The role of eosinophils in airway tissue remodelling in asthma

doi:10.1016/j.coi.2007.07.021

Current Opinion in Immunology

Volume 19, Issue 6, December 2007, Pages 681-686

https://doi.org/10.1016/j.coi.2007.07.021 Get rights and content

There is an increasing evidence that airway structural change (termed remodelling) is associated with the severity and chronicity of asthma. Recent studies support an important role for eosinophils in the remodelling process. In particular eosinophil depletion studies have demonstrated that several aspects of remodelling are attenuated. Eosinophils have been confirmed as an important source of TGF-β₁ as well as other important cytokines that can lead to the direct activation of epithelium and mesenchymal cells that are considered to drive airway remodelling. The current studies that support a role for eosinophils in airway remodelling are reviewed in article.

Introduction

Airway structural change termed remodelling is a characteristic feature of asthma. The clinical effects of airway remodelling are at present uncertain, but the accelerated lung function decline over time in asthmatics compared to non-asthmatics [1]. The development of fixed airflow obstruction in some asthmatics [2] and the association of AHR with remodelling [3] all suggest that remodelling must be an important area of therapeutic focus. It has been appreciated for a while that tissue eosinophilia and eosinophil degranulation is commonly associated with fibrotic disease [4]. Recent studies using eosinophil depletion strategies have highlighted an important role for eosinophils as important inflammatory cells in the process of airway remodelling in asthma.

Section snippets

Eosinophils

Eosinophils comprise less than 5% of the circulating white cell population in healthy individuals and are easily distinguished by their bi-lobed appearance and the characteristic granules that occupy up to one fifth of the cytoplasmic content. The primary role of the eosinophil has been considered as host defence against parasitic infection through the release of cytotoxic cellular contents. Major basic protein (MBP) accounts for 50% of the secondary granule crystalloid core and the

Eosinophils and asthma

The precise role of the eosinophil in asthma pathogenesis remains uncertain. Eosinophils traffic from the bone marrow into the lung in response to allergen challenge in atopic asthma. The products released by eosinophils have been demonstrated to promote some of the pathophysiological hallmarks of asthma such as airway hyper-responsiveness (AHR). For example direct installation of MBP and EPO induce both bronchoconstriction and AHR in the primate airway [6]. Post mortem analysis of asthma death

Airway remodelling and asthma

Inflammation can be viewed as the response of tissue to injury. The aim of this inflammatory response is to repair the injury. Rapid restoration of tissue structure following injury is essential for the maintenance of organ integrity and function and any dysregulated or excessive repair will lead to tissue fibrosis and contribute to disease states. In asthma the epithelium displays structural damage with marked goblet cell, smooth muscle and fibroblast hyperplasia together with the recruitment

Eosinophils and airway remodelling

Whilst the role of the eosinophil in asthma pathogenesis currently remains an area of vigorous debate, there has been growing recognition that the eosinophil may have an important role in airway remodelling. Most fibrotic diseases share a common paradigm of a persistent inflammatory stimulus with lymphocyte–monocyte interactions that generate fibrogenic cytokines that can initiate and even propagate fibrotic processes. It is, therefore, not unexpected that some aspects of airway structural cell

Mechanisms of eosinophil-induced remodelling

Eosinophils are implicated in both inflammation and remodelling by the release of cytokines and fibrogenic factors. Eosinophils have been identified as a significant source of TGF-β₁ in asthma. TGF-β₁ is one of the most fibrogenic factors known. Inflammatory cells probably account for the increased amounts of TGF-β₁ found in the asthmatic airway at baseline [16, 31, 32] with further increases in response to allergen challenge [32]. Eosinophils are of an activated phenotype following allergen

References (58)

