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Front Physiol
2018 Jan 01;9:1183. doi: 10.3389/fphys.2018.01183.
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Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma.
Dos Santos TM
,
Righetti RF
,
Camargo LDN
,
Saraiva-Romanholo BM
,
Aristoteles LRCRB
,
de Souza FCR
,
Fukuzaki S
,
Alonso-Vale MIC
,
Cruz MM
,
Prado CM
,
Leick EA
,
Martins MA
,
Tibério IFLC
.
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Background: Interleukin-17 (IL-17) and Rho-kinase (ROCK) play an important role in regulating the expression of inflammatory mediators, immune cell recruitment, hyper-responsiveness, tissue remodeling, and oxidative stress. Modulation of IL-17 and ROCK proteins may represent a promising approach for the treatment of this disease. Objective: To study the effects of an anti-IL17 neutralizing antibody and ROCK inhibitor treatments, separately and in combination, in a murine model of chronic allergy-induced lung inflammation. Methods: Sixty-four BALBc mice, were divided into eight groups (n = 8): SAL (saline-instilled); OVA (exposed-ovalbumin); SAL-RHOi (saline and ROCK inhibitor), OVA-RHOi (exposed-ovalbumin and ROCK inhibitor); SAL-anti-IL17 (saline and anti-IL17); OVA-anti-IL17 (exposed-ovalbumin and anti-IL17); SAL-RHOi-anti-IL17 (saline, ROCK inhibitor and anti-IL17); and OVA-RHOi-anti-IL17 (exposed-ovalbumin, anti-IL17, and ROCK inhibitor). A 28-day protocol of albumin treatment was used for sensitization and induction of pulmonary inflammation. The anti-IL17A neutralizing antibody (7.5 μg per treatment) was administered by intraperitoneal injection and ROCK inhibitor (Y-27632) intranasally (10 mg/kg), 1 h prior to each ovalbumin challenge (days 22, 24, 26, and 28). Results: Treatment with the anti-IL17 neutralizing antibody and ROCK inhibitor attenuated the percentage of maximal increase of respiratory system resistance and respiratory system elastance after challenge with methacholine and the inflammatory response markers evaluated (CD4+, CD8+, ROCK1, ROCK2, IL-4, IL-5, IL-6, IL-10 IL-13, IL-17, TNF-α, TGF-β, NF-κB, dendritic cells, iNOS, MMP-9, MMP-12, TIMP-1, FOXP3, isoprostane, biglycan, decorin, fibronectin, collagen fibers content and gene expression of IL-17, VAChT, and arginase) compared to the OVA group (p < 0.05). Treatment with anti-IL17 and the ROCK inhibitor together resulted in potentiation in decreasing the percentage of resistance increase after challenge with methacholine, decreased the number of IL-5 positive cells in the airway, and reduced, IL-5, TGF-β, FOXP3, ROCK1 and ROCK2 positive cells in the alveolar septa compared to the OVA-RHOi and OVA-anti-IL17 groups (p < 0.05). Conclusion: Anti-IL17 treatment alone or in conjunction with the ROCK inhibitor, modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in mice with chronic allergic lung inflammation.
FIGURE 1. Protocol for sensitization and induction of the inflammatory response. On days 1 and 14, the OVA, OVA-RHOi, OVA-anti-IL17, and OVA-RHOi-anti-IL17 groups were sensitized with ovalbumin (i.p.) and the control groups SAL, SAL-RHOi, SAL-anti-IL17, and SAL-RHOi-anti-IL17 received saline solution (i.p.). On days 22, 24, 26, and 28, 1 h prior to challenge, treatment groups received anti-IL17 (i.p.) and/or ROCK inhibitor (intranasal).
FIGURE 2. Markers, dilution, primary antibody, and specifications.
FIGURE 5. Effects of anti-IL17 and ROCK inhibitor treatment on BALF (A) Total cells, (B) cell differential for eosinophils, (C) cell differential for macrophages, (D) cell differential for neutrophils, (E) cell differential for lymphocytes. ∗p < 0.05 compared to SAL;∗∗p < 0.05 compared to OVA.
FIGURE 6. Effects of anti-IL17 and the ROCK inhibitor on IL-17 gene expression and IL-17 positive cell number. (A) Number of IL-17 positive cells in the airways, (B) number of IL-17 positive cells in the alveolar septa, and (C) the levels of IL-17 mRNA assessed by RT-PCR (AU). ∗p < 0.05 compared to the SAL group;∗∗p < 0.05 compared to the OVA group; #p < 0.05 compared to OVA-RHOi group.
FIGURE 7. Effects of anti-IL17 and the ROCK inhibitor on oxidative stress. (A,B) 8-iso-PGF2α volume fraction in the airway and alveolar septa, respectively, and (C,D) iNOS-positive cells in the airway and alveolar septa, respectively. The results are expressed as positive cells/104 μm2 and the volume fraction is expressed as percentages of total area (%). ∗p < 0.05 compared to the SAL group; ∗∗p < 0.05 compared to the OVA group; #p < 0.05 compared to the OVA-anti-IL17 group.
FIGURE 8. Effects of anti-IL17 and the ROCK inhibitor on arginase-1 (A) and VAChT (B) gene expression. The levels of mRNA in the lung were evaluated using RT-PCR (AU). ∗p < 0.05 compared to the SAL group; ∗∗p < 0.05 compared to the OVA group.
FIGURE 9. Inflammatory, extracellular matrix remodeling and oxidative stress markers in airways: Photomicrographs of IL-5, IL-13, IL-17, ROCK1, ROCK2, TIMP-1, MMP-9, iNOS, and isoprostane immunohistochemical stain in the airways. 1,000× magnification. All experimental groups are represented: SAL, OVA, OVA-RHOi, OVA-antiIL17, and OVA-RHOi-anti-IL17 groups. The red arrow indicate de positive cells.
FIGURE 10. Inflammatory, extracellular matrix remodeling and oxidative stress markers in alveolar septa: Photomicrographs of IL-5, IL-13, IL-17, ROCK1, ROCK2, TIMP-1, MMP-9, iNOS and isoprostane immunohistochemical stain in lung tissue. 1000× magnification. All experimental groups are represented: SAL, OVA, OVA-RHOi, OVA-antiIL17 and OVA-RHOi-anti-IL17 groups. The red arrow indicate de positive cells.
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