No 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 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.)

Acid aspiration induces lung injury through a complement-dependent mechanism that leads to microvascular permeability defects. Therefore, the possibility that complement inhibitors may have a salutary effect in humans with aspiration-induced lung injury should be investigated.

Interleukin-2 was recently shown to cause acute lung injury characterized by microvascular permeability defect, interstitial edema, and leukosequestration. Similar responses can also be produced by platelet activating factor (PAF). Thus, the present study aimed to examine whether PAF plays a key role in the development of IL-2-induced lung injury in the anesthetized rat. Intravenous infusion (60 min) of recombinant human IL-2 at 10'-10' U/rat (a = 7-9) dose-dependently elevated lung water content (27±1%, P < 0.01), myeloperoxidase activity (+84±23%, P < 0.05), and serum thromboxane B2 (990±70%, P < 0.01), but failed to alter blood pressure, hematocrit, serum tumor necrosis factor-a, and circulating leukocytes and platelets. Pretreatment (-30 min) with a potent and specific PAF antagonist, BN 50739 (10 mg/kg, intraperitoneally, n = 6) prevented the pulmonary edema (P < 0.05) and thromboxane B2 production (P < 0.01), and attenuated the elevation of lung myeloperoxidase activity (+18±16%, P < 0.05) induced by IL-2. These data suggest that PAF is involved in the pathophysiological processes leading to IL-2-induced lung injury, and point to the potential therapeutic capacity of PAF antagonists in preventing pulmonary edema during IL-2 therapy. (J. Clin. Invest.

No abstract