Activated Protein C in Cutaneous Wound Healing: From Bench to Bedside.

Ruilong Zhao,Haiyan Lin,Elizabeth Clarke,Christopher Jackson,Lara Bereza-Malcolm,Meilang Xue

doi:10.3390/ijms20040903

Ruilong Zhao, Haiyan Lin + Show 4 more

Open Access

https://doi.org/10.3390/ijms20040903

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Abstract

Independent of its well-known anticoagulation effects, activated protein C (APC) exhibits pleiotropic cytoprotective properties. These include anti-inflammatory actions, anti-apoptosis, and endothelial and epithelial barrier stabilisation. Such beneficial effects have made APC an attractive target of research in a plethora of physiological and pathophysiological processes. Of note, the past decade or so has seen the emergence of its roles in cutaneous wound healing—a complex process involving inflammation, proliferation and remodelling. This review will highlight APC’s functions and mechanisms, and detail its pre-clinical and clinical studies on cutaneous wound healing.

Highlights

Production and ActivationProtein C (PC) consists of several moieties: a Gla domain, an aromatic segment and two epidermal growth factor (EGF)-like domains within the light chain, and a serine protease domain and activation peptide within the heavy chain [5]
The findings on Activated protein C (APC)’s anti-inflammatory and cytoprotective properties prompted researchers to investigate its action on cutaneous wound healing in experimental animals (Table 1)
Recent data from our group in a porcine wound model did show increased healing through a combined topical and subcutaneous APC treatment regime, with no bleeding side effects. These results indicate that APC’s impacts are evident in cell culture and animal wounds, where it is both effective and safe to use

Summary

Production and Activation

Protein C (PC) was first noted to play a role in anticoagulation in 1960 [1], but was not isolated until 1976, when it was determined to be a vitamin K-dependent zymogen [2]. ZCyygtoopursodteecfiticvieenPcayth, wwahyisch causes neonatal purpura fulminans and its associated skin necrosis; its significance can be seen from the increased risk of venous thrombosis with APC’s heterozygous deficienAcPyC[2h0]a.s several cytoprotective properties, which are independent from its anticoagulation pathway [21] These include anti-inflammatory actions, anti-apoptosis, and endothelial and epithelial 1.3b.aCrryiteorpsrtoatebcitlivsaetPioanth[w3a].ysMany such properties require EPCR and protease-activated receptor (PAR)-. A recent study has further indicated that APC suppresses nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation via PAR-1 in mice macrophages and cardiac and renal tissue [34] These data identify APC as a viable and critical target of anti-inflammatory therapy. The wound promoting effects of APC on mouse full-thickness wounds depends on PAR-2 activity [54], and APC signals via PAR-2 and PAR-3 to expand regulator T-cells, mitigating graft-versus-host disease in mice [55]

Cell Culture

Animal Models

Active Protein C in Other Diseases

Findings

Conclusions