Interleukin (IL)-2-induced microvascular lung injury is an experimental paradigm commonly used to investigate the pathogenesis of the adult respiratory distress syndrome. Since tumor necrosis factor-alpha (TNF-alpha) is known to induce such an injury in vivo and since TNF-alpha is involved in other models of lung injury, we postulated that it might also mediate pulmonary toxicity after IL-2 administration. The present study tested this hypothesis by evaluating the effect of TNF-alpha inhibition on IL-2-induced lung injury in the rat. Recombinant human IL-2 (10(6) 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-alpha mRNA and peptide (1543 +/- 496 pg/g lung wet weight) localized to alveolar macrophages by in situ hybridization. In marked contrast, IL-2 failed to affect serum TNF-alpha, which remained at undetectable levels. Pretreatment with anti-TNF-alpha monoclonal antibody (25 mg/kg IV, n = 7) or the TNF-alpha synthesis inhibitor rolipram (200 micrograms/kg IV, n = 7) attenuated lung injury and reverted tissue hypoxia. Furthermore, TNF-alpha inhibition prevented the upregulation of lung tissue IL-1 beta, 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-alpha mediates IL-2-induced lung inflammation and tissue injury and point to the potential utilization of TNF-alpha inhibitors in treating the pulmonary toxicity of IL-2 immunotherapy.

Pulmonary edema and sepsislike syndrome are grave complications of interleukin-2 (IL-2) therapy. Recent animal studies have suggested IL-2-induced microvascular injury as the underlying mechanism. Since complement factors have been shown to mediate increased vascular permeability in diverse conditions that lead to pulmonary injury and recombinant human IL-2 is known to activate the complement system in patients undergoing IL-2 therapy, we hypothesized that complement factors play a pivotal role in the development of increased vascular permeability after IL-2 treatment. To test this hypothesis, we evaluated the capacity of recombinant soluble human complement receptor type 1 (sCR1, BRL 55730), a new highly specific complement inhibitor, to attenuate IL-2-induced lung injury in the rat. Recombinant human IL-2 (intravenously for 60 I nterleukin-2 (IL-2) is under investigation as an immunotherapeutic agent used in the treatment of advanced metastatic cancer.12 The clinical toxicity of the IL-2 regimen includes sepsislike syndrome and pulmonary edema secondary to increased vascular permeability.3'4 Although the pathophysiological processes leading to these side effects are still obscure, several mechanisms have been proposed. For example, recent in vitro data have suggested that tissue injury is mediated by lymphokine-activated killer cells activated in response to IL-2.56 However, several in vivo studies conducted in sheep7-9 and rats10 cast doubt on this possibility, since lung microvascular injury has been demonstrated as early as 2 to 6 hours after IL-2 infusion, a time interval insufficient for lymphokine-activated killer cell generation." Neutrophils, which are early-response inflammatory cells, have been recently implicated in the pulmonary response to acute IL-2 administration.10'12 In addition, increased vascular permeability could be consequent to the IL-2-induced production of several humoral inflammatory mediators such as interleukin-1,"3 tumor necrosis factor-a minutes) at 106 U per rat (n=4) elevated lung water content (37±6%, P<.05), myeloperoxidase activity (162±49%, P<.05), and serum thromboxane B2 (30+±1 pg/100 ,uL,P<.01) and had no effect on serum tumor necrosis factor-a. sCR-1 at 30 mg/kg (n=5), but not at 10 mg/kg (n=6), attenuated the elevation of lung water content (18±2%, P<.05) and myeloperoxidase activity (42±9%, P<.05) but failed to alter serum thromboxane B2 response to IL-2. These data suggest the involvement of complement in the pathogenesis of IL-2-induced pulmonary microvascular injury and point to the potential therapeutic capacity of complement inhibitors in combating this toxic effect of IL-2 therapy. (Circ Res. 1994;74:329-335.)

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