**7. Conclusion**

inflammation‐mediated signalling [77]. In addition, Flii has been shown to control inflamma‐ some activation by way of direct blocking of caspase‐1 and caspase‐11 and by modulating their subcellular localisation [80]. These findings suggest that Flii upregulation in response to wounding may be directed towards regulating inflammation with unfortunate consequences

Complete knockout of Flii leads to gastrulation failure and embryonic lethality [81], while Flii heterozygous and transgenic mice appear phenotypically normal [82] suggesting an important role in development. In foetal skin, Flii is transiently increased in E17 but not E19 mice skin; however, its expression is downregulated in the E17 keratinocytes immediately adjacent to the wound margin [83] suggesting that temporal regulation of Flii during healing may influence wound repair outcomes. In addition, Flii interaction with tight junction proteins Cld‐4 and ZO‐2 is instrumental in development of skin barrier function and recovery following injury [84]. Wound healing studies using Flii heterozygous and transgenic mice have demonstrated that reduced Flii expression results in improved rate of healing via effects on cellular migration, adhesion and proliferation [31, 48]. In contrast, Flii transgenic mice have thinner more fragile skin, reduced number of hemidesmosomes and impaired cellular migration and adhesion leading to delayed healing [31, 48]. In addition, studies using mice with an inducible fibroblast specific Flii overexpression have shown inhibited wound healing with larger wounds than non‐induced controls, suggesting that fibroblast‐derived Flii may have an important role

Flii impairs the turnover of focal adhesions via a Rac1‐dependant mechanism and Flii inter‐ action with Rac1‐interacting proteins may be crucial to its effects on cell migration [74, 86]. In addition, Flii inhibits actin polymerisation [73] and this delicate balance of actin monomers and polymers can be altered using Flii neutralising antibodies (FnAb) raised against LRR domain of Flii [84] affecting collagen contraction, angiogenesis and wound healing outcomes

Topical application of FnAb to wounds in preclinical models of wound repair results in a decreased wound area, a quicker rate of healing and decreased early scar formation [31, 88, 89] (**Figure 6**). Supporting these findings, both in vitro and in vivo studies have demonstrated that Flii plays a role in tissue scarring, collagen deposition and contraction [89, 90]. Using a preclinical model of porcine wound healing, studies have shown that Flii affects collagen I to collagen III ratio, impairs healing and contributes to the formation of early scars [89]. In addition, in vivo studies using human studies and animal models of bleomycin‐induced hypertrophic scaring show that Flii‐deficient mice exhibit reduced scarring in response to bleomycin as evident by decreased dermal thickness, smaller cross‐sectional scar areas, fewer myofibroblast numbers and increased collagen I to collagen III ratios [91]. Use of FnAb in porcine models of wound healing is the first example of using antibodies in large animal in vivo to modify the regulators of actin cytoskeleton that lead to improved wound healing outcomes. No side effects, complications or contraindications were observed when FnAb was administered locally to mouse or pigs suggesting the potential for the development of this therapy for human use. Application of such approaches to regulate different modulators of

on healing of wounded area.

146 Wound Healing - New insights into Ancient Challenges

during wound repair [85].

[31, 87, 88].

The actin cytoskeleton is an important regulator of numerous physiological processes that are important for efficient wound healing. Research has identified novel regulators of the actin cytoskeleton that can affect skin cell functions, tissue regeneration and repair. Identifying and understanding the role of the actin cytoskeleton and these regulating proteins will identify how they can affect outcomes of wound repair. The development of new approaches aimed at modulating actin remodelling proteins may therefore hold tremendous promise for therapeutic development and translation into clinical practice.
