The protein C system in cutaneous wounds and burns

Abstract

Cutaneous wound healing is a ubiquitous experience. Our largest organ provides a vital protective role in our interactions with an often-hostile environment. Any compromise in its integrity is restored with a coordinated cascade of events – haemostasis, inflammation, proliferation, and remodelling – that is sophisticated in its complexity, yet tantalising in its desire to be tamed by science. An understanding of these predictable phases of physiological healing has led to revelations of rogue processes such as unbridled inflammation that give rise to nonhealing wounds, or even cancer. Our best efforts at manipulating the wound microcosm have yielded several promising targets.

Of the few biological agents that have progressed to clinical trials, activated protein C (APC) has consistently exhibited robust healing capacity in case studies and a randomised clinical trial. Upon activation from its zymogen protein C (PC), APC serves as a well-known anticoagulant. More recently, and of particular relevance in complex processes such as wound healing, it has demonstrated pleiotropic cytoprotective properties including anti-inflammatory actions, anti-apoptosis, and endothelial and epithelial barrier stabilisation. To circumvent potential bleeding side effects, a bioengineered variant called 3K3A-APC was synthesised with minimal anticoagulant activity in vivo, and has primarily been examined for its neuroprotective activity. However it has not been tested in cutaneous wounds, which thus constitutes the first aim of this project.

This thesis presents several salient findings for 3K3A-APC as a topical wound healing agent in preclinical studies. 3K3A-APC promoted a healing phenotype in major skin cell types in culture (endothelial cells, fibroblasts, and keratinocytes), and reduced time to complete healing in mouse wounds by around three days (p < 0.0005), in a similar manner to APC. Its efficacy was then confirmed in pig wounds which more closely mimic human skin. Kaplan-Meie...