Interpretation of Data from Existing Studies

Endothelial adhesion is a normal physiological activity of neutrophils and monocytes. During venous hypertension the fall in blood flow to the lower limb and increase in diameter of capillaries result in a fall in the shear rate in cutaneous capillaries. This favors leukocyte adhesion, which may be observed, even in control subjects, but is of greater magnitude in patients with venous disease, presumably due to the modifications that take place in the endothelium in chronic venous disease.

It has been found that leukocyte-endothelial interaction occurs during short-term venous hypertension (within 30 minutes) and that during this period neutrophil degranulation may be detected, releasing primary and secondary granule enzymes into the region of the endothelium. At the same time an increase in von Willebrand factor and soluble endothelial adhesion molecules can be found in the leg blood. These arguments apply to control subjects as well as to patients, although the magnitude of change is always greater in the patients rather than the control subjects. The research shows that when the venous system becomes deranged, endothelial injury may be the result. Activated leukocytes leave the lower limbs of control subjects following venous hypertension. In patients with venous disease, these cells appear to remain in the lower limb, perhaps attached to the abnormal endothelium.

The chronic changes seen in liposclerotic skin may be the response to sustained, low-grade injury to the endothelium by neutrophils and monocytes over many months or years. The perivascular infiltration of vessels in the papillary dermis by macrophages and T-lymphocytes may simply be a tissue response to the chronic inflammatory processes referred to earlier (see Figure 6.8). Endothelial activation is seen during this phase with increased expression of endo-thelial adhesion molecules. This would favor the adhesion of further leukocytes encouraging this process to continue.

The chronic inflammatory process results in the release of cytokines, which encourage vascular proliferation. VEGF has been shown to be involved in this process. Whether this is simply an associated phenomenon or crucial to subsequent ulceration remains unclear at present. Extensive skin fibro-sis, which is part of the clinical syndrome of lipoder-matosclerosis, is a feature of chronic venous disease. The macrophages present in the perivascular inflammatory process release TGFp, and this in turn stimulates fibroblasts to synthesize more collagen and connective tissue proteins.

The progression from the chronic skin damage to actual ulceration remains difficult to understand. A possible explanation is that an initiating stimulus causes massive activation of the peri-vascular macrophages, resulting in extensive tissue and blood vessel destruction. This might occur spontaneously or minor trauma to the region may set in motion the series of events that lead to ulcer formation.

"Ü u u u ir-j^pj-i Ü u ö T loon ity^j^i ü ü y t

"Ü u u u ir-j^pj-i Ü u ö T loon ity^j^i ü ü y t

Capillary lumen

■Increased adhesion molecule expression

-D—Ü- Jj-X-fUl_ll.--ll-d^1^- Q n H-J.-Endothelial cell

-D—Ü- Jj-X-fUl_ll.--ll-d^1^- Q n H-J.-Endothelial cell

Fibrosis

MMPs

Vascular proliferation

Fibroblast

FIGURE 6.8 Diagrammatic summary of findings from many investigations in skin capillaries in patients with chronic venous disease. The capillaries comprise endothelial cells showing activation. The vessels are surrounded by an inflammatory cuff with a cellular infiltrate, which includes macrophages. These and other cell types release a range of cytokines that, among other things, produce vascular proliferation and skin fibrosis.

Fibrosis

MMPs

Vascular proliferation

Fibroblast

FIGURE 6.8 Diagrammatic summary of findings from many investigations in skin capillaries in patients with chronic venous disease. The capillaries comprise endothelial cells showing activation. The vessels are surrounded by an inflammatory cuff with a cellular infiltrate, which includes macrophages. These and other cell types release a range of cytokines that, among other things, produce vascular proliferation and skin fibrosis.

The data collected in the studies of neutrophil, monocyte, and endothelial cell activity have so far failed to identify major differences between those patients who develop skin changes and are at risk of ulceration and those who do not. Inflammatory mechanisms are very complex and identifying those which predispose to the development of skin changes and ulceration will be a complex task.

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