Mast cell degranulation inhibits IL-2-induced microvascular protein leakage.
The therapeutic efficacy of interleukin-2 (IL-2) in the treatment of cancer has been limited by a "vascular leak syndrome" and related toxicities. To better understand the pathophysiology of the "vascular leak syndrome," we tested a hypothesis that mast cell degranulation mediated the acute increase in microvascular protein leakage seen immediately following IL-2 administration. After the cremaster muscle was prepared for intravital microscopy, anesthetized Sprague-Dawley rats were injected with fluorescein isothiocyanate-labeled albumin for fluorescent microscopy. Animals were treated by the intravenous injection of IL-2 (1 x 10(6) U/kg) (n = 6), the control IL-2-vehicle (n = 5), or IL-2 (1 x 10(6) U/kg) after mast cell degranulation with compound 48/80 (n = 6). Relative interstitial fluorescent intensity was quantitated by a computerized image analysis system as an index of microvascular protein leakage. IL-2 acutely induced protein leakage from the microcirculation. Mast cell degranulation with 48/80 prior to IL-2 treatment prevented protein leakage, but did not alter IL-2-induced leukocyte-endothelial adherence. These data suggest that mast cell-mediated events may be responsible for the acute increase in microvascular permeability seen with IL-2 administration and that leukocyte-endothelial adherence alone is not solely responsible.
Edwards
M J
MJ
Department of Surgery, University of Louisville School of Medicine, Kentucky 40292.
Heniford
B T
BT
Miller
F N
FN
D000818:Animals; D002199:Capillary Permeability; D015550:Cell Degranulation / Q000502:physiology*; D016650:Fluorescein-5-isothiocyanate; D007091:Image Processing, Computer-Assisted; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism*; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D007376:Interleukin-2; D012709:Serum Albumin; D003189:p-Methoxy-N-methylphenethylamine; D016650:Fluorescein-5-isothiocyanate