LEUKOCYTE-ENDOTHELIAL INTERACTIONS VIA ICAM-1 ARE DETRIMENTAL IN POLYMICROBIAL SEPSIS

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Abstract
Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the transmigration of polymorphonuclear neutrophils (PMN) in sepsis. Moreover, the transmigration rate of leukocytes from the blood via endothelial adhesion molecules into tissues correlates with the severity of multi organ failure. We examined the effect of the deletion of the ICAM-1 gene in polymicrobial sepsis using a cecal ligation and puncture (CLP) sepsis model in mice. Twenty male ICAM-1 knockout (KO) mice and 20 wild-type (WT) male C57BL/6 mice were studied. CLP was performed. At several time points during a 96-hour postoperative observation period, we measured mortality, body weight, and temperature. The delayed type of hypersensitivity (DTH) reaction was determined by pinna swelling after sensitization with 50 μL of dinitrofluorobenzene (DNFB) 1%. Lymphocyte subpopulations (CD4+, CD8+, and CD56+) and cytokines [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10)] were measured using flow cytometry and ELISA testing, respectively. Also, a histologic examination of the liver and lung was performed. CLP-induced mortality was lower in the ICAM-1 −/− group compared to normal mice (5% vs 45.0%). So were the ratios of lymphocyte subpopulations in the KO versus the WT group [CD4+: 16.4 ± 1.6% vs 25.7 ± 4.7%; CD8+: 18.3 ± 1.4% vs 34.9 ± 2.9%; natural killer (NK) cells: 5.6 ± 0.3% vs 49.5 ± 0.7%; P < 0.01]. And also the cytokine blood levels of the KO mice were significantly lower versus the WT mice (TNF-α: 67.2 ± 42.2 vs 823.9 ± 170.5 pg/mL; IL-1β: 5.9 ± 0.9 vs 296.2 ± 66.2 pg/mL; IL-6: 223.1 ± 48.8 vs 3062.5 ± 1222.8 pg/mL; IL-10: 34.6 ± 5.8 vs 1565.6 ± 448.8 pg/mL; P < 0.01). With respect to the histology, significantly less leukocyte invasion and organ damage (eg, hydropic degeneration) were present in the ICAM-1 −/− group compared to controls in liver and lung tissues. The DTH reaction was significantly decreased in ICAM-1 −/− mice versus WT mice (0.34 vs 0.41 mm; P < 0.05). Our results demonstrate a significant reduction of mortality after septic challenge in ICAM-1 −/− mice compared to normal mice. This is associated with a decrease in lymphocyte subpopulations, cytokine levels, and DTH type 4 reaction, possibly reflecting an overall attenuation of the immune system.