MECHANISMS AND CONSEQUENCES OF CELL ACTIVATION IN THE MICROCIRCULATION

Cells undergo activation in response to a wide range of stimuli. In va scular cells (leukocytes, endothelial cells, and platelets), the diffe rent forms of activation include degranulation, oxygen free radical fo rmation, expression of membrane adhesion proteins, and biophysical cha nges such as pseudopod formation and increased cytoplasmic viscosity. Cell activation and low flow are common features of many cardiovascula r diseases. There is evidence that plasma from patients contains an ac tivating factor for neutrophils as well as other vascular cells. Activ ated neutrophils have the ability to impair microcirculatory transit b y elevation of endothelial permeability, leukocyte adhesion to the end othelium, leukocyte capillary plugging, release of vasoactive products , and capillary deformation and compression due to oxygen-radical-medi ated interstitial edema and cell dysfunction. In addition to reduced o rgan perfusion, cell activation can also cause cell dysfunction via re lease of cytotoxic mediators. A lower degree of neutrophil activation prior to acute circulatory challenge (i.e., low preactivation) correla tes with improved survival rates after challenge and suggests that ele vated levels of in vivo cell preactivation is a risk factor for cell i njury and organ failure. Under conditions of low in-vivo cell preactiv ation (e.g., as is the case in endotoxin-tolerant animals), there is r educed tissue injury and lower mortality after challenge. We hypothesi ze that in-vivo cell preactivation due to everyday activity (infection , diet, smoking) may be a mechanism for microvascular low blood flow w ith leukocyte accumulation and may represent a risk factor for various cardiovascular diseases.