Abstract
BackgroundPhosphatidylserine-containing liposomes (PSL) have been shown to reduce inflammation in experimental models of acute arthritis, by mimicking the apoptotic process. The aim of this study was to evaluate the effect of pegylated PSL (PEG-PSL) on chronic inflammation of collagen induced arthritis (CIA) in DBA/1J mice.MethodsCIA was induced in 24 DBA/1J mice (n = 6/group), which were divided into control (0.9 % saline) or treated with PEG-PSL (5, 10 and 15 mg/kg/day, subcutaneously for 20 days). Clinical score, limb histology and measurement of cytokines in knee joints of animals by ELISA and cytometric bead array (CBA) were evaluated. The in vitro study employed macrophage cultures stimulated with 100 ng/ml of LPS plus 10 ng/ml of PMA and treated with 100 μM PEG-PSL.ResultsResolution of the disease in vivo and the inflammatory process in vitro were not observed. PEG-PSL, in doses of 10 and 15 mg/kg, were not shown to reduce the score of the disease in animals, whereas with the dose of 5 mg/kg, the animals did not show the advanced stage of the disease when compared to the controls. The PEG- PSL 5, 10 and 15 mg/kg treatment groups did not show significant reduction of TNF-α, IL-1β, IL-6, IL-2 and IFN-γ when compared to the controls. Disease incidence and animal weights were not affected by treatment. Regarding the paw histology, PEG-PSL did not yield any reductions in the infiltrating mononuclear, synovial hyperplasia, extension of pannus formation, synovial fibrosis, erosion of cartilage, bone erosion or cartilage degradation. The concentration of 100 μM of PEG-PSL has not been shown to reduce inflammation induced by LPS/PMA in the in vitro study. Treated groups did not show any reduction in inflammatory cytokines in the knee joints of animals affected by the disease compared to the control, although there were higher concentrations of TGF-β1 in all experimental groups.ConclusionThe experimental model showed an expression of severe arthritis after the booster. TGF-β1 as well other pro inflammatory cytokines were presented in high concentrations in all groups. PEG-PSL had no impact on the clinical score, the histopathology from tibial-tarsal joints or the production of cytokines in the knee joints. Other alternatives such as dosage, route of administration, and as an adjunct to a drug already on the market, should be evaluated to support the use of PEG-PSL as a new therapeutic tool in inflammatory diseases.
Highlights
Phosphatidylserine-containing liposomes (PSL) have been shown to reduce inflammation in experimental models of acute arthritis, by mimicking the apoptotic process
Considering the length of treatment (20 days) and the daily administration of 5, 10 and 15 mg/kg of pegylated PSL (PEG-PSL), the results showed no significant difference in the reduction of disease progression as assessed by clinical score between the treatment groups (10 and 15 mg/kg) and the control group (Fig. 1)
The group treated with PEG-PSL 5 mg/kg presented an upper asymptote of clinical score significantly less than the control, i.e., the animals of the group treated with 5 mg/kg did not show a greater degree of disease severity (Fig. 1 and Table 2), evidencing a possible effect on the delay of disease activity
Summary
Phosphatidylserine-containing liposomes (PSL) have been shown to reduce inflammation in experimental models of acute arthritis, by mimicking the apoptotic process. Phosphatidylserine (PS) is a phospholipid found in the inner part of the plasma membrane of viable cells [1]. In the process of apoptosis, PS is externalized and presented as a phagocytic signal for macrophage-mediated removal of apoptotic bodies, contributing to the homeostasis of the organism [1,2,3,4,5]. Some protozoa mimic the exposure of PS to be phagocytosed and begin the process of infection in macrophages, mainly by inhibiting nitric oxide and stimulating TGF-β1 and IL-10 [6,7,8]. There are reports of tumoral cells which excessively exhibit PS to promote immunosuppression of the immune system, allowing their development without interference from the organism [11]
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