Blood Inflammatory-like and Lung Resident-like Eosinophils Affect Migration of Airway Smooth Muscle Cells and Their ECM-Related Proliferation in Asthma

Abstract

Airway remodeling is a hallmark feature of asthma, and one of its key structural changes is increased airway smooth muscle (ASM) mass and disturbed extracellular matrix (ECM) homeostasis. Eosinophil functions in asthma are broadly defined; however, we lack knowledge about eosinophil subtypes’ interaction with lung structural cells and their effect on the airway’s local microenvironment. Therefore, we investigated the effect of blood inflammatory-like eosinophils (iEOS-like) and lung resident-like eosinophils (rEOS-like) on ASM cells via impact on their migration and ECM-related proliferation in asthma. A total of 17 non-severe steroid-free allergic asthma (AA), 15 severe eosinophilic asthma (SEA) patients, and 12 healthy control subjects (HS) were involved in this study. Peripheral blood eosinophils were enriched using Ficoll gradient centrifugation and magnetic separation, subtyped by using magnetic separation against CD62L. ASM cell proliferation was assessed by AlamarBlue assay, migration by wound healing assay, and gene expression by qRT-PCR analysis. We found that blood iEOS-like and rEOS-like cells from AA and SEA patients’ upregulated genes expression of contractile apparatus proteins, COL1A1, FN, TGF-β1 in ASM cells (p < 0.05), and SEA eosinophil subtypes demonstrated the highest effect on sm-MHC, SM22, and COL1A1 gene expression. Moreover, AA and SEA patients’ blood eosinophil subtypes promoted migration of ASM cells and their ECM-related proliferation, compared with HS (p < 0.05) with the higher effect of rEOS-like cells. In conclusion, blood eosinophil subtypes may contribute to airway remodeling by upregulating contractile apparatus and ECM component production in ASM cells, further promoting their migration and ECM-related proliferation, with a stronger effect of rEOS-like cells and in SEA.

Serum Proteomic Analysis Revealed Biomarkers for Eosinophilic Chronic Rhinosinusitis with Nasal Polyps Pathophysiology

“… 50 Furthermore, MMP-2 promotes eosinophil migration and inflammation by enhancing microvessel permeability, resulting in edema formation at the site of inflammation. 51 It was widely recognized that nasal mucosal tissue remodeling and extensive eosinophil infiltration were significant pathological characteristics of eCRSwNP. 52 , 53 Overwhelming inflammatory reactions could lead to the impairment of nasal mucosa epithelial and basal cells, ultimately fostering increased cell migration and synthesis of the extracellular matrix.…”

“…50 Furthermore, MMP-2 promotes eosinophil migration and inflammation by enhancing microvessel permeability, resulting in edema formation at the site of inflammation. 51 It was widely recognized that nasal mucosal tissue remodeling and extensive eosinophil infiltration were significant formation of nasal polyps. 54 Despite previous studies confirming the upregulation of MMP2 expression in both neCRSwNP and eCRSwNP, an increasing body of evidence suggests that MMP2 plays a more significant role in tissue remodeling mediated by eosinophils.…”

Bronchial Asthma, Airway Remodeling and Lung Fibrosis as Successive Steps of One Process

“…One of the central features of asthma is airway remodeling, defined as changes in airway wall structure, including extensive epithelial damage, airway smooth muscle hypertrophy and hyperplasia, collagen deposition, subepithelial basement membrane thickening, and fibrosis [5]. Excessive proliferation of smooth muscle cells producing a wide range of pro-inflammatory and pro-fibrotic mediators may lead to amplified airflow obstruction and extracellular matrix (ECM) deposition, ultimately resulting in fibrosis in individuals affected by asthma [6,7]. Subepithelial fibrosis observed in asthma is associated with enhanced differentiation of bronchial fibroblasts into myofibroblasts-fibroblast-to-myofibroblast transition (FMT)-induced mainly by transforming growth factor-β (TGF-β) [8].…”