Trigger Mechanisms For Cell Activation

There are a large number of primary mechanisms that may serve to activate cells and stimulate an inflammatory cascade in the circulation. It is helpful to classify these mechanisms into several general categories:

a) Positive feedback mechanisms: There exists a class of inflammatory reactions that are mediated by direct action of plasma inflammatory stimulators (oxygen free radicals,82 platelet activating factor (PAF),83 cytokines (e.g., TNF-a, IL-1, IL-8),84 complement fragments,85 endotoxins, coagulation and fibrinolytic factors, leukotrienes, thrombin, and oxidized LDL). The list of inflammatory mediators is long, and may in part be triggered by trauma or by bacterial, viral, or fungal sources.

b) Negative feedback mechanisms: An alternative pathway for cell upregulation in the microcirculation is by depletion of anti-inflammatory factors. This list is somewhat shorter and includes nitric oxide, adenosine, glucocorticoids, selected cytokines (e.g., IL-10),86 estrogen,87 and some proteins like albumin.

c) Contact activation: A specialized form of cell activation by membrane contact has been proposed in the form of juxtacrine activation.88 A nonactivated endothelial cell may be stimulated during membrane contact by an activated leukocyte and vice versa, for example, by oxygen free radical production in the membrane contact region between the cells and by formation of platelet activating factor (PAF) and other bioactive lipids.

d) Activation by mechanotransduction: These mechanisms for cell activation involve fluid shear stress (force per unit area parallel to a surface) and normal stress (for per unit area normal to a surface, i.e., pressure). These two mechanical stresses likely play an important role in venous disease (see later).

e) Activation by physical transients: Transients of gas concentrations (like oxygen, carbon dioxide, etc.) or also temperature transients have the ability to stimulate cell activation irrespective of the direction of the transient (up or down) but dependent on the magnitude of the transient.89-93

f) Activation by hormonal pathways: Candidates are progesterone, insulin, and others94-98 but their action depends on cofactors.

g) Genetic mechanisms: There may be a large number, some associated with single nucleotide perturbations (SNPs), defects in transcription, and even lack of gene expression, expression of spice variants, to protein folding.

FIGURE 7.3 The plasma of (nonsmoking) patients with chronic venous disease contains an inflammatory mediator. Fraction of neutrophil activation as detected by nitroblue tetrazolium reduction to zymogen granules (left panel, red arrow) and by pseudopod projection (right panel, black arrow). Naïve leukocytes (NL) from healthy donors mixed with patient plasma has significantly higher activated neutrophil counts than either patient blood cells, healthy control cells, or patient neutrophils mixed with plasma of healthy controls. Adaped from (6). The cause of this activation is an important unresolved question in CVD.

FIGURE 7.3 The plasma of (nonsmoking) patients with chronic venous disease contains an inflammatory mediator. Fraction of neutrophil activation as detected by nitroblue tetrazolium reduction to zymogen granules (left panel, red arrow) and by pseudopod projection (right panel, black arrow). Naïve leukocytes (NL) from healthy donors mixed with patient plasma has significantly higher activated neutrophil counts than either patient blood cells, healthy control cells, or patient neutrophils mixed with plasma of healthy controls. Adaped from (6). The cause of this activation is an important unresolved question in CVD.

Over the long periods of time required to develop manifestations of venous disease, it is likely that several—if not all—of these mechanisms may at one time or another stimulate inflammation in the circulation. The challenge is to identify prevailing mechanisms in chronic venous disease. Clearly, the neutrophils of patients with CVD are activated (see Figure 7.3).

A useful starting point is to look at clinically established risk factors for venous disease.99103 Notable in this respect are hormonal risk factors associated with pregnancy, especially in the first trimester when less effect on venous blood flow is expected, orthostatic exposure associated with a lack of blood pressure reduction due to limb movement, and enhanced body mass index have been cited in many studies. Such risks may well be associated with cell activation and in the following I will elaborate. Definitive studies have yet to be carried out.

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