Foundation
                Funded by: Åke Wibergs Foundation
                Funded by: FundRef http://dx.doi.org/10.13039/100008738, Jeanssons Stiftelser;
                Categories
                Review
                Custom metadata
                © Springer International Publishing 2016

                Molecular biology
                macrophage,fibroblast,bioactive lipid mediator,reactive oxygen species,toll-like receptor,transcription factor,microrna

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