Abstract
BACKGROUND: The model of pleurisy induced by carrageenan exhibits a biphasic response (4 and 48 h) and permits the quantification of exudate, cell migration and certain enzymes such as myeloperoxidase (MPO) and adenosine-deaminase (ADA) that are markers of activated leukocytes. AIMS: The present study evaluates whether there exists, in the pleurisy model, a significant inhibition of ADA and MPO enzymes, leukocyte kinetics and other markers of inflammation [nitric oxide (NO) levels, exudation] caused by methotrexate treatment by the intraperitoneal (i.p.) route. METHODS: The pleurisy was induced by carrageenan (1%) in mice, and the parameters were analyzed 4 and 48 h after. RESULTS: After the induction of inflammation (4 h), methotrexate (20 mg/kg, i.p., 24 h before pleurisy induction) inhibited the leukocyte infiltration (p < 0.05), NO levels and MPO activity (p < 0.01), but not ADA activity and fluid leakage (p > 0.05). Regarding the second phase of pleurisy (48 h), methotrexate (40 mg/kg, i.p., 0.5 h before pleurisy induction) inhibited the leukocyte infiltration (p < 0.05), fluid leakage, NO levels (p < 0.01), and ADA and MPO activity (p < 0.05). CONCLUSIONS: These findings support the evidence that the acute administration of methotrexate has an important systemic anti-inflammatory activity in the studied inflammatory model. This effect was due to a significant inhibition on both neutrophil and mononuclear cells, being less marked in relation to exudation 48 h after. In relation to the enzymes studied and to NO levels, the findings support the evidence that methotrexate inhibits both enzymes (MPO and ADA) from leukocytes at the site of injury, thus reflecting the activation of both neutrophils and lymphocytes, respectively. Furthermore, the inhibiting effect on NO in both phases of pleurisy induced by carrageenan (4 and 48 h) indicates that methotrexate acts on constitutive and/or inducible NO synthases by means of different cells of the pleural cavity.
Highlights
Methotrexate, a folate antagonist, is a potent antiinflammatory agent.[1]
It has been proposed that these effects are probably mediated, in part, by adenosine release from endothelial cells, followed by adenosine receptor occupancy on macrophages and lymphocytes, since it is reversed by adenosine-deaminase (ADA).[8,9]
Methotrexate did not inhibit fluid leakage that occurs in the early phase (4 h) of this pleurisy model, but did at 48 h (Fig. 1A,B, inset)
Summary
Methotrexate, a folate antagonist, is a potent antiinflammatory agent.[1]. Because of its efficiency as an immunosuppressive agent, which at low doses does not affect cellular proliferation, it has been used in the treatment of rheumatoid arthritis.[2]. Evidence indicates that methotrexate treatment decreases neutrophil–endothelial adhesion in vitro by modulating the expression of integrins This drug suppresses neutrophil accumulation and exudation in the reverse passive Arthus reaction of rat dorsal skin, nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) in murine lung epithelial cells in vitro, and decrease of the prostaglandin E2 release in the cultured human rheumatoid synoviocytes,[5,6,7] among others. Conclusions: These findings support the evidence that the acute administration of methotrexate has an important systemic anti-inflammatory activity in the studied inflammatory model This effect was due to a significant inhibition on both neutrophil and mononuclear cells, being less marked in relation to exudation 48 h after. The inhibiting effect on NO in both phases of pleurisy induced by carrageenan (4 and 48 h) indicates that methotrexate acts on constitutive and/or inducible NO synthases by means of different cells of the pleural cavity
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