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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In this specific model of endotoxin-induced lung injury, LEH does not exacerbate microvascular leakage and leukosequestration, the hallmarks of adult respiratory distress syndrome.

studies were designed to compare and contrast the influence of hypercholesterolemia on the local and systemic inflammatory response to demand ischemia (ie, exercise) in a murine model of vascular occlusive disease.Methods: Apolipoprotein E Ϫ/Ϫ (ApoE) and aged C57BL6 (C57) mice underwent unilateral femoral artery ligation. At day 14, animals were divided into sedentary and exercise groups. Basal hind limb and demand ischemia was quantified using laser Doppler imaging. Neurologic function was quantified using a standardized scale. Animals in the exercise groups underwent daily treadmill exercise (15 m/min, 10°incline) on days 14 through 28. On day 28, serum and skeletal muscle from ischemic and contralateral limbs were harvested immediately after exercise for measurement of keratinocyte-derived chemokine (KC), vascular endothelial growth factor (VEGF), interleukin (IL)-6, macrophage inflammatory protein (MIP)-2, and histology.Results: The degree of ischemia and neurologic function was similar between groups before initiation of exercise. Under sedentary conditions, compared with C57 mice, plasma VEGF and IL-6, but not KC or MIP-2 were higher in ApoE mice. After exercise, serum levels of VEGF, KC, and MIP-2, but not IL-6, were lower in ApoE compared with C57 mice. Local response to demand ischemia was higher in ApoE mice as measured by KC levels. ApoE mice produced a significant increase in the percentage of immature centrally nucleated skeletal muscle fibers under both sedentary and demand conditions (Table).Conclusion: In the setting of demand ischemia, the systemic inflammatory response is different in ApoE mice compared with C57 mice. The altered inflammatory response to exercise in hypercholesterolemic mice may play a role in postischemic skeletal muscle remodeling and mimic postischemic muscle dysfunction in humans with claudication.

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