RESUMO
OBJECTIVE: To determine the effects of SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5] decane-2-propanamine dihydrochloride) on the arthritic lesions in the tibiotarsal joint of adjuvant arthritic (AA) rats. METHODS: Inhibition of hindpaw inflammation was measured by water displacement. The protective effects on joint integrity were determined by measuring radiographic and histological changes and by scanning electron microscopy. RESULTS: Compared to AA control rats, SK&F 105685 suppressed hindpaw edema 64% or 41-54% in AA rats receiving 30 or 20 mg/kg/day, respectively. Radiographic evaluation showed marked decreases in soft tissue swelling and in the severity of skeletal tissue loss at the tibiotarsal joint in both dose groups. Histologically SK&F 105685 markedly attenuated the extent and severity of the inflammatory lesion and preserved the basic integrity of bone and cartilaginous tissues, including the content and distribution of proteoglycans of the articular cartilages. Cellular changes included decreases in the inflammatory infiltrate and in the number of osteoclasts and chondroclasts. Whereas AA control rats exhibited marked to severe loss (41-70%) of skeletal tissue mass, the loss in rats given 30 mg/kg SK&F 105685 was mild (< 20%). Scanning electron microscopy of the talus revealed only slight erosion of the articular cartilage and general preservation of the underlying bone. In contrast, in AA controls, there was marked erosion of the talar articular cartilage and severe loss of subchondral bone. Spleen cells from SK&F 105685 treated rats had a reduced capacity to respond to concanavalin A and contained suppressor cell activity as measured in a coculture assay. CONCLUSION: Our studies show that SK&F 105685 has remarkable protective effects on the joints of AA rats and suggests that it may attenuate the overall inflammatory process and retard the degenerative loss of skeletal tissue in rheumatoid arthritis in humans.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Imunossupressores/uso terapêutico , Compostos de Espiro/uso terapêutico , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/patologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/ultraestrutura , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Edema/prevenção & controle , Imunossupressores/farmacologia , Inflamação/tratamento farmacológico , Ativação Linfocitária , Masculino , Microscopia Eletrônica de Varredura , Osteoclastos/ultraestrutura , Ratos , Ratos Endogâmicos Lew , Compostos de Espiro/farmacologia , Baço/imunologia , Baço/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos da radiaçãoRESUMO
Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Encoded by the HIV genome are several precursor proteins that undergo proteolytic cleavage to yield functional proteins. The env precursor protein is cleaved by a cellular protease. The gag precursor protein of HIV (p55), however, is cleaved by a virally encoded aspartate protease (HIV Protease). Cleavage of p55 is required for viral maturation and infectivity. There are also several host cell aspartate proteases that serve important homeostatic functions. Cathepsins D and E are lysosomal aspartate proteases which are believed to play an important role in macrophage function, and it has been suggested that inhibition of these enzymes by an HIV protease inhibitor may exacerbate immunosuppression in AIDS patients. We have studied the effect of SK&F 107461 (a hydroxyethylene dipeptide isostere inhibitor of HIV protease), on various host defense functions of human monocytes. Pepstatin A (an inhibitor of most aspartate proteases) and leupeptin (an inhibitor of serine and cysteine proteases) were included as controls. Although less potent than the prototypic aspartate protease inhibitor pepstatin, SK&F 107461 inhibited partially purified cathepsin D in vitro. However, in cell-based assays, SK&F 107461 had no effect on the degradation of hemoglobin, antigen processing of the protein antigen streptokinase, or secretion of 17-kD IL-1 beta by monocytes at concentrations which inhibit maturation of intracellular virus in HIV infected monocytes. Furthermore, SK&F 107461 had no effect on constitutive candidacidal activity. In contrast, leupeptin and pepstatin A partially inhibited accessory cell function of monocytes in the proliferative response to the recall antigen streptokinase. In addition, leupeptin partially inhibited degradation of hemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Inibidores da Protease de HIV/farmacologia , Monócitos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Células Apresentadoras de Antígenos/efeitos dos fármacos , Candida albicans/imunologia , Catepsina D/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , HIV-1/ultraestrutura , Humanos , Técnicas In Vitro , Interleucina-1/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Monócitos/imunologia , Monócitos/fisiologia , Fagocitose/efeitos dos fármacos , Proteínas/metabolismoRESUMO
The hepatic uptake of recombinant human tissue-type plasminogen activator (tPA) has been studied by electron microscope autoradiography (EMARG) of serial hepatic biopsies taken from anaesthetized, laparotomized rats following intravenous injection of 125I labeled tPA. Serial blood samples showed both radiolabel and biologic activity to be eliminated from circulation with an initial half-life of approximately two minutes. Grain half-distance distribution profiles and grain density analysis showed that the para-sinusoidal region of the hepatic parenchymal cell is the only site in the liver to concentrate radiolabeled tPA after intravenous injection. These data support the hypothesis that the parenchymal cell is the principal cell responsible for hepatic clearance of tPA from circulation and suggest that receptor mediated endocytosis may be the mechanism of cellular uptake.