ROLE OF INTERLEUKIN-1 IN ENDOTOXIN-INDUCED LUNG INJURY IN THE RAT

The effects of the recombinant interleukin-I receptor antagonist (rIL- 1ra) on the systemic vascular and lung injury following intraperitonea l Salmonella enteritidis lipopolysaccharide (LPS) were determined in m ale Sprague-Dawley rats. Initial experiments identified that maximal m ortality occurred with an intraperitoneal LPS dose of 20 mg/kg, and th is dose was used in subsequent experiments. Albumin permeability, meas ured in an ex vivo perfused heart-lung preparation from the rats 2 h a fter injection of LPS, was increased with endotoxin as was the wet:dry weight ratio. Pretreatment of the rats with intravenous rIL-1ra, 1 to 10 mg/kg, followed by a continuous intravenous infusion at 30 to 50 m ug/kg/min resulted in restoration of blood pressure at 100 min followi ng endotoxin administration. Moreover, coadministration of rIL-1ra wit h endotoxin totally prevented the rise in albumin permeability of the pulmonary vasculature and the increase in wet:dry lung weight ratios o bserved in rats treated with LPS alone. LPS injected intraperitoneally caused a marked decrease in circulating leukocyte count, an effect no t reversed by rIL-1ra. RNA extraction of whole-lung homogenates reveal ed that mRNA for IL-1beta was constitutively expressed in the absence of endotoxin, but transcripts increased progressively from 0.5 to 2 h after endotoxin administration. Increases in mRNAs for tumor necrosis factor-alpha (TNF-alpha) and for macrophage inflammatory protein-2 (MI P-2), a potent neutrophil chemoattractant, were also observed from 0.5 until 2 h after endotoxin administration. These data identify up-regu lation of IL-1beta, TNF-alpha, and MIP-2 in rat lungs after administra tion of endotoxin and suggest an important role for IL-1 in the system ic hypotension and increase in lung leak of albumin and water with end otoxin. However, other systemic effects, such as leukopenia, appear to be unrelated to IL-1, indicating a need for broader examination of th e effects of endotoxin on cytokine production in general.