SpontaneousIn VitroRelease of Alveolar-Macrophage Cytokines after the Intratracheal Instillation of Bleomycin in Rats: Characterization and Kinetic Studies

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Abstract
The intratracheal administration of bleomycin in rats elicits an acute inflammatory response in the lung followed by the development of pulmonary fibrosis. The alveolar macrophage (AM) is a key effector cell involved in this process because of the potential to release a variety of hormone like molecules (cytoknes) that can modulate systemic responses as well as the local response of other lung cells including the interstitial fibroblast. In this report, we have documented the chronology of the in vitro spontaneous release of AM cytokines after a single instillation of bleomycin. We show that supernatants from AM harvested after the administration of bleomycin but not after saline contain lymphocyte-activating factor (interleukin-1) activity. Maximal activity was detected between 6 and 12 h and was barely detectable by Day 7 after bleomycin. In addition, supernatants showing interleukin-1 (IL-1) activity also inhibited the proliferation of log-phase normal rat lung fibroblasts. Fractionation of supernatants from AM harvested 6 h after bleomycin demonstrated that both lymphocyte-activating factor and fibroblast modulatory activity coelute in the same 18-kDa region, suggesting that IL-1 may demonstrate both activities. We also report there the spontaneous release of a second AM cytokine, hepatocyte-stimulating factor, which we have recently shown in humans to be identical to interferon .beta.2 and which initiates the hepatic acute-phase protein response. The release of this 30-kDa cytokine from AM of rats exposed to bleomycin has a different chronology than does IL-1, showing a steady increase over time, with maximal activity at Day 28 after bleomycin. This different chronology cannot be explained on the basis of co-released inhibitors to either one of these cytokines. Finally, we document that supernatants of normal unstimulated AM exposed in vitro to intermediate doses of bleomycin (5 .times. 10-4 to 5 .times. 10-7 mg/ml) contain significant lymphocyte-activating factor activity.

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