Abstract
The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlierin vitro. The Transforming Growth Factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds.
Highlights
Impaired wound healing represents a significant clinical problem in elderly
Pathogenesis of chronic wounds caused by diabetes mellitus, malnutrition, immunodeficiency, and aging is characterized by a prolonged self-sustaining inflammatory response, a defective fibroblast-dependent extracellular matrix (ECM) formation, and a failure of neovascularization and reepithelialization [1]
Granulation tissue of SkQ1-treated mice contained increased amount of fibroblast-like cells expressing smooth muscle α-actin (α-SMA), (Fig. 3). These cells referred to myofibroblasts produce more collagen, other extracellular matrix proteins and growth factors involved in granulation tissue formation and angiogenesis in wounds [35]
Summary
Impaired wound healing represents a significant clinical problem in elderly. Pathogenesis of chronic wounds caused by diabetes mellitus, malnutrition, immunodeficiency, and aging is characterized by a prolonged self-sustaining inflammatory response, a defective fibroblast-dependent extracellular matrix (ECM) formation, and a failure of neovascularization and reepithelialization [1]. One of the common factors underlying compromised wound healing is excessive oxidative stress [2]. The leukocyte NADPH oxidase (Nox) is one of the major sources of ROS involved in pathogen killing [3], vascular endothelial growth factor (VEGF) signaling [4, 5], and TNF response [6]. Emerging evidence suggests that mitochondrial ROS (mtROS) are important at various phases of the wound healing process. It was reported that mtROS promoted actin-based closure of epithelial wounds in Caenorhabditis elegans [7].
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