Attenuation of IL-2 Induced Multi-System Organ Edema by Phalloidin and Antamanide

摘要

Interleukin (IL)-2 is a potent cytokine with diverse effects including the ability to stimulate lymphocyte differentiation into cells capable of lysing tumor. Its therapeutic efficacy is limited because of side effects characterized by breakdown of the microvascular barrier, edema and weight gain, the mechanisms of which are largely unknown. Control of the microvascular barrier, thought to be a major function of the endothelial cell (EC), is in part regulated by cytoskeletal contractile proteins associated with the plasma membrane. This study tests whether the cyclopeptide phalloidin, which maintains actin filament organization and distribution and reduces macromolecular flux across the EC junction in vitro, would similarly maintain barrier tightness and prevent early edema produced by IL-2 in vivo. Anesthetized rats were treated at 30 min periods with IV: saline (0.5 ml, n = 41); phalloidin (20 micrograms in 0. 5 ml, n = 21); or antamanide, an analogue of phalloidin (20 micrograms in 0.5 ml, n = 21), starting 30 min prior to the 1 h infusion of 10(exp 6)U recombinant human IL-2 or saline. Six hours after the start of IL-2, there was edema in the saline/IL-2 group, as measured by increased wet to dry (W/d) ratios: in the lungs (W/d ratio 4.75 +/- 0.14 relative to 3.94 +/- 0.20 in saline controls), heart (4.12 +/- 0.09 vs. 3.80 +/- 0.06) and kidney (4.36+/- 0.03 vs. 4.18 +/- 0. 05) (all p<0.05). With saline/IL-2, bronchoalveolar lavage (BAL) fluid contained an elevated protein concentration of 1770 +/- 260 micrograms/ml, higher than 458 +/- 84 micrograms/ml in saline controls p<0.05, and plasma thromboxane (Tx)B2 levels were raised to 1032 +/- 204 pg/ml, higher than 238 +/- 23 in saline controls (p<0.05). Neutrophils were sequestered in the lungs 49 +/- 6 PMN/10 high power fields (HPF) relative to saline controls 21 +/- 2 PMN/10 HPF (p<0.05) .