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Plasmodium berghei-infected mice, a well-recognized model of experimental cerebral malaria (ECM), exhibit a systemic inflammatory response. Most investigators hypothesize that leukocytes bind to endothelial cells via intercellular adhesion molecule 1 (ICAM-1), which causes endothelial damage, increased microvascular permeability, and, ultimately, death. ICAM-1-deficient mice on an ECM-susceptible C57BL/6 background were significantly ( p = .04) protected from P. berghei mortality compared with ICAM-1 intact controls. ICAM-1 expression assessed by the dual radiolabeled monoclonal antibody technique was increased in the brain and lung in C57BL/6 mice on day 6 of P. berghei infection compared with uninfected controls (5.3-fold, p = .0003 for brain and 1.8-fold, p = .04 for lung). The increase in ICAM-1 expression coincided with significant ( p < .05) increases in microvascular permeability in the brain and lung. In contrast to the hypothesized role for ICAM-1, in vivo analysis by intravital microscopy of leukocyte rolling and adhesion in brain microvasculature of mice revealed markedly increased levels of leukocyte rolling and adhesion in ICAM-1-deficient mice on day 6 of P. berghei infection compared with uninfected controls. In addition, ICAM-1 expression and microvascular permeability were increased in infected ECM-resistant BALB/c mice compared with uninfected BALB/c controls. These results collectively indicate that although ICAM-1 contributes to the mortality of experimental malaria, it is not sufficient for the development of severe experimental malaria. In addition, ICAM-1 expressed on the endothelium or on leukocytes is not required for leukocyte rolling or adhesion to the brain microvasculature of mice during P. berghei malaria. Leukocyte rolling and adhesion in the brain vasculature during P. berghei malaria use different ligands than observed during inflammation in other vascular beds.

— While there is a growing body of evidence suggesting that hypercholesterolemia prior to the onset of atherosclerosis renders tissues more susceptible to inflammation, the mechanisms that underlie this exaggerated inflammatory response remain poorly defined. The overall objective of this study was to assess the influence of hypercholesterolemia on endotoxin-induced endothelial cell adhesion molecule (CAM) expression in different vascular beds. Another objective was to determine whether the altered endothelial CAM expression in hypercholesterolemic animals is associated with a corresponding change in plasma cytokine levels. Male Sprague/Dawley rats (SD) were placed either on a normal (control) or high cholesterol (HC) diet for 3 weeks. The dual radiolabeled monoclonal antibody (mAb) technique was used to measure the expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 in different vascular beds after intraperitoneal injection of endotoxin (LPS) derived from Salmonella abortus equi. LPS induced a significant increase in the expression of all endothelial CAMs in both normocholesterolemic and hypercholesterolemic groups. However, hypercholesterolemia enhanced LPS-induced expression of P-selectin, E-selectin, and ICAM-1 in several vascular beds, while VCAM-1 expression was unaffected. Thrombocytopenia, induced with anti-platelet serum, did not alter LPS-induced P-selectin expression in either group, suggesting that platelets do not contribute to this response. Hypercholesterolemia was associated with an exaggerated increase in plasma TNF-α, but not IL-1β, after LPS treatment. These results indicate that hypercholesterolemia in rats may render tissues more vulnerable to the inflammatory effects of LPS by enhancing the expression of certain endothelial CAMs.