g(m1)-ganglioside and Pulmonary-Edema

Topics: Anemia, Hemolytic; Animals; Chemical and Drug Induced Liver Injury; Female; G(M1) Ganglioside; Hepatomegaly; Immunization, Passive; Inflammation; Interleukin-2; Killer Cells, Lymphokine-Activated; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Pulmonary Edema; Pulmonary Eosinophilia; Rats; Receptors, Interleukin-1; Recombinant Proteins; Severe Combined Immunodeficiency; Splenomegaly; Tumor Necrosis Factor-alpha; Viscera

We evaluated in anesthetized rabbits the compositional changes of plasmalemmal lipid microdomains from lung tissue samples after inducing pulmonary interstitial edema (0.5 ml/kg for 3 h, leading to approximately 5% increase in extravascular water). Lipid microdomains (lipid rafts and caveolae) were present in the detergent-resistant fraction (DRF) obtained after discontinuous sucrose density gradient. DRF was enriched in caveolin-1, flotillin, aquaporin-1, GM1, cholesterol, sphingomyelin, and phosphatidylserine, and their contents significantly increased in interstitial edema. The higher DRF content in caveolin, flotillin, and aquaporin-1 and of the ganglioside GM1 suggests an increase both in caveolar domains and in lipid rafts, respectively. Compositional changes could be ascribed to endothelial and epithelial cells that provide most of plasma membrane surface area in the air-blood barrier. Alterations in lipid components in the plasma membrane may reflect rearrangement of floating lipid platforms within the membrane and/or lipid translocation from intracellular stores. Lipid traffic could be stimulated by the marked increase in hydraulic interstitial pressure after initial water accumulation, from approximately -10 to 5 cmH2O, due to the low compliance of the pulmonary tissue, in particular in the basement membranes and in the interfibrillar substance. Compositional changes in lipid microdomains represent a sign of cellular activation and suggest the potential role of mechanotransduction in response to developing interstitial edema.

Topics: Animals; Aquaporin 1; Aquaporin 5; Aquaporins; Blood-Air Barrier; Caveolin 1; Caveolins; Cell Membrane; Detergents; Drug Resistance; Fluorescent Antibody Technique; G(M1) Ganglioside; Lipid Metabolism; Lung; Membrane Microdomains; Membrane Proteins; Pulmonary Edema; Rabbits

Human recombinant interleukin-2 (rIL-2) was administered to normal and tumor-bearing BDF mice for 1 to 3 weeks, and the hematologic, clinical chemistry, gross and histopathologic findings were evaluated. Vascular leak syndrome (pulmonary edema, pleural effusion, ascites), hepatocyte necrosis, elevated hepatic serum transaminases, hypoalbuminemia, tissue and peripheral eosinophilia, thrombocytopenia, and prerenal azotemia were the detrimental effects of rIL-2 treatment. Vascular leak syndrome and hepatocyte necrosis were causally associated with vascular-oriented lymphocytic infiltration of pulmonary and hepatic parenchyma. Pleural effusions contained up to 99,000 cells/mm3, most of which were large granular lymphocytes. Antiserum to the glycolipid asialo GM1 (ganglio-n-tetrosylceramide), given simultaneously with rIL-2, prevented overt toxicity of rIL-2 (mortality, vascular leak syndrome, and hepatic damage) and substantially reduced infiltration of pulmonary and hepatic vasculature by asialo GM1+ lymphocytes. Asialo GM1 antiserum did not inhibit lymphoid hyperplasia, tissue infiltration by Lyt 2+ lymphocytes, tissue and peripheral eosinophilia, or thrombocytopenia in rIL-2 treated mice. Additionally, asialo GM1 antisera prevented toxicity, but not anti-tumor efficacy, of high dose rIL-2 therapy in BDF mice bearing the colon 38 adenocarcinoma. These results suggest that, in BDF mice and with this tumor model, vascular leak syndrome and hepatocyte necrosis are mediated by an endogenous subset of rIL-2-stimulated lymphocytes which are asialo GM positive, that mechanisms of toxicity and efficacy associated with high dose rIL-2 therapy are not necessarily the same, and that these mechanisms can be therapeutically separated.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Capillary Permeability; Colonic Neoplasms; G(M1) Ganglioside; Glycosphingolipids; Hyperplasia; Immunotherapy; Interleukin-2; Killer Cells, Natural; Liver Diseases; Lymphocyte Activation; Lymphocytes; Mice; Pleural Effusion; Pulmonary Edema; Recombinant Proteins; Spleen