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Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice.

Li X, Johnson KR, Bryant M, Elkahloun AG, Amar M, Remaley AT, De Silva R, Hallenbeck JM, Quandt JA - PLoS ONE (2011)

Bottom Line: A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin.This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes.Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE-/- mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE-/- mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke.

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Treatment regimens.Mice received 2 rounds of intranasal delivery of E-selectin or PBS. The 2 rounds of intranasal delivery were separated by 2 weeks and each round of intranasal delivery was composed of 5 doses (PBS or 5 µg E-selectin per dose) with 1 dose (10 µl) every other day. In regimen A (N = 10 per group), we initiated the intranasal delivery of solutions and the high-fat diet simultaneously. In regimen B (N = 25 per group), we gave the mice intranasal delivery of solutions prior to initiating the high-fat diet.
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pone-0020620-g001: Treatment regimens.Mice received 2 rounds of intranasal delivery of E-selectin or PBS. The 2 rounds of intranasal delivery were separated by 2 weeks and each round of intranasal delivery was composed of 5 doses (PBS or 5 µg E-selectin per dose) with 1 dose (10 µl) every other day. In regimen A (N = 10 per group), we initiated the intranasal delivery of solutions and the high-fat diet simultaneously. In regimen B (N = 25 per group), we gave the mice intranasal delivery of solutions prior to initiating the high-fat diet.

Mentions: Animals in this pilot study were assessed after 7 weeks on high-fat diet and having received either regimen A (N = 10 per group), with intranasal administration begun at the start of high-fat diet; or regimen B (pre-tolerization, N = 25 per group), with intranasal administrations completed just prior to the initiation of high-fat diet (Figure 1). In regimen A, after 7 weeks on high-fat diet, we collected aortas (for En Face), and splenocytes (for T cell proliferation and cytokine assays); after 13 weeks on high-fat diet, we collected upper hearts and proximal aortas for immunohistochemistry from 5 mice per group. In regimen B, after 7 weeks on a high-fat diet, we collected aortas (10 mice per group for En Face and 5 mice per group for Movet staining), and splenocytes (5 mice per group for T cell proliferation and cytokine assays); after 10 weeks on a high-fat diet, we collected aortic RNA and performed microarray (3 mice for PBS group, 4 mice for E-selectin group). For both regimens, we collected serum for all analyses performed on serum after 7 weeks on a high-fat diet (5 mice per group in regimen A and 24 mice for the PBS group and 23 mice for the E-selectin group in regimen B).


Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice.

Li X, Johnson KR, Bryant M, Elkahloun AG, Amar M, Remaley AT, De Silva R, Hallenbeck JM, Quandt JA - PLoS ONE (2011)

Treatment regimens.Mice received 2 rounds of intranasal delivery of E-selectin or PBS. The 2 rounds of intranasal delivery were separated by 2 weeks and each round of intranasal delivery was composed of 5 doses (PBS or 5 µg E-selectin per dose) with 1 dose (10 µl) every other day. In regimen A (N = 10 per group), we initiated the intranasal delivery of solutions and the high-fat diet simultaneously. In regimen B (N = 25 per group), we gave the mice intranasal delivery of solutions prior to initiating the high-fat diet.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3119064&req=5

pone-0020620-g001: Treatment regimens.Mice received 2 rounds of intranasal delivery of E-selectin or PBS. The 2 rounds of intranasal delivery were separated by 2 weeks and each round of intranasal delivery was composed of 5 doses (PBS or 5 µg E-selectin per dose) with 1 dose (10 µl) every other day. In regimen A (N = 10 per group), we initiated the intranasal delivery of solutions and the high-fat diet simultaneously. In regimen B (N = 25 per group), we gave the mice intranasal delivery of solutions prior to initiating the high-fat diet.
Mentions: Animals in this pilot study were assessed after 7 weeks on high-fat diet and having received either regimen A (N = 10 per group), with intranasal administration begun at the start of high-fat diet; or regimen B (pre-tolerization, N = 25 per group), with intranasal administrations completed just prior to the initiation of high-fat diet (Figure 1). In regimen A, after 7 weeks on high-fat diet, we collected aortas (for En Face), and splenocytes (for T cell proliferation and cytokine assays); after 13 weeks on high-fat diet, we collected upper hearts and proximal aortas for immunohistochemistry from 5 mice per group. In regimen B, after 7 weeks on a high-fat diet, we collected aortas (10 mice per group for En Face and 5 mice per group for Movet staining), and splenocytes (5 mice per group for T cell proliferation and cytokine assays); after 10 weeks on a high-fat diet, we collected aortic RNA and performed microarray (3 mice for PBS group, 4 mice for E-selectin group). For both regimens, we collected serum for all analyses performed on serum after 7 weeks on a high-fat diet (5 mice per group in regimen A and 24 mice for the PBS group and 23 mice for the E-selectin group in regimen B).

Bottom Line: A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin.This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes.Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE-/- mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE-/- mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke.

Show MeSH
Related in: MedlinePlus