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Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
Angiopreventive versus angiopromoting effects of allopurinol in the murine sponge model
L A A Orellano1, S A Almeida1, P P Campos2
1Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627- Campus Pampulha, Cx Post 468, CEP 31270-901 Belo Horizonte, MG, Brazil.
Abstract:
Recent data has indicated that, besides its classical therapeutic indication in hyperurecemia and gout, xanthine oxidase inhibitors can be used to various forms of ischemia and other types of tissue and vascular injuries. We tested the hypothesis that allopurinol, an inhibitor of xanthine oxidase (XO), might modulate acute and/or chronic inflammatory angiogenesis induced by subcutaneous implantation of synthetic matrix in mice. C57/BL6 male mice (6-7 weeks) were implanted with polyether-polyurethane sponge discs. The animals received by oral gavage 1.0mg/kg of allopurinol for six consecutive days in two treatment regimen. In the first series of experiments, the treatment was initiated 24h post-implantation and the implants were removed at day 7 post-implantation. For the assessment of the effect of the compound on chronic inflammation, the treatment was initiated at day 8 post-implantation and the implants removed 14days post-implantation. Angiogenesis as determined by hemoglobin content, VEGF levels and number of vessels intraimplant, and inflammation (myeloperoxidase -MPO, n-acetyl-β-d-glucosaminidase -NAG, TNF-α and CCL2 levels) were reduced by allopurinol treatment in acute phase. Similarly, the treatment inhibited nitric oxide and H2O2 production. However, fibrogenesis determined by collagen deposition and levels of TGF-β1 increased in the implants after allopurinol treatment. In marked contrast with the effects when the treatment initiated 24h post-implantation, allopurinol increased angiogenesis and inflammation but reduced collagen and TGF-β1 levels intra-implant, when the treatment was started during the chronic inflammatory process. The dual effects of allopurinol described here, extend its range of actions as a potential agent able to modulate the components of the fibrovascular tissue present in both physiological (healing processes) as well as in chronic fibroproliferative diseases. These modulatory effects depended on the phase at which the treatment was initiated.
Insights
Allopurinol, a xanthine oxidase inhibitor, shows dual effects on tissue healing and inflammation. It reduces acute inflammation but promotes chronic inflammation and fibrosis depending on treatment timing.
Area of Science:
- Biomedical research
- Pharmacology
- Tissue engineering
Background:
- Xanthine oxidase inhibitors, like allopurinol, are primarily used for gout and hyperuricemia.
- Emerging evidence suggests their potential in treating ischemia and tissue/vascular injuries.
- The role of allopurinol in modulating inflammatory angiogenesis during tissue repair is not fully understood.
Purpose of the Study:
- To investigate the effects of allopurinol on acute and chronic inflammatory angiogenesis.
- To determine if allopurinol modulates inflammation, angiogenesis, and fibrogenesis in a mouse model.
- To assess the impact of allopurinol treatment timing on these processes.
Main Methods:
- Mice (C57/BL6) were implanted with synthetic sponge discs.
- Allopurinol (1.0mg/kg) was administered orally in two regimens: early (day 1 post-implantation) and late (day 8 post-implantation).
- Angiogenesis (hemoglobin, VEGF, vessel count), inflammation (MPO, NAG, TNF-α, CCL2), fibrogenesis (collagen, TGF-β1), nitric oxide, and H2O2 were assessed.
Main Results:
- Early allopurinol treatment reduced acute angiogenesis, inflammation, nitric oxide, and H2O2 production but increased fibrogenesis.
- Late allopurinol treatment, initiated during chronic inflammation, increased angiogenesis and inflammation while decreasing fibrogenesis.
- These findings highlight the context-dependent, dual role of allopurinol in modulating fibrovascular tissue.
Conclusions:
- Allopurinol exhibits differential effects on angiogenesis and inflammation based on the phase of the healing process.
- Its ability to modulate fibrovascular tissue components suggests potential applications beyond hyperuricemia.
- Allopurinol may serve as a therapeutic agent for both physiological healing and chronic fibroproliferative diseases, depending on treatment initiation timing.
