Limits...
Sulfonamide inhibitors of α2β1 integrin reveal the essential role of collagen receptors in in vivo models of inflammation.

Nissinen L, Ojala M, Langen B, Dost R, Pihlavisto M, Käpylä J, Marjamäki A, Heino J - Pharmacol Res Perspect (2015)

Bottom Line: Since α2β1 integrin is abundantly expressed on various inflammation-associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti-inflammatory properties.Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid-induced ear edema, PAF stimulated air pouch, ovalbumin-induced skin hypersensitivity, adjuvant arthritis, and collagen-induced arthritis.Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Turku 20014, Turku, Finland ; Biotie Therapies Corp Turku, Finland.

ABSTRACT
Small molecule inhibitors of α2β1 integrin, a major cellular collagen receptor, have been reported to inhibit platelet function, kidney injury, and angiogenesis. Since α2β1 integrin is abundantly expressed on various inflammation-associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti-inflammatory properties. Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid-induced ear edema, PAF stimulated air pouch, ovalbumin-induced skin hypersensitivity, adjuvant arthritis, and collagen-induced arthritis. Thus, these sulfonamides are potential drugs for acute and allergic inflammation, hypersensitivity, and arthritis. One sulfonamide with potent anti-inflammatory activity has previously been reported to be selective for activated integrins, but not to inhibit platelet function. Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.

No MeSH data available.


Related in: MedlinePlus

BTT-3034 inhibits inflammatory response in mouse skin hypersensitivity model. Subcutaneous sensitization with ovalbumin and Al(OH)3 (100 μg and 3.3 mg/400 μL, respectively) was done on day 1 and 8 for female BALB/cAnNCrl mice. On day 13 vehicle, dexamethasone (0.1 mg/kg) and the indicated concentrations of BTT-3034 were administrated p.o. 48 h, 24 h, and 2 h before ovalbumin challenge. There were 10 mice in each group. Ear thickness was measured 3 h, 24 h, and 48 h after ovalbumin challenge. *P < 0.05; ***P < 0.001 (One-way ANOVA followed by Bonferroni’s post hoc comparisons tests). The data are shown as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492762&req=5

fig03: BTT-3034 inhibits inflammatory response in mouse skin hypersensitivity model. Subcutaneous sensitization with ovalbumin and Al(OH)3 (100 μg and 3.3 mg/400 μL, respectively) was done on day 1 and 8 for female BALB/cAnNCrl mice. On day 13 vehicle, dexamethasone (0.1 mg/kg) and the indicated concentrations of BTT-3034 were administrated p.o. 48 h, 24 h, and 2 h before ovalbumin challenge. There were 10 mice in each group. Ear thickness was measured 3 h, 24 h, and 48 h after ovalbumin challenge. *P < 0.05; ***P < 0.001 (One-way ANOVA followed by Bonferroni’s post hoc comparisons tests). The data are shown as mean ± SEM.

Mentions: To investigate the effects of the integrin inhibitor BTT-3034 on allergic inflammation, mice were sensitized with ovalbumin. This model measures delayed type hypersensitivity reaction. Ear thickness was determined 3 h, 24 h, and 48 h after the challenge. Dexamethasone significantly reduced inflammation (about 53% at 3 h, about 40% at 24 h, and about 47% at 48 h). BTT-3034 had also significant but slightly weaker inhibitory effect on inflammation at 48 h time point (about 35%) (Fig.3). BTT-3033 was not effective at 10 mg/kg but reduced ear thickness at 40 mg/kg at 24 h and 48 h time point (data not shown).


Sulfonamide inhibitors of α2β1 integrin reveal the essential role of collagen receptors in in vivo models of inflammation.

Nissinen L, Ojala M, Langen B, Dost R, Pihlavisto M, Käpylä J, Marjamäki A, Heino J - Pharmacol Res Perspect (2015)

BTT-3034 inhibits inflammatory response in mouse skin hypersensitivity model. Subcutaneous sensitization with ovalbumin and Al(OH)3 (100 μg and 3.3 mg/400 μL, respectively) was done on day 1 and 8 for female BALB/cAnNCrl mice. On day 13 vehicle, dexamethasone (0.1 mg/kg) and the indicated concentrations of BTT-3034 were administrated p.o. 48 h, 24 h, and 2 h before ovalbumin challenge. There were 10 mice in each group. Ear thickness was measured 3 h, 24 h, and 48 h after ovalbumin challenge. *P < 0.05; ***P < 0.001 (One-way ANOVA followed by Bonferroni’s post hoc comparisons tests). The data are shown as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492762&req=5

fig03: BTT-3034 inhibits inflammatory response in mouse skin hypersensitivity model. Subcutaneous sensitization with ovalbumin and Al(OH)3 (100 μg and 3.3 mg/400 μL, respectively) was done on day 1 and 8 for female BALB/cAnNCrl mice. On day 13 vehicle, dexamethasone (0.1 mg/kg) and the indicated concentrations of BTT-3034 were administrated p.o. 48 h, 24 h, and 2 h before ovalbumin challenge. There were 10 mice in each group. Ear thickness was measured 3 h, 24 h, and 48 h after ovalbumin challenge. *P < 0.05; ***P < 0.001 (One-way ANOVA followed by Bonferroni’s post hoc comparisons tests). The data are shown as mean ± SEM.
Mentions: To investigate the effects of the integrin inhibitor BTT-3034 on allergic inflammation, mice were sensitized with ovalbumin. This model measures delayed type hypersensitivity reaction. Ear thickness was determined 3 h, 24 h, and 48 h after the challenge. Dexamethasone significantly reduced inflammation (about 53% at 3 h, about 40% at 24 h, and about 47% at 48 h). BTT-3034 had also significant but slightly weaker inhibitory effect on inflammation at 48 h time point (about 35%) (Fig.3). BTT-3033 was not effective at 10 mg/kg but reduced ear thickness at 40 mg/kg at 24 h and 48 h time point (data not shown).

Bottom Line: Since α2β1 integrin is abundantly expressed on various inflammation-associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti-inflammatory properties.Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid-induced ear edema, PAF stimulated air pouch, ovalbumin-induced skin hypersensitivity, adjuvant arthritis, and collagen-induced arthritis.Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Turku 20014, Turku, Finland ; Biotie Therapies Corp Turku, Finland.

ABSTRACT
Small molecule inhibitors of α2β1 integrin, a major cellular collagen receptor, have been reported to inhibit platelet function, kidney injury, and angiogenesis. Since α2β1 integrin is abundantly expressed on various inflammation-associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti-inflammatory properties. Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid-induced ear edema, PAF stimulated air pouch, ovalbumin-induced skin hypersensitivity, adjuvant arthritis, and collagen-induced arthritis. Thus, these sulfonamides are potential drugs for acute and allergic inflammation, hypersensitivity, and arthritis. One sulfonamide with potent anti-inflammatory activity has previously been reported to be selective for activated integrins, but not to inhibit platelet function. Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.

No MeSH data available.


Related in: MedlinePlus