Mechanisms of chronic skin ulceration linking lactate, transforming growth factor-beta, vascular endothelial growth factor, collagen remodeling, collagen stability, and defective angiogenesis.
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.
Dalton
Stephen John
SJ
Department of Vascular Surgery, Southmead Hospital, Bristol, UK.
Whiting
Christine Vivienne
CV
Bailey
Jennifer Ruth
JR
Mitchell
David Charles
DC
Tarlton
John Francis
JF
D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D003094:Collagen / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D004198:Disease Susceptibility; D004355:Drug Stability; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007511:Ischemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D007773:Lactates / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply*; D012883:Skin Ulcer / Q000209:etiology*; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D007773:Lactates; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; D040262:Receptors, Vascular Endothelial Growth Factor