D.T. Wong et al.
Eosinophils from patients with blood eosinophilia express transforming growth factor beta 1
Blood
(1991)
V.J. Thannickal et al.
Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase
J Biol Chem
(2003)
R.A. Ignotz et al.
Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-beta
J Biol Chem
(1987)
A. Solomon et al.
Nerve growth factor is preformed in and activates human peripheral blood eosinophils
J Allergy Clin Immunol
(1998)
M. Hoshino et al.
Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma
J Allergy Clin Immunol
(2001)
M. Hoshino et al.
Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis
J Allergy Clin Immunol
(2001)
S.S. Aceves et al.
Esophageal remodeling in pediatric eosinophilic esophagitis
J Allergy Clin Immunol
(2007)
P. Lange et al.
A 15-year follow-up study of ventilatory function in adults with asthma
N Engl J Med
(1998)
D. Bumbacea et al.
Parameters associated with persistent airflow obstruction in chronic severe asthma
Eur Respir J
(2004)
H.H. Kariyawasam et al.
Remodeling and airway hyperresponsiveness but not cellular inflammation persist after allergen challenge in asthma
Am J Respir Crit Care Med
(2007)

H. Noguchi et al.

Tissue eosinophilia and eosinophil degranulation in syndromes associated with fibrosis

Am J Pathol

(1992)

H.H. Kariyawasam et al.

The eosinophil: the cell and its weapons, the cytokines, its locations

Semin Respir Crit Care Med

(2006)

R.H. Gundel et al.

Human eosinophil major basic protein induces airway constriction and airway hyper-responsiveness in primates

J Clin Invest

(1991)

A.D. Fryer et al.

Antibody to VLA-4, but not to L-selectin, protects neuronal M2 muscarinic receptors in antigen-challenged guinea pig airways

J Clin Invest

(1997)

M.C. O’Donnell et al.

Activation of basophil and mast cell histamine release by eosinophil granule major basic protein

J Exp Med

(1983)

J.N. Moy et al.

Noncytotoxic activation of neutrophils by eosinophil granule major basic protein. Effect on superoxide anion generation and lysosomal enzyme release

J Immunol

(1990)

A.S. Cowburn et al.

Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma

J Clin Invest

(1998)

Z. Marom et al.

Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro

Am Rev Respir Dis

(1982)

I. Joris et al.

The mechanism of vascular leakage induced by leukotriene E4. Endothelial contraction

Am J Pathol

(1987)

E. Adelroth et al.

Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls

N Engl J Med

(1986)

A.E. Postlethwaite et al.

Identification of a chemotactic epitope in human transforming growth factor-beta 1 spanning amino acid residues 368–374

J Cell Physiol

(1995)

A.M. Vignola et al.

Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis

Am J Respir Crit Care Med

(1997)

R.J. McAnulty et al.

Regulation of fibroblast procollagen production. Transforming growth factor-beta 1 induces prostaglandin E2 but not procollagen synthesis via a pertussis toxin-sensitive G-protein

Biochem J

(1995)

P.T. Flood-Page et al.

Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway

Am J Respir Crit Care Med

(2003)

J.J. Lee et al.

Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma

J Exp Med

(1997)

J.Y. Cho et al.

Inhibition of airway remodeling in IL-5-deficient mice

J Clin Invest

(2004)

C. Yu et al.

Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo

J Exp Med

(2002)

A.A. Humbles et al.

A critical role for eosinophils in allergic airways remodeling

Science

(2004)

J.J. Lee et al.

Defining a link with asthma in mice congenitally deficient in eosinophils

Science

(2004)

Cited by (92)

