RESUMO
Infiltration of monocytes into arteries is an early event in the pathogenesis of atherosclerosis. This recruitment is interpreted as enhancing lesion development, but it could also be a host response limiting lipid accumulation. The ability of macrophages to limit cholesterol uptake, however, can be reduced by the impaired mobility and metabolic activity associated with foam cell development. As lesions enlarge, foam cells die and become the nidus for the necrotic core. Treatments to improve viability might improve foam cell function and promote regression. Macrophage colony-stimulating factor (M-CSF) is vital to monocyte/macrophage differentiation, proliferation, and activation. We found that foam cells of Watanabe heritable hyperlipidemic (WHHL) rabbits had faint staining for M-CSF. Treatment of rabbits with recombinant human M-CSF (rhM-CSF) increased M-CSF staining, which correlated with reduced cholesterol content of these foam cells.
Assuntos
Arteriosclerose/metabolismo , Hipercolesterolemia/genética , Fator Estimulador de Colônias de Macrófagos/biossíntese , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Arteriosclerose/etiologia , Arteriosclerose/genética , Arteriosclerose/patologia , Movimento Celular , Colesterol/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/metabolismo , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/uso terapêutico , Masculino , Coelhos , Proteínas Recombinantes/uso terapêuticoRESUMO
We have extensively characterized the hematological response of normal and myelosuppressed nonhuman primates to treatment with recombinant human interleukin 11 (rHuIL-11) in vivo. In normal cynomolgus monkeys, rHuIL-11 significantly increased peripheral platelet counts when administered at doses of 10 micrograms/kg/day to 100 micrograms/kg/day either by constant i.v. infusion or s.c. injection. As few as four days of rHuIL-11 treatment were sufficient to increase peripheral platelet counts significantly. In addition, extending the treatment period enhanced both the magnitude and the duration of the response. Bone marrow megakaryocytes from animals treated with 100 micrograms/kg/day of rHuIL-11 were increased in size compared to controls and were ultrastructurally normal. A nonhuman primate myelosuppression model using carboplatin, which causes severe thrombocytopenia with platelet counts of < or = 20 x 10(3) platelets/microliters, was developed. This novel model was used to evaluate the effectiveness of rHuIL-11 in platelet restoration. rHuIL-11, administered s.c. at a dose of 125 micrograms/kg/day either concurrently or following chemotherapy, prevented severe thrombocytopenia in addition to accelerating platelet recovery compared to control animals receiving no rHuIL-11. These data demonstrate that rHuIL-11 has potent in vivo thrombopoietic effects when administered to normal and myelosuppressed nonhuman primates, and that rHuIL-11 can be an important therapy to reduce the severity and duration of thrombocytopenia following chemotherapy.