Wound Environment

During wound healing new capillaries are stimulated to migrate towards the hypoxic and acidotic area at the wound edge. Cells in the advancing wound edge produce lactate, growth factors and chemotactic stimuli that diffuse back toward the developing vasculature. Wound angiogenesis needs stromal support. On the other hand, fibroblasts which supply the stromal support require nutrients to make collagen, fibronectin, and proteoclycans. The wound architecture is partly controlled by the energy needs of the wound cells. In the wound environment a delicate interaction exists between the inflammatory cells, new capillaries and fibroblasts.2-4

Migration of reparative cells towards the wound edge occurs along steep concentration gradients. Gradients of oxygen, carbon dioxide, pH, lactate, and glucose have been measured. Measurements of oxygen tension gradients by means of ultramicro electrodes in a rabbit ear chamber model demonstrate that PO2, which is of the order of 60-90 mmHg over the most distal capillary at the wound edge, decreases to near zero at the zone of macrophages, leukocytes and the central dead space. In the area of dividing fibroblasts, which is almost confined to the leading capillary zone, the PO2 is in the region of 30-80 mmHg. Almost no cell division can be found where oxygen tension is consistently below 20 mmHg. Maximum synthetic and crosslinking activity of collagen takes place in a zone in which the PO2 is 20-60 mmHg and where the oxygen diffusion gradients are less steep than those at the wound edge.2,5

Growth-promoting substances are present in the wound environment. Transforming growth factor a (TGF-a), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), leukocyte-derived growth factor (LDGF) and insulin-like growth factor (IGF-1) as well as interleukins 1, 6, and 8 (IL-1,6,8) have been found there. The presence of these substances in the wound environment can be contributed by blood circulation, but it is generally agreed that most are synthesized or released locally.1

Several growth factors and interleukins are elicited by exposing wound cells to hypoxia. Thus, it is reasonable to hypothesize that low oxygen tensions could play a role as an early stimulus for tissue repair/angiogenesis. As a result of this observation, there has been interest in the impact of low oxygen tension on growth factor synthesis and gene activation in general.6

Another look at wound environment discloses that a surrogate or equivalent of hypoxia, high lactate concentrations, is also a constant feature. Lactate levels in the range of as high as 5-20 mmol/l are characteristic in human and animal wounds,7-9 and these levels remain high even when the oxygen tension increases in the wound tissue. Further studies have shown that lactate is in fact one of the driving forces of repair, and that the effects of lactate in many ways duplicate those of hypoxia and are even more powerful.1

Conventional thought dictates that lactate must accumulate because of hypoxia, but in wounds this is only partially the case. In wounds the major portion of lactate load is contributed by leukocytes, which derive the great majority of their energy from glycolysis even in the presence of oxygen with the end product of their energy metabolism being lactate. Lactate accumulation is therefore relatively insensitive to changes in oxygen tension in wounds. Lactate, in common with oxygen, excites many cells to release growth factors and cytokines such as TGF-a, VEGF, and IL-1 and 8, and can excite their production in the presence of oxygen. Furthermore, lactate alone can stimulate and govern collagen synthesis and angiogenesis, two of the major components of wound healing.10,11 Hypoxia does not share this property and in fact has the opposite effect.1,6

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