Woodley David T, Wysong Ashley, DeClerck Brittany, Chen Mei, Li Wei
Department of Dermatology, USC Laboratories for Investigative Dermatology, USC/Norris Cancer Center, The Keck Medical Center and the Los Angeles Greater VA Healthcare System, University of Southern California , Los Angeles, California.
Adv Wound Care (New Rochelle). 2015 Apr 1;4(4):203-212. doi: 10.1089/wound.2014.0566.
The treatment and care of patients with skin wounds are a major healthcare expenditure. Burn wounds, iatrogenic surgical wounds, venous stasis dermatitis ulcers, diabetic lower limb ulcers, pressure ulcers, and skin wounds from peripheral neuropathies are largely treated with only supportive care. Despite a great deal of research into using growth factors as therapeutic agents, to date, the field has been disappointing. The only biologic agent that is Federal Drug Administration (FDA) approved for promoting skin wound healing is recombinant platelet-derived growth factor (PDGF-BB), but its modest efficacy and expense limit its use clinically. Acute hypoxia induced by the clotting of dermal blood vessels during the wounding of skin is a major stress factor that leads to the re-programming of basal keratinocytes to initiate re-epithelialization. The laterally migrating keratinocytes secrete extracellular heat shock protein 90 alpha. Heat shock protein 90 alpha (hsp90α) engages low-density lipoprotein receptor-related protein-1 (LRP-1) cellular receptors and works as an autocrine factor to stimulate keratinocyte migration (re-epithelialization) and as a paracrine factor to stimulate the migration of dermal fibroblasts (fibroplasia) and microvascular endothelial cells (neo-vascularization). Hypoxia-triggered extracellular heat shock protein 90 alpha acts as the master regulator of initial skin wound healing. It is not yet known how the engagement of hsp90α with the LRP-1 receptor leads to increased motility of keratinocytes, fibroblasts, or microvascular endothelial cells. Understanding the sequence of how an acute skin wound via hypoxic stress leads to cellular events that ultimately induce accelerated wound closure provides numerous targets for new wound-healing therapeutic agents. Developing data for an investigational new drug (IND) application to the FDA for a Phase I study using hsp90α in human skin wounds. Identifying the cellular signaling mechanisms by which hsp90α enhances skin cell migration, leading to accelerated wound closure.
皮肤伤口患者的治疗和护理是一项重大的医疗保健支出。烧伤创面、医源性手术伤口、静脉淤滞性皮炎溃疡、糖尿病下肢溃疡、压疮以及周围神经病变导致的皮肤伤口，目前大多仅采用支持性护理进行治疗。尽管对使用生长因子作为治疗药物进行了大量研究，但迄今为止，该领域的进展并不理想。唯一获得美国食品药品监督管理局（FDA）批准用于促进皮肤伤口愈合的生物制剂是重组血小板衍生生长因子（PDGF - BB），但其疗效一般且费用高昂，限制了其临床应用。皮肤受伤时真皮血管凝血所诱导的急性缺氧是一个主要应激因素，它会导致基底角质形成细胞重新编程，从而启动再上皮化过程。横向迁移的角质形成细胞会分泌细胞外热休克蛋白90α。热休克蛋白90α（hsp90α）与低密度脂蛋白受体相关蛋白1（LRP - 1）细胞受体结合，作为自分泌因子刺激角质形成细胞迁移（再上皮化），并作为旁分泌因子刺激真皮成纤维细胞迁移（纤维增生）和微血管内皮细胞迁移（新生血管形成）。缺氧触发的细胞外热休克蛋白90α是皮肤伤口初期愈合的主要调节因子。目前尚不清楚hsp90α与LRP - 1受体的结合如何导致角质形成细胞、成纤维细胞或微血管内皮细胞的运动性增加。了解急性皮肤伤口通过缺氧应激导致细胞事件最终促使伤口加速愈合的过程，可为新型伤口愈合治疗药物提供众多靶点。正在为一项使用hsp90α治疗人类皮肤伤口的I期研究向FDA提交研究性新药（IND）申请收集数据。确定hsp90α增强皮肤细胞迁移从而加速伤口愈合的细胞信号传导机制。
