ArticleInflammopharmacology2025
Targeting the cytokine-redox axis: dose-dependent immunomodulation by methotrexate in a biomarker-guided ovine endotoxaemia model.
Article in Inflammopharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundOxidative stress and excessive inflammation are central to the pathophysiology of sepsis and its large-animal analogue, endotoxaemia. Current anti-inflammatory treatments in ruminants lack efficacy in modulating redox balance or acute-phase responses. Low-dose methotrexate (MTX), a known immunometabolic modulator, may offer targeted attenuation of these processes.
objectiveTo evaluate the anti-inflammatory, antioxidant, and organ-sparing effects of two low-dose MTX regimens in a controlled ovine model of lipopolysaccharide (LPS)-induced endotoxaemia.
methods20 clinically healthy ewes were randomised into four groups (n = 5/group): Ctrl - (saline), Ctrl + (LPS), LD-MTX1 (LPS + MTX 0.45 mg/kg), and LD-MTX2 (LPS + MTX 0.90 mg/kg). Endotoxaemia was induced via intravenous Escherichia coli O55:B5 LPS, and MTX was administered intramuscularly 1 h post-challenge. Serum biomarkers (TAC, GPx, MDA, haptoglobin, ALT, AST, urea, creatinine and CK-MB), clinical parameters and behavioural scores were assessed at five time points over 24 h. Data were analysed using mixed-effects models with adjusted post hoc contrasts.
resultsBoth MTX regimens improved TAC within 6 h; LD-MTX2 showed a higher 6 h peak vs Ctrl + (p = 0.0006) and LD-MTX1 increased TAC AUC₀-6 h (p = 0.048). GPx displayed a Group × Time interaction: LD-MTX1 rebounded by 4-6 h, whereas LD-MTX2 recovered later by 24 h. HP was non-monotonic: AUC₀-6 h was lower with LD-MTX1 vs Ctrl + (p = 0.045) but higher with LD-MTX2 vs Ctrl + (p = 0.0002). LD-MTX2 markedly suppressed fever (+ 0.36 °C vs + 1.88 °C in Ctrl + ; p = 0.0011). The organ signals were dose-specific; LD-MTX1 showed no biochemical organ stress, and LD-MTX2 caused transient ALT/AST rises (p ≤ 0.006) with renal indices trending lower and no CK-MB increase. The clinical and behavioural metrics mirrored these effects.
conclusionLow-dose MTX at 0.45 mg kg⁻
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