Suppression of Eosinophil Integrins Prevents Remodeling of Airway Smooth Muscle in Asthma

Abstract

Background: Airway smooth muscle (ASM) remodeling is an important component of the structural changes to airways seen in asthma. Eosinophils are the prominent inflammatory cells in asthma, and there is some evidence that they contribute to ASM remodeling via released mediators and direct contact through integrin–ligand interactions. Eosinophils express several types of outer membrane integrin, which are responsible for cell–cell and cell–extracellular matrix interactions. In our previous study we demonstrated that asthmatic eosinophils show increased adhesion to ASM cells and it may be important factor contributing to ASM remodeling in asthma. According to these findings, in the present study we investigated the effects of suppression of eosinophil integrin on eosinophil-induced ASM remodeling in asthma.Materials and Methods: Individual combined cell cultures of immortalized human ASM cells and eosinophils from peripheral blood of 22 asthmatic patients and 17 healthy controls were prepared. Eosinophil adhesion was evaluated using eosinophil peroxidase activity assay. Genes expression levels in ASM cells and eosinophils were measured using quantitative real-time PCR. ASM cell proliferation was measured using alamarBlue® solution. Eosinophil integrins were blocked by incubating with Arg-Gly-Asp-Ser peptide.Results: Eosinophils from the asthma group showed increased outer membrane α4β1 and αMβ2 integrin expression, increased adhesion to ASM cells, and overexpression of TGF-β1 compared with eosinophils from the healthy control group. Blockade of eosinophil RGD-binding integrins by Arg-Gly-Asp-Ser peptide significantly reduced adhesion of eosinophils to ASM cells in both groups. Integrin-blocking decreased the effects of eosinophils on TGF-β1, WNT-5a, and extracellular matrix protein gene expression in ASM cells and ASM cell proliferation in both groups. These effects were more pronounced in the asthma group compared with the control group.Conclusion: Suppression of eosinophil-ASM interaction via RGD-binding integrins attenuates eosinophil-induced ASM remodeling in asthma.Trial Registration: ClinicalTrials.gov Identifier: NCT02648074.

Shaping eosinophil identity in the tissue contexts of development, homeostasis, and disease

“…Moreover, eosinophils contain heparanase, a pivotal enzyme for ECM degradation, and eosinophil MBP was identified as heparanase‐inhibiting protein . TGF‐β release by eosinophils plays another important role in asthma, as TGF‐β1 has been shown to induce airway smooth muscle (ASM) cell growth and is a key mediator involved in the tissue remodeling of the asthmatic lung . ASM cells also have an effect on eosinophils by stimulating eosinophil differentiation.…”

“…114 TGF-release by eosinophils plays another important role in asthma, as TGF-1 has been shown to induce airway smooth muscle (ASM) cell growth and is a key mediator involved in the tissue remodeling of the asthmatic lung. 115 ASM cells also have an effect on eosinophils by stimulating eosinophil differentiation. Both IL-5 and GM-CSF are suggested as the key factors produced by ASM cells that promote this process.…”

In Vivo Allergen-Activated Eosinophils Promote Collagen I and Fibronectin Gene Expression in Airway Smooth Muscle Cells via TGF-β1 Signaling Pathway in Asthma

“…It was shown that eosinophils have various integrins, but the two heterodimers (αMβ2 and α4β1) are the most important integrins in migration as they recognize the adhesion molecules of pulmonary structural cells and are dysregulated in asthma [31]. In our previous publications, we showed that AA eosinophils had higher outer membrane integrins αMβ2 and α4β1 gene expression compared to HS [27,32]. It shows that AA eosinophils are more activated as the molecules that are responsible for adherence are upregulated, and it helps eosinophils to migrate through the wall of vessels and continue the movement to bronchial tissue interacting with pulmonary structural cells and ECM proteins.…”

Gene co-expression networks in whole blood implicate multiple interrelated molecular pathways in obese asthma

“…That a gene module associated with obese asthma is enriched for these two molecular pathways may be especially important, potentially identifying molecular processes that contribute to impaired lung function [32], increased airway obstruction [10], and reduced responsiveness to corticosteroid [33] and bronchodilator therapies [34] observed in obese asthmatics. Supporting this notion, in vitro suppression of eosinophil-derived integrins prevented airway smooth muscle remodeling in samples from asthmatic individuals (of unknown BMI) [35]. Airway smooth muscle function has also been shown to be affected by consumption of a high-fat diet [36], a key exposure in the development of obesity.…”