INVOLVEMENT OF TUMOR-NECROSIS-FACTOR-ALPHA, INTERLEUKIN-1-BETA, INTERLEUKIN-8, AND INTERLEUKIN-1 RECEPTOR ANTAGONIST IN ACUTE LUNG INJURY CAUSED BY LOCAL SHWARTZMAN REACTION

A local Shwartzman reaction (LSR) was prepared in rabbit lung as a mod el of acute lung injury. To induce LSR, intratracheal injection of lip opolysaccharide (LPS) 10 mu g into the lower lobe of the right lung, f ollowed 24 h later by i.v. injection of LPS (10 mu g/kg). In the lung with the LSR, myeloperoxidase activity, representing neutrophil accumu lation, peaked at 1-2 h and was sustained for 48 h after challenge wit h i.v. LPS. The lung water content peaked at 12 h, and decreased gradu ally. Histological findings showed diffuse interstitial widening, intr a-alveolar leukocyte infiltration with hemorrhage, and alveolar exudat e formation. The production of tumor necrosis factor-alpha (TNF-alpha) , interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8), and IL-l recep tor antagonist (IL-1Ra) in the lung was analyzed. TNF-alpha first elev ated and peaked at 0.5 h (66.5 +/- 16.7 ng/g . lung), subsequently, IL -1 beta and IL-8 increased and peaked at 2 h (17.8 +/- 3.4 ng/g . lung and 336.9 +/- 49.6 ng/g . lung, respectively). IL-1Ra was present eve n before the challenge, and the production increased to show a dual pe ak (0.5 h, 1.5 +/- 0.2 mu g/g . lung; and 2 h, 1.6 +/- 0.1 mu g/g . lu ng), and a large concentration of IL-l Ra was sustained for 48 h. Immu nohistochemistry showed that the cellular source of these cytokines wa s alveolar macrophages and infiltrating neutrophils. Thus, disclosing the kinetics of the generation of cytokines led to a better understand ing of their roles, namely TNF-alpha as an initiator, IL-l and IL-8 as amplifier and effector, and IL-l Ra as regulator of the intensity of acute inflammation.