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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 guinea pig skin allergic inflammation model. Male HA guinea pigs were sensitized intraperitoneally with ovalbumin and Al(OH)3 (20 μg and 20 mg, respectively). In the final experiment after 3 weeks the guinea pigs were challenged with 0.1% ovalbumin solution on the back skin. Vehicle (n = 6), dexamethasone (Dexam, 0.1 mg/kg, n = 5), and indicated concentrations of BTT-3034 (n = 6 in both groups) were administrated orally once a day for 3 days before the ovalbumin treatment. The response was measured 60 min after the challenge by measuring the diameter of allergic wheals. The data are presented as change in the area of allergic wheals. *P < 0.05; ***P < 0.001 (One-way ANOVA followed by Bonferroni’s post hoc comparisons tests). The data are shown as mean ± SEM.
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fig04: BTT-3034 inhibits inflammatory response in guinea pig skin allergic inflammation model. Male HA guinea pigs were sensitized intraperitoneally with ovalbumin and Al(OH)3 (20 μg and 20 mg, respectively). In the final experiment after 3 weeks the guinea pigs were challenged with 0.1% ovalbumin solution on the back skin. Vehicle (n = 6), dexamethasone (Dexam, 0.1 mg/kg, n = 5), and indicated concentrations of BTT-3034 (n = 6 in both groups) were administrated orally once a day for 3 days before the ovalbumin treatment. The response was measured 60 min after the challenge by measuring the diameter of allergic wheals. The data are presented as change in the area of allergic wheals. *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: BTT-3034 was further tested using a guinea pig allergic skin inflammation model. For this experiment, guinea pigs were sensitized to ovalbumin in a way (i.p.) to promote allergic immune responses. BTT-3034 inhibited the ovalbumin-induced increase in the area of allergic wheals when administrated in doses 0.75 mg/kg, 2.5 mg/kg or 10 mg/kg (Fig.4). Thus, BTT-3034 inhibited both hypersensitivity and allergic inflammation.


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 guinea pig skin allergic inflammation model. Male HA guinea pigs were sensitized intraperitoneally with ovalbumin and Al(OH)3 (20 μg and 20 mg, respectively). In the final experiment after 3 weeks the guinea pigs were challenged with 0.1% ovalbumin solution on the back skin. Vehicle (n = 6), dexamethasone (Dexam, 0.1 mg/kg, n = 5), and indicated concentrations of BTT-3034 (n = 6 in both groups) were administrated orally once a day for 3 days before the ovalbumin treatment. The response was measured 60 min after the challenge by measuring the diameter of allergic wheals. The data are presented as change in the area of allergic wheals. *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

fig04: BTT-3034 inhibits inflammatory response in guinea pig skin allergic inflammation model. Male HA guinea pigs were sensitized intraperitoneally with ovalbumin and Al(OH)3 (20 μg and 20 mg, respectively). In the final experiment after 3 weeks the guinea pigs were challenged with 0.1% ovalbumin solution on the back skin. Vehicle (n = 6), dexamethasone (Dexam, 0.1 mg/kg, n = 5), and indicated concentrations of BTT-3034 (n = 6 in both groups) were administrated orally once a day for 3 days before the ovalbumin treatment. The response was measured 60 min after the challenge by measuring the diameter of allergic wheals. The data are presented as change in the area of allergic wheals. *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: BTT-3034 was further tested using a guinea pig allergic skin inflammation model. For this experiment, guinea pigs were sensitized to ovalbumin in a way (i.p.) to promote allergic immune responses. BTT-3034 inhibited the ovalbumin-induced increase in the area of allergic wheals when administrated in doses 0.75 mg/kg, 2.5 mg/kg or 10 mg/kg (Fig.4). Thus, BTT-3034 inhibited both hypersensitivity and allergic inflammation.

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