REALITI-A Study: Real-World Oral Corticosteroid-Sparing Effect of Mepolizumab in Severe Asthma
2022, Journal of Allergy and Clinical Immunology: In Practice
Patients with severe asthma may require maintenance oral corticosteroids (mOCS) for disease control as well as systemic corticosteroid (SCS) bursts for clinically significant exacerbations. However, mOCS and SCS use are associated with adverse effects, which increases patient disease burden.
To assess the real-world corticosteroid-sparing effect of mepolizumab in patients with severe asthma.
REALITI-A was a 24-month international, prospective, observational cohort study involving 84 centers across Europe, Canada, and the United States, with a 1-year pre-post mepolizumab treatment preplanned interim analysis. A total of 822 adults with a clinical diagnosis of asthma and a physician decision to initiate mepolizumab treatment (100 mg subcutaneously) were included. End points included daily mOCS dose at baseline (penultimate 28 days of pretreatment) and 1 year after treatment; percent reduction from baseline in mOCS dose; patients discontinuing mOCS 1 year after treatment; and the rate of clinically significant exacerbations (those requiring OCS for 3 days or more [or parenteral administration], emergency room visit, and/or hospital admission) before and after treatment.
A total of 319 patients received mOCS at baseline (median [interquartile range]: 10.0 [5.0-15.0] mg/d). At 1 year after treatment, median mOCS dose was reduced by 75% (2.5 [0.0-5.0] mg/d); 64% of patients had a reduction in mOCS dose of 50% or greater compared with baseline and 43% discontinued mOCS. Clinically significant exacerbations decreased between pretreatment and posttreatment (rate ratio [95% confidence interval] 0.29 [0.26-0.32]; P < .001).
This 1-year analysis demonstrates that real-world mepolizumab treatment is clinically effective in patients with severe asthma, providing disease control while reducing the need for mOCS and SCS bursts.
Allergic and eosinophilic asthma in the era of biomarkers and biologics: similarities, differences and misconceptions: Similarities, differences, and misconceptions
2022, Annals of Allergy, Asthma and Immunology
Severe asthma is associated with substantial personal and economic burden; maintaining disease control is the key management goal. Increased understanding of asthma heterogeneity and development of type 2 (T2)-targeting biologics has substantially advanced disease management and outcomes; however, despite both being driven by T2 inflammation, allergic and eosinophilic asthma have different treatment recommendations. We sought to better understand the similarities and differences between allergic and eosinophilic asthma and highlight where misconceptions may arise.
Published articles, pivotal trials, post hoc analyses, and asthma clinical guidelines sourced from PubMed.
Sources reporting allergic and eosinophilic asthma classifications, disease mechanisms, and biomarkers associated with treatment response.
This review highlights that severe allergic and eosinophilic asthma are both driven by T2 inflammation with eosinophils playing a cardinal role. Despite this overlap, treatment recommendations differ based on asthma classification. T2 cytokine gene expression is a reasonably well-established research tool, but not a well-established biomarker in clinical practice, unlike blood eosinophil counts, fractional exhaled nitric oxide, and immunoglobulin E; the clinical relevance of immunoglobulin E as a predictive biomarker remains unclear.
Asthma classifications that can be easily characterized at patient level to ensure accurate diagnosis, predict disease trajectory, and treatment response are required. The current dichotomy of allergic and eosinophilic asthma classifications is likely too simplistic, given the similar eosinophil-mediated disease pathophysiology in both classifications. Our results provide future directions to guide clinically meaningful interpretation of asthma endophenotypes, which may improve understanding of severe asthma characterization and aid future advances in defining responders more precisely with personalized medicine approaches.
Benralizumab Effectiveness in Severe Eosinophilic Asthma with and without Chronic Rhinosinusitis with Nasal Polyps: A Real-World Multicenter Study
