ABSTRACT
A major limitation in the use of AZT for AIDS treatment is the occurrence of side effects, such as leukopenia. The effects of antioxidant vitamins C and E on AZT-induced leukopenia were investigated in mice. Mice were divided into four groups: (1) controls; (2) AZT-treated; (3) treated with AZT plus vitamins C and E; and (4) pre-treated with vitamins and then treated with AZT plus vitamins. Our results demonstrate that AZT causes leukopenia in mice, which was abrogated by administration of vitamins C and E in the pre-treated group. These vitamins prevented the decrease in cellular content induced by AZT in bone marrow and diminished peroxide levels in myeloid precursors in bone marrow. AZT also caused an increase in plasma malondialdehyde and blood oxidized glutathione levels, which was prevented by the administration of antioxidant vitamins. In conclusion, oxidative stress is involved in AZT-induced leukopenia which may be prevented by antioxidant treatment.
Subject(s)
Anti-HIV Agents/antagonists & inhibitors , Antioxidants/therapeutic use , Ascorbic Acid/therapeutic use , Leukopenia/prevention & control , Vitamin E/therapeutic use , Zidovudine/antagonists & inhibitors , Animals , Anti-HIV Agents/toxicity , Bone Marrow Cells/drug effects , Leukopenia/chemically induced , Male , Mice , Mice, Inbred Strains , Zidovudine/toxicityABSTRACT
Severe acute pancreatitis causes a high incidence of mortality due to the systemic inflammatory response syndrome leading to multiple organ failure. At present, there is no treatment against severe acute pancreatitis, other than supportive critical care. The relationship between pancreatic injury and the uncontrolled systemic response is not completely understood. Nevertheless, experimental and clinical evidences have shown that pro-inflammatory cytokines and oxidative stress are critically involved in the development of local and systemic complications associated with severe acute pancreatitis. Serum levels of pro-inflammatory cytokines, such as TNF-alpha and IL-1beta, increase during the course of acute pancreatitis and they appear to be the driving force for the initiation and propagation of the systemic response. Accordingly, pretreatment with an antibody against TNF-alpha or blockade of TNF-alpha production with pentoxifylline ameliorates experimental acute pancreatitis. In addition, serum IL-6 and IL-8 levels appear to be correlated with severity of pancreatic inflammation. The role of oxidative stress in acute pancreatitis has been evidenced indirectly by beneficial effects of antioxidants as well as directly by pancreatic glutathione depletion and increased lipid peroxidation. Furthermore, circulating xanthine oxidase released by the damaged pancreas acts as a source of systemic oxidative stress contributing to lung inflammation. In conclusion, pancreatic injury seems to trigger at least two different pathways, i.e. pro-inflammatory cytokines and oxidative stress, both involved in the systemic effects of acute pancreatitis. Elucidation of these mechanisms and their interactions is critical to develop a treatment based on the pathophysiology of acute pancreatitis.
