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Up‐regulated lactate, TGF‐β and collagen synthesis in the ischaemic skin of patients with peripheral vascular disease
Author(s) -
Dalton S.J,
Whiting C.V,
Mitchell D.C.,
Tarlton J.F.
Publication year - 2004
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/j.0959-9673.2004.369al.x
Subject(s) - medicine , ischemia , pathology , endocrinology
We have previously shown that dermal hypoxia alters collagen turnover in chronically ischaemic skin; however, no mechanism for this has been determined. In cultured human dermal fibroblasts, hypoxia causes an up‐regulation of collagen synthesis, probably mediated by TGF‐β (Falanga et al . 2002) in the presence of increased lactate. Here, we examine whether these processes are present in vivo in chronically ischaemic skin. Materials and methods Paired biopsies of uninjured skin were harvested at below knee amputation from 16 patients with a history of peripheral vascular disease (PVD), following the quantification of ischaemia, using the ankle brachial pressure index (ABPI) and by lactate measurement. Nonischaemic samples were taken proximally from the amputation resection margin and ischaemic samples from a predetermined distal site. Site‐matched biopsies were taken for control at total knee replacement and varicose vein operations. Lactate levels were measured using enzymatic determination (Sigma, UK), collagen type‐I synthesis was determined by immunoassay for released C‐terminal propeptide (PICP) (Prolagen C, Quidel) and TGF‐β by ELISA. TGF‐β RI and RII were localized using immunohistochemistry. Results The ABPI in all patients with PVD was <0.4 indicating severe ischaemia. Levels of lactate were elevated in the ischaemic tissue of these patients when compared to nonischaemic samples ( P < 0.001), and an up‐regulation of collagen type‐I synthesis was demonstrated in the ischaemic samples ( P < 0.01). Levels of TGF‐β were also raised ( P < 0.05). TGF‐β RI and RII were expressed on dermal fibroblasts, keratinocytes and endothelial cells. Discussion Increased lactate levels resulting from hypoxic metabolism have been demonstrated in skin flaps of animal models (Hoopes & Im 1978); however, lactate levels in human tissue, as a direct assessment of chronic ischaemia, have not previously been reported. Hypoxia, lactate and TGF‐β have been shown to stimulate collagen synthesis in vitro (Falanga et al . 2002; Cerbon‐Ambriz et al . 1991) but not in vivo in PVD. These findings are consistent with the hypothesis that chronic hypoxia leads to changes in the ECM of uninjured but ischaemic skin and may predispose it to dermal failure.