2021, Journal of Allergy and Clinical Immunology: In Practice
Chronic rhinosinusitis with nasal polyps (CRSwNP) affects around 60% of patients with severe eosinophilic asthma (SEA). Benralizumab was recently approved for SEA add-on treatment.
To assess the real-world effectiveness of benralizumab in SEA with or without CRSwNP.
We conducted a multicenter observational study, including patients with SEA treated with benralizumab for 24 weeks in 12 Italian specialized facilities. Asthma exacerbations, Asthma Control Test (ACT), lung function, oral corticosteroid (OCS) dosage, and eosinophil and basophil count in peripheral blood were recorded at baseline and after 4, 12, and 24 weeks. The 22-item Sino-Nasal Outcome Test (SNOT-22) and Lund-Mackay scores were assessed at baseline and after 24 weeks in SEA+CRSwNP.
A total of 137 patients with late-onset SEA were included; 57.7% (79 of 137) showed the copresence of CRSwNP. Overall, severe asthma exacerbations decreased from 4 (3-6) to 0 (0-2) (P < .0001) after 24 weeks of treatment, and significant improvements were observed as early as 4 weeks in ACT score, OCS dosage, forced expiratory volume in the 1st second (FEV₁)%, FEV₁ (L), forced vital capacity (FVC)%, FEV₁/FVC% (P < .0001), and forced expiratory flow between 25% and 75% of FVC (FEF_25-75)% (P = .0022). Eosinophils and basophils in peripheral blood were rapidly depleted. In patients with SEA+CRSwNP, SNOT-22 decreased from 46 (39.5-64.5) to 32 (19-46) (P < .0001). Furthermore, in comparison with SEA, they showed enhanced responses with regard to ACT minimal clinically important difference (P = .0387), FEV₁% (P = .017), FEV₁ (L) (P = .02), and FEF_25-75% (P = .0362).
These real-world data suggest that benralizumab can represent a valid add-on therapeutic option for patients with SEA, especially with comorbid CRSwNP.
Eosinophils
2021, Encyclopedia of Respiratory Medicine, Second Edition
Eosinophils are predominantly tissue resident cells with a bilobed nucleus and granular cytoplasm and are derived from bone marrow CD34⁺ GATA1⁺ hemopoietic progenitor cells. Lineage selection and maturation is critically dependent on interleukin-5 (IL-5), and release from marrow occurs in response to further IL-5 and eotaxin. In disease states, selective accumulation into tissue occurs in response to a series of interactions between eosinophils and endothelial cells with migration along specific chemokine gradients. Lung eosinophilia is implicated in a variety of allergic and non-allergic diseases. Mature eosinophils are an important source of basic proteins, lipid-derived mediators, growth factors, and proinflammatory cytokines that contribute to a spectrum of lung diseases that range from allergic airway inflammation such as asthma to parenchymal and vasculitic diseases. As a result, there is a substantial effort to target therapy at critical events involved in the eosinophil life cycle and functional pathways.
Clinical and biological factors associated with irreversible airway obstruction in adult asthma
2020, Respiratory Medicine
Citation Excerpt :
In our study IRAO occurred almost twice more often in patients with increased percentages of sputum eosinophils. Eosinophilic airway inflammation has the potential to induce airway remodeling [33] and is present in 41% of a general population of asthmatics [34]. We previously found that patients exhibiting elevated blood and sputum eosinophils were characterized by poorer lung function [35].
Airway remodeling, as many other factors, may lead to lung function decline and irreversible airflow obstruction (IRAO) in asthma. This study was undertaken in order to highlight predictors of incomplete reversibility of airflow obstruction in adult asthmatics to identify patients with poorer prognosis and improve their care, and decrease morbidity.
A retrospective study was conducted in 973 asthmatics recruited from the University Asthma Clinic of Liege. Patients with IRAO (post-BD FEV₁/FVC<0.7 & FEV₁<80% predicted) were compared to patients with reversible airway obstruction (RAO) (post-BD FEV₁/FVC≥0.7 & FEV₁≥80% predicted). TGF-β was measured in sputum supernatant of 85 patients.
