Role of interleukin-1 in endotoxin-induced lung injury in the rat

The effects of the recombinant interleukin-1 receptor antagonist (rIL-1ra) on the systemic vascular and lung injury following intraperitoneal Salmonella enteritidis lipopolysaccharide (LPS) were determined in male Sprague-Dawley rats. Initial experiments identified that maximal mortality occurred with an intraperitoneal LPS dose of 20 mg/kg, and this dose was used in subsequent experiments. Albumin permeability, measured in an ex vivo perfused heart-lung preparation from the rats 2 h after 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 micrograms/kg/min resulted in restoration of blood pressure at 100 min following endotoxin administration. Moreover, coadministration of rIL-1ra with endotoxin totally prevented the rise in albumin permeability of the pulmonary vasculature and the increase in wet:dry lung weight ratios observed in rats treated with LPS alone. LPS injected intraperitoneally caused a marked decrease in circulating leukocyte count, an effect not reversed by rIL-1ra. RNA extraction of whole-lung homogenates revealed that mRNA for IL-1 beta 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 (MIP-2), a potent neutrophil chemoattractant, were also observed from 0.5 until 2 h after endotoxin administration.(ABSTRACT TRUNCATED AT 250 WORDS)