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Glycosaminoglycan analogs as a novel anti-inflammatory strategy.

Severin IC, Soares A, Hantson J, Teixeira M, Sachs D, Valognes D, Scheer A, Schwarz MK, Wells TN, Proudfoot AE, Shaw J - Front Immunol (2012)

Bottom Line: In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation.However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment.In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.

View Article: PubMed Central - PubMed

Affiliation: Merck Serono Geneva Research Centre Geneva, Switzerland.

ABSTRACT
Heparin, a glycosaminoglycan (GAG), has both anti-inflammatory and anti-coagulant properties. The clinical use of heparin against inflammation, however, has been limited by concerns about increased bleeding. While the anti-coagulant activity of heparin is well understood, its anti-inflammatory properties are less so. Heparin is known to bind to certain cytokines, including chemokines, small proteins which mediate inflammation through their control of leukocyte migration and activation. Molecules which can interrupt the chemokine-GAG interaction without inhibiting coagulation could therefore, represent a new class of anti-inflammatory agents. In the present study, two approaches were undertaken, both focusing on the heparin-chemokine relationship. In the first, a structure based strategy was used: after an initial screening of potential small molecule binders using protein NMR on a target chemokine, binding molecules were optimized through structure-based design. In the second approach, commercially available short oligosaccharides were polysulfated. In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation. However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment. In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.

No MeSH data available.


Related in: MedlinePlus

Inhibition of antigen induced arthritis. An injection of mBSA into the synovial cavity was used to induce disease. 50 μg of the inhibitors were administered s.c. immediately after the mBSA injection, and the cells in the synovial cavity were enumerated 24 h later. (A) Total cells; (B) lymphocytes; (C) mononuclear cells. *P < 0.05.
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Figure 6: Inhibition of antigen induced arthritis. An injection of mBSA into the synovial cavity was used to induce disease. 50 μg of the inhibitors were administered s.c. immediately after the mBSA injection, and the cells in the synovial cavity were enumerated 24 h later. (A) Total cells; (B) lymphocytes; (C) mononuclear cells. *P < 0.05.

Mentions: The sulfated GAG compounds also displayed anti-inflammatory properties in mBSA-immunized mice, a rodent model for arthritis. We found a statistically significant reduction of neutrophil and mononuclear cell recruitment into the knee cavity after treatment with MHxS or NisS, and a reduction of mononuclear cells after treatment with heparin (Figure 6).


Glycosaminoglycan analogs as a novel anti-inflammatory strategy.

Severin IC, Soares A, Hantson J, Teixeira M, Sachs D, Valognes D, Scheer A, Schwarz MK, Wells TN, Proudfoot AE, Shaw J - Front Immunol (2012)

Inhibition of antigen induced arthritis. An injection of mBSA into the synovial cavity was used to induce disease. 50 μg of the inhibitors were administered s.c. immediately after the mBSA injection, and the cells in the synovial cavity were enumerated 24 h later. (A) Total cells; (B) lymphocytes; (C) mononuclear cells. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472544&req=5

Figure 6: Inhibition of antigen induced arthritis. An injection of mBSA into the synovial cavity was used to induce disease. 50 μg of the inhibitors were administered s.c. immediately after the mBSA injection, and the cells in the synovial cavity were enumerated 24 h later. (A) Total cells; (B) lymphocytes; (C) mononuclear cells. *P < 0.05.
Mentions: The sulfated GAG compounds also displayed anti-inflammatory properties in mBSA-immunized mice, a rodent model for arthritis. We found a statistically significant reduction of neutrophil and mononuclear cell recruitment into the knee cavity after treatment with MHxS or NisS, and a reduction of mononuclear cells after treatment with heparin (Figure 6).

Bottom Line: In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation.However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment.In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.

View Article: PubMed Central - PubMed

Affiliation: Merck Serono Geneva Research Centre Geneva, Switzerland.

ABSTRACT
Heparin, a glycosaminoglycan (GAG), has both anti-inflammatory and anti-coagulant properties. The clinical use of heparin against inflammation, however, has been limited by concerns about increased bleeding. While the anti-coagulant activity of heparin is well understood, its anti-inflammatory properties are less so. Heparin is known to bind to certain cytokines, including chemokines, small proteins which mediate inflammation through their control of leukocyte migration and activation. Molecules which can interrupt the chemokine-GAG interaction without inhibiting coagulation could therefore, represent a new class of anti-inflammatory agents. In the present study, two approaches were undertaken, both focusing on the heparin-chemokine relationship. In the first, a structure based strategy was used: after an initial screening of potential small molecule binders using protein NMR on a target chemokine, binding molecules were optimized through structure-based design. In the second approach, commercially available short oligosaccharides were polysulfated. In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation. However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment. In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.

No MeSH data available.


Related in: MedlinePlus