Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing.
For many years, lactate has been known to accelerate collagen deposition in cultured fibroblasts and, without detailed explanation, has been presumed to stimulate angiogenesis. Similarly, hypoxia has been linked to angiogenic effects and collagen deposition from cultured cells. Paradoxically, however, wound angiogenesis and collagen deposition are increased by breathing oxygen and decreased by hypoxia. Lactate accumulates to 4-12 mM in wounds for several reasons, only one of which is the result of hypoxia. Oxygen in wounds is usually low but can be increased by breathing oxygen (without change in lactate). We have reported that lactate elicits vascular endothelial growth factor (VECF) from macrophages, as well as collagen, some heat shock proteins, and VECF from endothelial cells, and collagen from fibroblasts, even in the presence of normal amounts of oxygen. Hypoxia exerts many of these same effects in cultured cells. In this study, we elevated extracellular lactate in wounds by implanting purified solid-state, hydrolysable polyglycolide. A steady-state 2-3 mM additional elevation of lactate resulted. With it, there was a significant short-term elevation of interleukin-1beta, a long-term elevation of VECF (2x) and transforming growth factor-beta1 (2-3x), a 50% elevation in collagen deposition, and a large reduction of insulin-like growth factor-1 (- 90%). We propose that lactate induces a biochemical "perception" of hypoxia and instigates several signals that activate growth factor/cytokine signals while the continued presence of molecular oxygen allows endothelial cells and fibroblasts to reproduce and deposit collagen. The data are consistent with ADP-ribosylation effects and oxidant signaling. (WOUND REP REG 2003;11:504-509)
Trabold
Odilo
O
Department of Surgery, University of California, San Francisco, San Francisco, California 94143, USA.
Wagner
Silvia
S
Wicke
Corinna
C
Scheuenstuhl
Heinz
H
Hussain
M Zamirul
MZ
Rosen
Noah
N
Seremetiev
Alan
A
Becker
Horst D
HD
Hunt
Thomas K
TK
D000818:Animals; D005122:Exudates and Transudates / Q000737:chemistry; D006019:Glycolysis / Q000502:physiology; D007773:Lactates / Q000032:analysis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D010100:Oxygen / Q000502:physiology*; D011098:Polyglactin 910 / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D007773:Lactates; D042461:Vascular Endothelial Growth Factor A; D011098:Polyglactin 910; D010100:Oxygen