Endotoxin infusion in anesthetized sheep is associated with intrapulmonary sequestration of leukocytes that immunohistochemically express tumor necrosis factor-α

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Abstract
Plasma levels of tumor necrosis factor-α (TNF-α) peak between 2 and 4 h during a 12-h continuous infusion of endotoxin in awake sheep. We hypothesized that a source of this TNF-α is the pool of leukocytes that accumulate in the pulmonary circulation. To test this hypothesis, we physiologically monitored six anesthetized sheep during baseline and 4-h endotoxin infusion periods (10 ng/kg min). We obtained open-lung biopsies at baseline and at 20 min and 2 and 4 h during the endotoxin infusion period for immunohistochemical localization of TNF-α. The plasma concentration of TNF-α increased from an average baseline concentration of 0.06 ± 0.03 ng/ml (mean ± SD) to a peak of 1.40 ± 0.28 ng/ml at 2 h of the endotoxin infusion. We observed increased cytoplasmic TNF-α immunoreactivity in situ among neutrophils and intravascular mononuclear phagocytes during the endotoxin infusion compared with baseline. Also, the number of immunopositive leukocytes increased in the pulmonary circulation during the continuous infusion of endotoxin. We conclude that TNF-α-producing leukocytes accumulate in the pulmonary circulation during endotoxemia. These cells probably contribute to both the rise in the circulating levels of TNF-α and the development of acute lung injury. J. Leukoc. Biol. 57: 820–826; 1995.

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