The objective of this study was to investigate mechanisms by which polymorphonuclear neutrophils (PMNs) contribute to the tolerance induced by repeated lipopolysaccharide (LPS) injections. Tolerance was developed by daily intraperitoneal injections of sublethal doses of LPS for 4 days (LPS-tolerant group); controls were not pretreated (LPS-control group). Both groups were challenged with 9 mg/kg i.v. Escherichia coli LPS, a dose that resulted in 25% survival in LPS-control rats compared with 100% survival in LPS-tolerant rats. LPS injection caused an initial neutropenia in both groups. The neutropenia persisted throughout the experiment in LPS-control rats, whereas in LPS-tolerant rats the circulating PMN count increased dramatically; after 6 hours, the PMN count was 16-fold higher than that in LPS-control rats. Activation of circulating PMNs, PMN adhesion to nylon fibers, and tumor necrosis factor/cachectin activity were all increased in control rats given LPS. In contrast, LPS-tolerant rats had low activation of circulating PMNs, no trend for PMN adhesion to nylon fibers, and markedly reduced tumor necrosis factor activity. To determine whether neutropenia was associated with a trapping of PMNs in the microcirculation, we used a carbon perfusion technique 6 hours after LPS injection and examined histological sections of the myocardium. All of the arterioles and venules in both groups contained carbon; only capillaries showed evidence of obstruction. A significantly higher percentage of obstructed capillaries was observed in LPS-control rats than in LPS-tolerant rats. Obstruction of capillaries was consistently associated with trapped leukocytes. We conclude that PMN cytotoxicity induced by LPS involves microcirculatory entrapment and activation of PMNs. Repeated LPS pretreatment reduces dramatically circulating PMN activation and adhesion and is associated with an elevated circulating PMN count, a low degree of microvascular plugging, and survival after a normally lethal dose of LPS.
Recent evidence shows that circulating granulocytes play an important role in capillary stasis and tissue injury. We investigated two aspects of the problem in a Wiggers hemorrhagic shock model of the rat: the survival rate and the microvascular no-reflow phenomenon. A conventional group of rats with normal blood cells and a neutropenic group of rats pretreated with intraperitoneal antigranulocyte antibody were used to evaluate the effects of granulocytes. Two hemorrhagic shock protocols (HSP) were carried out. In HSP-1, the rats were subjected to 40 mm Hg mean arterial pressure for 3 hours. The conventional group (n = l l ) showed a 36% survival rate compared with 100% in the neutropenic group (« = 6). In HSP-2, the hypotension was more severe, 30 mm Hg mean arterial pressure for 7 hours. There were no survivors in the conventional group (n = 8), compared with a 100% survival rate in the neutropenic group (n = 6). The extent, location, and mechanism of the no-reflow phenomenon was investigated by examining histological sections from several organs after infusion of a contrast medium to mark vessels with flow in a control group without shock and in the HSP-2 model 2 hours after blood replacement. The arterioles and venules uniformly contained contrast medium in all three groups; only capillaries showed no-reflow. A significantly higher percentage of no-reflow was observed in the capillaries of the conventional shock group than in the neutropenic shock group. We concluded that the obstruction of capillaries was largely due to trapped granulocytes, suggesting that these leukocytes play a key role in the capillary no-reflow phenomenon and survival from hemorrhagic shock. (Circulation Research 1988;63:437-447)
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