Mechanisms of Chronic Skin Ulceration Linking Lactate, Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Collagen Remodeling, Collagen Stability, and Defective Angiogenesis

Abstract

Up to one million people suffer from chronic skin ulcers in the US. Little is known of the mechanisms leading to tissue breakdown, although inadequate circulation and ischemia are common elements in most dermal ulcers. Collagen is the principal source of mechanical strength in most tissues, and its molecular and fibrillar stability is dependent on adequate oxygen supply. In wound repair, localized ischemia leads to fibrogenic responses culminating in elevated collagen synthesis and remodeling. This study examines factors influencing collagen turnover and stabilization before ulceration in "at risk" patients. Severely ischemic but uninjured ischemic skin (IS) was compared with patient- and site-matched non-ischemic skin. Biochemical mechanisms of tissue repair were activated in IS, with increased lactate, transforming growth factor-beta, vascular endothelial growth factor, collagen synthesis and matrix metalloproteinases (MMPs)-1 and 2. The absence of MMP-9 and inflammatory cells confirmed that this upregulation was inappropriate and not in response to injury. Molecular stability of collagen was reduced in IS, and there was increased susceptibility to enzymic degradation. In conclusion, chronic ischemia and long-term hypoxia result in elevated collagen remodeling in an oxygen-poor environment. Unstable collagen molecules are synthesized together with upregulated MMPs, resulting in collagen denaturation, defective angiogenesis, weaker skin, and predisposition to ulceration.

Wound Healing Angiogenesis: Innovations and Challenges in Acute and Chronic Wound Healing

“…A recent study of comparative proteomics of acute and chronic wounds using this approach 7 has demonstrated that the nonhealing ulcers have decreased amount of several extracellular matrix components, namely, heparan sulfate proteoglycan and collagen type I, both of which are critical for normal wound revascularization. 21,22 Moreover, this study confirms a previously established and significant increase in production of multiple proteases, which are detrimental for both wound extracellular matrix components and proangiogenic growth factors. 23 In addition, it identifies species that are exclusively present in acute healing, such as the serine protease thrombin and the antimicrobial dermicidin.…”

Computational Approaches to Solving Equations Arising from Wound Healing

“…16). The keratinized layer is a wellknown source of chemoattractant during the wound healing process (Dalton et al, 2007;Desmouliére et al, 2003;Moore et al, 1997).…”

Topical Oxygen Emulsion

“…1,2 Recent research has demonstrated that increasedoxygentensioninawoundpromotes wound healing by stimulating several processes, including phagocytosis (engulfing of microorganisms, cells, or debris by macrophages or neutrophils), 3 degradation of necrotic wound tissue, 4 collagen production, [5][6][7] neovascularization, 8,9 and neutrophil-mediated oxidative microbial killing. 10 Many different treatment modalities have been attempted to increase local oxygen supply to wounds to accelerate repair.…”