[논문]Suppressive Effect of CYM50358 S1P4 Antagonist on Mast Cell Degranulation and Allergic Asthma in Mice

Jeon, Wi-Jin; Chung, Ki Wung; Lee, Joon-Hee; Im, Dong-Soon

doi:10.4062/biomolther.2020.206

Suppressive Effect of CYM50358 S1P4 Antagonist on Mast Cell Degranulation and Allergic Asthma in Mice 원문보기

Biomolecules & therapeutics, v.29 no.5, 2021년, pp.492 - 497

Jeon, Wi-Jin (College of Pharmacy, Pusan National University) , Chung, Ki Wung (College of Pharmacy, Pusan National University) , Lee, Joon-Hee (College of Pharmacy, Pusan National University) , Im, Dong-Soon (College of Pharmacy, Pusan National University)

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Levels of sphingosine 1-phosphate (S1P), an intercellular signaling molecule, reportedly increase in the bronchoalveolar lavage fluids of patients with asthma. Although the type 4 S1P receptor, S1P4 has been detected in mast cells, its functions have been poorly investigated in an allergic asthma model in vivo. S1P4 functions were evaluated following treatment of CYM50358, a selective antagonist of S1P4, in an ovalbumin-induced allergic asthma model, and antigen-induced degranulation of mast cells. CYM50358 inhibited antigen-induced degranulation in RBL-2H3 mast cells. Eosinophil accumulation and an increase of Th2 cytokine levels were measured in the bronchoalveolar lavage fluid and via the inflammation of the lungs in ovalbumin-induced allergic asthma mice. CYM50358 administration before ovalbumin sensitization and before the antigen challenge strongly inhibited the increase of eosinophils and lymphocytes in the bronchoalveolar lavage fluid. CYM50358 administration inhibited the increase of IL-4 cytokines and serum IgE levels. Histological studies revealed that CYM50358 reduced inflammatory scores and PAS (periodic acid-Schiff)-stained cells in the lungs. The pro-allergic functions of S1P4 were elucidated using in vitro mast cells and in vivo ovalbumin-induced allergic asthma model experiments. These results suggest that S1P4 antagonist CYM50358 may have therapeutic potential in the treatment of allergic asthma.

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표/그림 (5)

그림 Fig. 1. CYM50358 represses antigen-induced degranulation in RBL-2H3 mast cells. After sensitization with anti-DNP IgE for 18 h, RBL-2H3 cells were challenged with DNP human serum albumin (HSA). CYM50358 was treated at the indicated concentrations 30 min before antigen challenge. Basal degranulation shows samples without IgE and HSA, and the positive control of antigen-induced degranulation is shown in the samples with IgE and HSA. The results are presented as the means ± standard error (SE) of three independent experiments. ***p<0.001 vs. the HSA-untreated group. ^###p<0.001 vs. the HSA-treated group.
그림 Fig. 2. CYM50358 represses OVA-induced immune cell accumulation in BALF. (A) Mice were sensitized with OVA twice by i.p. injection on day 0 (D0) and D14, and later challenged on D28, D29, and D30 with nebulized OVA. CYM50358 was administrated intraperitoneally at the dose of 10 mg/kg, 30 min before OVA sensitization or before OVA challenge. BALF cells were stained using May- Grünwald stain and counted. (B) Total cell counts, eosinophils, and macrophages in BALF. (C) Lymphocytes counts in the BALF. The results are presented as the mean ± SE cell count values (n=5). ***p<0.001 vs. the PBS-treated group, ^##p<0.01, ^###p<0.001 vs. the OVA-treated group.
그림 Fig. 3. CYM50358 protects against airway inflammation. (A) Panels show H&E-stained sections of lung tissues from the PBS group, OVA group, and CYM50358-treated OVA groups (before sensitization or before challenge). Small navy blue dots around the bronchioles indicates eosinophils. Eosinophils are scarcely observed in the PBS group, whereas they are densely accumulated around bronchioles in the OVA group (green arrows). However, eosinophil accumulation was less obvious in the OVA+CYM50358 groups than in the OVA group. (B) Lung inflammation was semi-quantitatively evaluated; histological findings were scored as described in the Materials and methods section. Values represent the means ± SEs (n=5). ***p<0.001 vs. the PBS-treated group, ^###p<0.001 vs. the OVA-treated group.
그림 Fig. 4. CYM50358 protects against mucin production. (A) Panels show PAS/hematoxylin-stained sections of lung tissues from the PBS group, OVA group, and CYM50358-treated OVA groups (before sensitization or before challenge). In PAS staining, mucin is stained as purple color. Darker and thicker purple color is observed surrounding the bronchiole in the OVA group compared to the PBS group. (B) Mucous production was measured by counting the number of PAS-positive cells (red arrows) per mm of bronchiole (n=5 per group). ***p<0.001 vs. the PBS-treated group, ^###p<0.001 vs. the OVA-treated group.
그림 Fig. 5. Effect of CYM50358 on IgE levels in serum and IL-4 levels in BALF. (A) Serum IgE levels. Results are presented as means ± SEM (n=5). ***p<0.001 vs. the PBS-treated group, ^#p<0.05, ^###p<0.001 vs. the OVA-treated group. (B) ELISA was used to measure the protein levels of IL-4 in BALF. The results represent the mean ± SE of protein levels (n=5). ***p<0.001 vs. the PBS-treated group, ^###p<0.001 vs. the OVA-treated group.

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