Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing

Abstract

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)

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

“…Lactate enhances a remarkable set of actions that could be causally linked to its ability to induce the formation of reactive oxygen species. Elevated lactate induces: (i) HIF-1α stabilization, (ii) VEGF and TGFβ (41), (iii) metalloproteinases (25), (iv) endothelial cell mobility (5), (v) vascularization (current data), (vi) increased collagen synthesis, and its post translational modification and deposition (13,41), (vii) cell proliferation (43), (viii) transcription of genes for proteoglycans, CD44, caveolin-1, Hyal-1 and -2 (11), and (ix) an environment suitable for the recruitment of progenitor cells (current data).…”

“…Hydrolysis of the said lactide polymer in water, however, released lactate ion that slightly increases pH because of it's association with protons in water. When the lactate polymer was placed in wounds in which extracellular fluid could be collected, the level of lactate monomer rose to a concentration relevant to wounds (4-12 mM in mice, (41)), and no pH change was detected (41). To test whether surface characteristics of the lactide polymer might be inflammatory and hence might stimulate endogenous lactate production, we tested the effects of a larger polymer poly(Llactide) (mol wt 85,000-160,000; Cat#P1566, Sigma, MO).…”

“…However, sustained periods of equally severe hypoxia limit neovascularization (17), proliferation of dermal cells (28), collagen deposition (33), bacterial killing and resistance to infection (3), and more severe hypoxia causes tissue death and dysfunction (33). On the other hand, supplemental O 2, in vivo accelerates wound vessel growth (12,16,17), collagen deposition (34,41) and angiogenesis (12). Intermittent hyperbaric oxygen stimulates vessel growth (17), accelerates the proliferation of granulation tissue (23,24), and facilitates epithelial healing (34).…”

“…It is well demonstrated that hypoxia and/or dysoxia are master controllers of the signals that drive new vessel formation (37). Lactate, on the other hand is also a known instigator of cytokines and growth factors such as VEGF, TGF-β, and IL-1 (10,41). Lactate stabilizes HIF-1α even in the presence of oxygen because lactate and pyruvate bind to and inhibit the HIF prolyl hydroxylases that would otherwise hydroxylate HIF-1α and mark it for rapid degradation (21,22).…”

Metabolomics in the Analysis of Inflammatory Diseases

“…It also induces the upregulation of lactate dehydrogenase A, therefore promoting the conversion of pyruvate (produced during glycolysis) to lactate (Wheaton & Chandel, 2011). Lactate has been detected in many chronic inflammatory conditions such as in inflamed joints (Chang & Wei, 2011, Treuhaft & McCarty, 1971, multiple sclerosis , pulmonary inflammation (Serkova et al, 2008) and is thought to play a role in wound healing (Trabold et al, 2003). Conversely, the acidosis associated with increasing lactate concentrations is thought to play a pathogenic role in cell transformation and autoantigen development in some inflammatory environments (Chang & Wei, 2011).…”