Synergism of intratracheally administered tumor necrosis factor with interleukin-1 in the induction of lung edema in rats

Abstract

Intratracheal (IT) instillation of human recombinant interleukin 1 (IL-1) in rats induces an influx of neutrophils into alveolar structures and a dose-dependent increase in lung vascular permeability. We sought to determine whether increased alveolar concentrations of tumor necrosis factor (TNF) enhanced lung injury induced by intrapulmonary administration of low-dose IL-1. Rats were divided into five groups and treated with IT instillation of saline (0.1 ml) containing (1) no additional compound (controls), (2) human recombinant IL-1 (10 ng), (3) human recombinant TNF (2 micrograms), (4) IL-1 + TNF (10 ng + 2 micrograms), or (5) lipopolysaccharide (LPS, 10 micrograms). At 3, 6, 24, and 48 hours after treatment, we counted neutrophils recovered by bronchoalveolar lavage (BAL), assessed TNF activity in BAL fluid, and measured lung wet:dry weight ratio. At 3 and 6 hours after treatment, we measured levels of the lipid peroxide derivative malondialdehyde (MDA) in lung homogenates. IT instillation of LPS, IL-1, or IL-1 + TNF rapidly increased BAL neutrophil recovery, whereas recovery was not increased by TNF alone. TNF activity in BAL fluid was markedly increased by LPS, TNF, and IL-1 + TNF, with a smaller increase induced by IL-1. Instillation of TNF or IL-1 alone at these doses did not increase the lung wet:dry ratio. IT administration of LPS increased the wet:dry ratio at 6 hours only (p < 0.05), whereas IL-1 + TNF increased this ratio beginning 3 hours (p < 0.01) after treatment with persistent increases through 48 hours (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)