Attenuation of IL-2-induced multisystem organ edema by phalloidin and antamanide.
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)
Welbourn
R
R
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Goldman
G
G
Kobzik
L
L
Valeri
C R
CR
Hechtman
H B
HB
Shepro
D
D
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D004489:Edema, Cardiac / Q000139:chemically induced / Q000517:prevention & control; D007376:Interleukin-2 / Q000633:toxicity; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D008107:Liver Diseases / Q000517:prevention & control; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010590:Phalloidine / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011919:Rats, Inbred Strains; D013929:Thromboxane B2 / Q000097:blood
D007376:Interleukin-2; D010456:Peptides, Cyclic; C100265:antamanide; D010590:Phalloidine; D013929:Thromboxane B2