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The present study tested this hypothesis by evaluating the effect of TNF-\u03b1 inhibition on IL-2\u2013induced lung injury in the rat. Recombinant human IL-2 (10<jats:sup>6<\/jats:sup>U IV per rat, n=6) elevated lung water, myeloperoxidase activity, and protein accumulation in bronchoalveolar lavage fluid and induced tissue hypoxia. Also, IL-2 enhanced lung tissue TNF-\u03b1 mRNA and peptide (1543\u00b1496 pg\/g lung wet weight) localized to alveolar macrophages by in situ hybridization. In marked contrast, IL-2 failed to affect serum TNF-\u03b1, which remained at undetectable levels. Pretreatment with anti\u2013TNF-\u03b1 monoclonal antibody (25 mg\/kg IV, n=7) or the TNF-\u03b1 synthesis inhibitor rolipram (200 \u03bcg\/kg IV, n=7) attenuated lung injury and reverted tissue hypoxia. Furthermore, TNF-\u03b1 inhibition prevented the upregulation of lung tissue IL-1\u03b2, IL-6, cytokine-induced neutrophil chemoattractant, and E-selectin (ELAM-1) but not intercellular adhesion molecule-1 mRNAs in response to IL-2. These data imply that locally produced TNF-\u03b1 mediates IL-2\u2013induced lung inflammation and tissue injury and point to the potential utilization of TNF-\u03b1 inhibitors in treating the pulmonary toxicity of IL-2 immunotherapy.<\/jats:p>","DOI":"10.1161\/01.res.78.2.329","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:47:05Z","timestamp":1339462025000},"page":"329-336","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["Locally Produced Tumor Necrosis Factor-\u03b1 Mediates Interleukin-2Induced Lung Injury"],"prefix":"10.1161","volume":"78","author":[{"given":"R.","family":"Rabinovici","sequence":"first","affiliation":[{"name":"From the Departments of Surgery (R.R., F.A., M.W., P.B., E.S., D.-R.P., P.O., L.F.N.) and Medicine (L.B., O.B.), Jefferson Medical College, Philadelphia, Pa, and SmithKline Beecham (G.F.), King of Prussia, 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