Interleukin-2-Induced Lung Injury: The Role of Complement

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Abstract

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 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 μL, 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.

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