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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 peritoneal cellular recruitment. Cellular recruitment into the peritoneal cavity was induced by CCL5 (A) and (B) and inhibited by different doses of CCL5 binders administered 30 min prior to the CCL5 administration. Cellular recruitment into the peritoneal cavity was induced by thioglycollate (C) and (D) and treated by increasing doses of heparin (C) and MHxS (D) using dexamethasone as a positive control. The statistical differences versus the control groups (CCL5 alone-treated mice in A and B; or Thioglycollate alone-treated mice in C and D) are shown whenever present and indicated by *P < 0.05; **P < 0.01 or ***P < 0.001.
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Figure 4: Inhibition of peritoneal cellular recruitment. Cellular recruitment into the peritoneal cavity was induced by CCL5 (A) and (B) and inhibited by different doses of CCL5 binders administered 30 min prior to the CCL5 administration. Cellular recruitment into the peritoneal cavity was induced by thioglycollate (C) and (D) and treated by increasing doses of heparin (C) and MHxS (D) using dexamethasone as a positive control. The statistical differences versus the control groups (CCL5 alone-treated mice in A and B; or Thioglycollate alone-treated mice in C and D) are shown whenever present and indicated by *P < 0.05; **P < 0.01 or ***P < 0.001.

Mentions: In order to determine, if the inhibition of heparin and receptor binding produces an anti-inflammatory effect, we used a simple in vivo model of inflammation. The model we chose was thioglycollate-induced peritonitis. As shown in Figure 4, despite its lack of potency in the in vitro assays, Molecule 1 inhibited cell recruitment to the peritoneum in a dose dependent manner. However, when we tested Molecule 3 designed to bind to two separate sites of CCL5, we observed an enhancement of cell recruitment to the peritoneal cavity (Figure 4B).


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 peritoneal cellular recruitment. Cellular recruitment into the peritoneal cavity was induced by CCL5 (A) and (B) and inhibited by different doses of CCL5 binders administered 30 min prior to the CCL5 administration. Cellular recruitment into the peritoneal cavity was induced by thioglycollate (C) and (D) and treated by increasing doses of heparin (C) and MHxS (D) using dexamethasone as a positive control. The statistical differences versus the control groups (CCL5 alone-treated mice in A and B; or Thioglycollate alone-treated mice in C and D) are shown whenever present and indicated by *P < 0.05; **P < 0.01 or ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Inhibition of peritoneal cellular recruitment. Cellular recruitment into the peritoneal cavity was induced by CCL5 (A) and (B) and inhibited by different doses of CCL5 binders administered 30 min prior to the CCL5 administration. Cellular recruitment into the peritoneal cavity was induced by thioglycollate (C) and (D) and treated by increasing doses of heparin (C) and MHxS (D) using dexamethasone as a positive control. The statistical differences versus the control groups (CCL5 alone-treated mice in A and B; or Thioglycollate alone-treated mice in C and D) are shown whenever present and indicated by *P < 0.05; **P < 0.01 or ***P < 0.001.
Mentions: In order to determine, if the inhibition of heparin and receptor binding produces an anti-inflammatory effect, we used a simple in vivo model of inflammation. The model we chose was thioglycollate-induced peritonitis. As shown in Figure 4, despite its lack of potency in the in vitro assays, Molecule 1 inhibited cell recruitment to the peritoneum in a dose dependent manner. However, when we tested Molecule 3 designed to bind to two separate sites of CCL5, we observed an enhancement of cell recruitment to the peritoneal cavity (Figure 4B).

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