Interleukin 2 (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 such as breakdown of the microvascular barrier and
edema. Control of the microvascular barrier is in part regulated by endothelial cell cytoskeletal
contractile proteins. This study tests whether the
cyclopeptides that maintain actin filament organization and distribution and reduce macromolecular flux across the endothelial cell 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 intravenous saline (0.5 ml, n = 41),
phalloidin (20 micrograms in 0.5 ml, n = 21), or
antamanide, (20 micrograms in 0.5 ml, n = 21), starting 30 min before the 1-h infusion of 10(6) U of 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 ratios (W/D) in the lungs, heart, and kidney. With saline/IL-2, bronchoalveolar lavage (BAL) fluid contained an elevated
protein concentration and higher plasma
thromboxane levels compared with controls. The number of neutrophils sequestered in the lungs was more than twice that of saline controls.
Phalloidin significantly attenuated
edema in lung and reduced BAL
protein leak.
Antamanide treatment was as effective in limiting lung and heart
edema, but, in contrast to
phalloidin,
antamanide prevented kidney
edema and did not lead to an alteration in the liver W/D.
Antamanide also prevented BAL fluid
protein leak.(ABSTRACT TRUNCATED AT 250 WORDS)