Effect of anti-IL17 and/or Rho-kinase inhibitor treatments on vascular remodeling induced by chronic allergic pulmonary inflammation

Abstract

Background and aims: Expansion and morphological dysregulation of the bronchial vascular network occurs in asthmatic airways. Interleukin (IL) -17 and Rho-kinase (ROCK) are known to act in inflammation control and remodeling. Modulation of Rho-kinase proteins and IL-17 may be a promising approach for the treatment of asthma through the control of angiogenesis. Our objective was to analyze the effects of treatment with anti-IL17 and/or Rho-kinase inhibitor on vascular changes in mice with chronic allergic pulmonary inflammation. Methods: Sixty-four BALB/c mice, with pulmonary inflammation induced by ovalbumin were treated with anti-IL17A (7.5/µg per dose, intraperitoneal) and/or Rho-kinase inhibitor (Y-27632-10 mg/kg, intranasal), 1 h before each ovalbumin challenge (22, 24, 26, and 28/days). Control animals were made to inhale saline. At the end of the protocol, lungs were removed, and morphometric analysis was performed to quantify vascular inflammatory, remodeling, and oxidative stress responses. Results: Anti-IL17 or Rho-kinase inhibitor reduced the number of CD4+, CD8+, dendritic cells, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, Rho-kinase 1 and 2, transforming growth factor (TGF-β), vascular endothelial growth factor (VEGF), nuclear factor (NF)-KappaB, iNOS, metalloproteinase (MMP)-9, MMP-12, metalloproteinase inhibitor-1 (TIMP-1), FOXP-3, signal transducer and activator of transcription 1 (STAT1) and phospho-STAT1-positive cells, and actin, endothelin-1, isoprostane, biglycan, decorin, fibronectin and the collagen fibers volume fraction compared with the ovalbumin group ( p < 0.05). The combination treatment, when compared with anti-IL17, resulted in potentiation of decrease in the number of IL1β- and dendritic cells-positive cells. When we compared the OVA-RHO inhibitor-anti-IL17 with OVA-RHO inhibitor we found a reduction in the number of CD8+ and IL-17, TGF-β, and phospho-STAT1-positive cells and endothelin-1 in the vessels ( p < 0.05). There was an attenuation in the number of ROCK 2-positive cells in the group with the combined treatment when compared with anti-IL17 or Rho-kinase inhibitor-treated groups ( p < 0.05). Conclusion: We observed no difference in angiogenesis after treatment with Rho-kinase inhibitor and anti-IL17. Although the treatments did not show differences in angiogenesis, they showed differences in the markers involved in the angiogenesis process contributing to inflammation control and vascular remodeling. The reviews of this paper are available via the supplemental material section.

Targeting Common Inflammatory Mediators in Experimental Severe Asthma and Acute Lung Injury

“…The treatment guideline for asthma [ 57 ] offers multiple monoclonal antibodies-based treatment options for severe asthma in a phenotype-oriented manner, but there is a gap in the case of severe asthma characterized by the Th2-low/Th17 phenotype. Although anti-Il-17 administration in the later asthma phenotype [ 1 , 2 , 3 , 58 ] and in ALI [ 5 ] in murine models showed promising results, SECU effects, particularly, have not been tested yet. Moreover, in the clinical scenario of severe asthma exacerbated by infection/pneumonia that evolves to ALI, the targeting of Il-17 brings benefits not only in asthma, but may prevent or at least diminish the development of ALI.…”

“…At first sight, severe asthma and acute lung injury (ALI) do not seem to have much in common besides the clinical manifestation of acute respiratory failure. However, the inhibition of IL-17 has been demonstrated to ameliorate de Lipopolysaccharide (LPS) exacerbated asthma in murine models [ 1 , 2 , 3 , 4 ] and, at the same time, to exert protective effects on LPS-induced ALI in mice [ 5 ]. Moreover, asthma is associated with an increased risk of pneumonia [ 6 ], a predisposing clinical factor for ALI [ 7 ].…”

“…Previous experimental research revealed beneficial effects of anti-Il-17 in LPS exacerbated asthma in murine models [ 1 , 2 , 3 , 4 ] and an alleviation of ALI inflammation [ 21 ], possibly by reducing the expression of cytokines and oxidative stress [ 5 ]. Consequently, IL-17 can be considered a legitimate target in the management of acute respiratory failure associated either with severe asthma or with ALI.…”

Effects of environmental exposure to iron powder on healthy and elastase-exposed mice

“…The slides were counterstained with Harris hematoxylin (Merck, Darmstadt, Germany). Finally, the slides were mounted using Entellan microscopy resin (Merck) and subjected to morphometric analysis as described below 23 , 24 .…”

Th17/Treg Imbalance in Chronic Obstructive Pulmonary Disease: Clinical and Experimental Evidence

“…More recently, the efficiency of treatment with anti-IL-17 has been demonstrated to improve the inflammation observed in asthma ( 76 , 77 ), asthma exacerbated by LPS ( 78 , 79 ) and LPS-induced lung injury ( 80 ). In an elastase-induced model of emphysema, it was also demonstrated that both preventive and therapeutic treatment with anti-IL17 improved the evaluated inflammatory parameters in mice, including specific markers for the Th17 response ( 81 ).…”