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γ-Secretase Inhibitor Alleviates Acute Airway Inflammation of Allergic Asthma in Mice by Downregulating Th17 Cell Differentiation.

Zhang W, Zhang X, Sheng A, Weng C, Zhu T, Zhao W, Li C - Mediators Inflamm. (2015)

Bottom Line: Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma.GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs.GSI also significantly suppressed Th17-cell responses in spleen and reduced IL-17 levels in serum.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Pulmonology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou, Zhejiang 325027, China.

ABSTRACT
T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma. The aim of this study was to evaluate the effect of GSI on Th17 cell differentiation in a mouse model of allergic asthma. OVA was used to induce mouse asthma model in the presence and absence of GSI. GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs. GSI also significantly suppressed Th17-cell responses in spleen and reduced IL-17 levels in serum. These findings suggest that GSI directly regulates Th17 responses through a Notch signaling-dependent pathway in mouse model of allergic asthma, supporting the notion that GSI is a potential therapeutic agent for the treatment of allergic asthma.

No MeSH data available.


Related in: MedlinePlus

γ-Secretase inhibitor (GSI) reduced OVA-induced airway inflammation. (a) BALB/C mice were sensitized i.p. with OVA and challenged with OVA in the presence and absence of GSI. Mice were sacrificed within 24 hr after last challenge. Lung tissues were stained with haematoxylin and eosin and subjected to light microscope (×200) examination. (b) Semiquantitative pathology scores among sham, OVA, and OVA + GSI groups. Data expressed as Mean ± SEM. N = 8 mice per group. ∗P < 0.01 compared with the sham group; #P < 0.01 compared with the vehicle group.
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fig2: γ-Secretase inhibitor (GSI) reduced OVA-induced airway inflammation. (a) BALB/C mice were sensitized i.p. with OVA and challenged with OVA in the presence and absence of GSI. Mice were sacrificed within 24 hr after last challenge. Lung tissues were stained with haematoxylin and eosin and subjected to light microscope (×200) examination. (b) Semiquantitative pathology scores among sham, OVA, and OVA + GSI groups. Data expressed as Mean ± SEM. N = 8 mice per group. ∗P < 0.01 compared with the sham group; #P < 0.01 compared with the vehicle group.

Mentions: To explore the effect of GSI on OVA-induced asthma, BABL/C mice were sensitized and challenged with OVA (or NS for sham mice). Those mice received GSI, a highly selective inhibitor of γ-secretase or vehicle (DMSO), during the challenge phase. Mice were sacrificed within 24 h after the last allergen challenge and lung tissue was fixed, embedded, and sectioned for HE staining. The degree of airway inflammation of HE-stained lung tissue was scored as described in Materials and Methods. As shown in Figure 2(a), OVA + DMSO group demonstrated significant infiltration of eosinophils and lymphocytes with marked thickening of airway wall and epithelial goblet cell metaplasia, as compared with the sham group. GSI treatment reduced such inflammation and airway wall thickening (Figure 2(b)). OVA-challenged mice showed an inflammation score of 3.25 ± 0.46 as compared to sham control (0.38 ± 0.52). GSI treated group showed a score of 1.88 ± 0.64 that is significantly lower than OVA-DMSO group (Figure 2(b), P < 0.01).


γ-Secretase Inhibitor Alleviates Acute Airway Inflammation of Allergic Asthma in Mice by Downregulating Th17 Cell Differentiation.

Zhang W, Zhang X, Sheng A, Weng C, Zhu T, Zhao W, Li C - Mediators Inflamm. (2015)

γ-Secretase inhibitor (GSI) reduced OVA-induced airway inflammation. (a) BALB/C mice were sensitized i.p. with OVA and challenged with OVA in the presence and absence of GSI. Mice were sacrificed within 24 hr after last challenge. Lung tissues were stained with haematoxylin and eosin and subjected to light microscope (×200) examination. (b) Semiquantitative pathology scores among sham, OVA, and OVA + GSI groups. Data expressed as Mean ± SEM. N = 8 mice per group. ∗P < 0.01 compared with the sham group; #P < 0.01 compared with the vehicle group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4539120&req=5

fig2: γ-Secretase inhibitor (GSI) reduced OVA-induced airway inflammation. (a) BALB/C mice were sensitized i.p. with OVA and challenged with OVA in the presence and absence of GSI. Mice were sacrificed within 24 hr after last challenge. Lung tissues were stained with haematoxylin and eosin and subjected to light microscope (×200) examination. (b) Semiquantitative pathology scores among sham, OVA, and OVA + GSI groups. Data expressed as Mean ± SEM. N = 8 mice per group. ∗P < 0.01 compared with the sham group; #P < 0.01 compared with the vehicle group.
Mentions: To explore the effect of GSI on OVA-induced asthma, BABL/C mice were sensitized and challenged with OVA (or NS for sham mice). Those mice received GSI, a highly selective inhibitor of γ-secretase or vehicle (DMSO), during the challenge phase. Mice were sacrificed within 24 h after the last allergen challenge and lung tissue was fixed, embedded, and sectioned for HE staining. The degree of airway inflammation of HE-stained lung tissue was scored as described in Materials and Methods. As shown in Figure 2(a), OVA + DMSO group demonstrated significant infiltration of eosinophils and lymphocytes with marked thickening of airway wall and epithelial goblet cell metaplasia, as compared with the sham group. GSI treatment reduced such inflammation and airway wall thickening (Figure 2(b)). OVA-challenged mice showed an inflammation score of 3.25 ± 0.46 as compared to sham control (0.38 ± 0.52). GSI treated group showed a score of 1.88 ± 0.64 that is significantly lower than OVA-DMSO group (Figure 2(b), P < 0.01).

Bottom Line: Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma.GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs.GSI also significantly suppressed Th17-cell responses in spleen and reduced IL-17 levels in serum.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Pulmonology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou, Zhejiang 325027, China.

ABSTRACT
T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma. The aim of this study was to evaluate the effect of GSI on Th17 cell differentiation in a mouse model of allergic asthma. OVA was used to induce mouse asthma model in the presence and absence of GSI. GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs. GSI also significantly suppressed Th17-cell responses in spleen and reduced IL-17 levels in serum. These findings suggest that GSI directly regulates Th17 responses through a Notch signaling-dependent pathway in mouse model of allergic asthma, supporting the notion that GSI is a potential therapeutic agent for the treatment of allergic asthma.

No MeSH data available.


Related in: MedlinePlus