SYNERGISM OF INTRATRACHEALLY ADMINISTERED TUMOR-NECROSIS-FACTOR WITH INTERLEUKIN-1 IN THE INDUCTION OF LUNG EDEMA IN RATS

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 necro sis factor (TNF) enhanced lung injury induced by intrapulmonary admini stration of low-dose IL-1. Rats were divided into five groups and trea ted with IT instillation of saline (0.1 ml) containing (1) no addition al compound (controls), (2) human recombinant IL-1 (10 ng), (3) human recombinant TNF (2 mu g), (4) IL-1 + TNF (10 ng + 2 mu g), or (5) lipo polysaccharide (LPS, 10 mu g). At 3, 6, 24, and 48 hours after treatme nt, we counted neutrophils recovered by bronchoalveolar lavage (BAL), assessed TNF activity in BAL fluid, and measured lung wet:dry weight r atio. At 3 and 6 hours after treatment, we measured levels of the lipi d peroxide derivative malondialdehyde (MDA) in lung homogenates. IT in stillation of LPS, IL-1, or IL-1 + TNF rapidly increased BAL neutrophi l recovery, whereas recovery was not increased by TNF alone. TNF activ ity in BAL fluid was markedly increased by LPS, TNF, and IL-1 + TNF, w ith a smaller increase induced by IL-1. Instillation of TNF or IL-1 al one at these doses did not increase the lung wet:dry ratio. IT adminis tration 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), Lung MDA content was not increased after instillation of II-I alone, but it was increased 6 hours after instillation of IL-1 + TNF (p < 0.0 5). These findings indicate that increased alveolar concentrations of TNF in rats enhance oxidant stress and the development of lung edema a ssociated with intrapulmonary administration of IL-1.