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wound site.  The initial  population of white  blood cells   elicited by injury are only helpful to the healing process if
                    [15]
          in  the  wound is  composed of neutrophils. Thrombin   they are timely and transient. However, the inflammation
                                                                                                          [34]
          and IL‑8  stimulate  endothelial permeability  through   is not essential for skin wound healing. Martin et al.  has
          the  modulations  of adherens‑junction  endothelial cell   shown that the PU.1 null  mouse, which is devoid of both
          adhesion  and cell contraction, thereby  facilitating   macrophages and neutrophils, healed both incisional and
          leukocyte exit  from the circulation. [16,17]  Within  the   excisional wounds at statistically similar rates to wild‑type
          wound, neutrophils employ various strategies  to kill   littermates, but without scar formation. The cytokine and
          bacteria  and decontaminate  the  wound, including  the   growth‑factor profiles at the wound site in the PU.1 null
          secretion of proteases and antimicrobial peptides, as well   mouse differed from those of the wild‑type. As a result, cell
          as the generation of reactive oxygen  intermediates  via   death was reduced, and scar formation did not occur.
                                                                                                             [34]
          the  respiratory  burst.   In  the  absence  of inflammatory   Studies have focused on platelets and mast cells as targets,
                            [18]
          mediators,  neutrophils  will  undergo  spontaneous  and have shown that neither of these mediators is essential
          apoptosis. The apoptosis  is mediated by cathepsin D   to effective wound repair. This further  suggests that a
          release from neutrophil granules, which then facilitates   dampened or modified inflammatory response could reduce
          the cleavage and activation of caspase  8, ultimately   scar formation. [13,35]  Impairment of macrophage function
          resulting  in  caspase 3 activation,  DNA  fragmentation  and   at  the  wound  site  derails  the  resolution  of  inflammation.
                  [19]
          apoptosis.   In  the  absence  of  neutrophils, wound site   A  persistent  inflammatory  state  of  diabetic  wound
          macrophages lack  guidance in conducting  the healing   macrophages is caused by impairment in the ability of these
          process.  Although neutrophils play a role in decreasing   cells  to  phagocytose  apoptotic  cells  at  the  wound  site,  in
                 [20]
          infection during wound healing,  their  absence does not   turn preventing the switch from M1 to M2 phenotype.
                                                                                                             [36]
          prevent the overall progress of wound healing.  However,   Prolonged  inflammation  may  not  only  compromise  wound
                                                 [21]
          their prolonged presence in the wound may be a factor in   closure but may also worsen scar outcomes. [37,38]  Lipid
          the  conversion of  acute  wounds into  nonhealing  chronic   mediators, such as the lipoxins, resolvins, protectins and
          wounds.                                             maresins,  have  emerged  as  a  novel  genus  of  potent  and
          Within  two  to  three  days,  monocytes  become  the   stereoselective players that counter regulate excessive
          predominant inflammatory cell population in the wound.   acute inflammation and stimulate molecular and cellular
                                                                                         [39]
          Monocyte  chemotaxis  to  the  wound  occurs  via  CC   events that define resolution.  The production and
          chemokines like CCL2. The chemokines can be released   activity  of  several  proteases  including  metalloproteinase,
          by  neutrophils,  by  the  monocytes  themselves  and  by   serine proteases and neutrophil elastases which are tightly
          keratinocytes at different stages of healing. [22‑24]  Circulating   regulated  in  acute  wound  healing  may  be  altered  in
                                                                            [1]
          monocytes and mast cells are attracted to and infiltrate the   chronic wounds.  For example, non‑healing human wound
          wound site. [1,25]  Within the wound, monocytes differentiate   fluid and tissue have increased protease activity, which
          into  macrophages.  Macrophages  in  turn  remove   rapidly degrades exogenously applied peptide growth
          apoptotic neutrophils and other dead cells, function as   factors. [40,41]  Products targeting excessive protease activity
          antigen‑presenting cells, and secrete cytokines and multiple   such as  protease‑scavenging  matrices  (e.g.  Promogran),
          peptide  growth  factors.   Phagocytosis  of  the  apoptotic   selective inhibitors or specific antibodies may be useful in
                              [10]
          neutrophils  by  macrophages  then  leads  to  removal  of   the treatment of chronic wounds refractory to conventional
          chemokines from the area of inflammation, preventing   treatments. [42,43]
          further leukocyte influx.  Several cytokines and growth   The lymphocytes are the last type of leukocytes to arrive
                               [10]
          factors are known to be secreted by macrophages.  Such   at the wound site.  The lymphocytes exert a specific
                                                    [26]
          growth factors include TGF‑b, TGF‑α, basic FGF  (bFGF),   response against microbes and other foreign  material
          VEGF and PDGF. These growth factors activate and attract   in the wound: B‑lymphocytes via antibodies and  the
          local endothelial cells, fibroblasts and keratinocytes, and   T‑lymphocytes through production of cytokines and
          enable wound healing by causing cell proliferation and   stimulation  of  cytolytic activity.  Lymphocyte‑induced
          synthesis  of  ECM  and  inducing  angiogenesis  VEGF, [27‑30]    inflammation  is  then  resolved by  apoptosis when
          which stimulates angiogenesis, also stimulates the   interferon (IFN)‑c and  TNF‑α are produced  at the wound
          macrophages to express LIGHT, a member of the tumor   site.  Mast cells also appear during the later part of the
                                                                  [10]
          necrosis factor alpha  (TNF‑α) family of cytokines, which   inflammatory  phase,  but  their  function remains  unclear.
          binds to lymphotoxin‑b receptor and induces macrophage   Impaired wound healing has been reported in mast
          death. [31]                                         cell‑deficient mice.  Mast cells have also been implicated
                                                                              [44]
          Macrophages play a crucial role in enabling wound healing.   in skin wound fibrosis. [45,46]  Recently, the role of mast cells
          Macrophage depletion is known to markedly impair wound   in wound healing has become an area of intense research
                                                         [33]
          closure. [27,32]   In  a  landmark  study,  Leibovich  and  Ross    because of a correlation between mast cells and both
          demonstrated that the antimacrophage serum combined   keloids and hypertrophic scars. [45,46]
          with hydrocortisone diminished the accumulation of
          macrophages in healing skin wounds of adult guinea pigs.   PROLIFERATION PHASE
          Such depletion resulted in impaired  disposal  of  damaged
          tissue and provisional matrix, compromised fibroblast   The proliferative phase of wound healing is accepted  to
          count, and delayed healing. Inflammatory responses   start around two  days after injury and typically lasts up

           252                                                           Plast Aesthet Res || Vol 2 || Issue 5 || Sep 15, 2015
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