Seventeen percent of asthmatics presented with IRAO. These patients were significantly older, more smokers, with a lower proportion of female, a longer disease duration, were more poorly controlled with a lower quality of life. This sub-population of asthmatics also showed more often elevated blood and sputum eosinophils and neutrophils, and higher exacerbation and hospitalisation rates in the previous year. The multivariable analysis revealed male gender, longer disease duration, cigarette smoking, ACQ score, sputum eosinophils and neutrophils, ICS dose and OCS maintenance, BMI, and asthma onset as variables independently linked to IRAO. Total TGF-β levels appeared higher in patients with IRAO (n = 38) compared to patients with RAO (n = 47).
These data show that risk factors for IRAO are male gender, smoking, a longer disease duration, uncontrolled asthma, eosinophilic or neutrophilic airway inflammation, lower BMI, and later asthma onset. Moreover, TGF-β levels are higher in IRAO.
Real-Life effects of benralizumab on exacerbation number and lung hyperinflation in atopic patients with severe eosinophilic asthma
2020, Biomedicine and Pharmacotherapy
Citation Excerpt :
Blood eosinophil count further increases during life-threatening asthma attacks, and predicts the risk of future disease exacerbations [51]. In addition to crucially participating in inflammatory cell infiltration, at level of small airways of patients with severe asthma eosinophils play a key role also in the induction of structural remodeling [52,53]. which is responsible for fixed bronchial obstruction and lung function decline.
The humanized monoclonal antibody benralizumab targets the α subunit of the interleukin-5 (IL-5) receptor and the FcγRIIIa receptor expressed by natural killer cells. Through this dual mechanism of action, benralizumab neutralizes the pro-eosinophil functions of IL-5 and promotes eosinophil apoptosis.
The present real-life study aimed to evaluate, in 22 allergic patients with severe eosinophilic asthma, the effects of benralizumab on asthma exacerbations and lung hyperinflation.
In this regard here we show that, after 24 weeks of add-on treatment, benralizumab completely depleted peripheral blood eosinophils (from 810 to 0 cells/μL; p < 0.0001), and significantly decreased both asthma exacerbation number (from 4 to 0; p < 0.0001) and residual volume (from 2720 to 2300 mL; p < 0.01). Moreover, at the same time point (24 weeks) benralizumab also increased pre-bronchodilator FEV₁ (from 1295 to 1985 mL; p < 0.0001), FVC (from 2390 to 2974 mL; p < 0.0001), FEF₂₅₋₇₅ (from 0.6 to 1.42 L/sec; p < 0.0001), IC (from 1940 to 2460 mL; not significant), and ACT score (from 14.73 to 22.95; p < 0.0001), as well as reduced prednisone intake (from 25 to 0 mg; p < 0.0001).
In conclusion, our results suggest that via its anti-eosinophil actions benralizumab improved airflow limitation, lung hyperinflation, and respiratory symptoms, as well as lowered asthma exacerbation rate and abrogated OCS consumption in most patients.

View all citing articles on Scopus

View full text

The role of eosinophils in airway tissue remodelling in asthma

Introduction

Section snippets

Eosinophils

Eosinophils and asthma

Airway remodelling and asthma

Eosinophils and airway remodelling

Mechanisms of eosinophil-induced remodelling

Blood

J Biol Chem

J Biol Chem

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

A 15-year follow-up study of ventilatory function in adults with asthma

N Engl J Med

Parameters associated with persistent airflow obstruction in chronic severe asthma

Eur Respir J

Remodeling and airway hyperresponsiveness but not cellular inflammation persist after allergen challenge in asthma

Am J Respir Crit Care Med

Tissue eosinophilia and eosinophil degranulation in syndromes associated with fibrosis

Am J Pathol

The eosinophil: the cell and its weapons, the cytokines, its locations

Semin Respir Crit Care Med

Human eosinophil major basic protein induces airway constriction and airway hyper-responsiveness in primates

J Clin Invest

Antibody to VLA-4, but not to L-selectin, protects neuronal M2 muscarinic receptors in antigen-challenged guinea pig airways

J Clin Invest

Activation of basophil and mast cell histamine release by eosinophil granule major basic protein

J Exp Med

Noncytotoxic activation of neutrophils by eosinophil granule major basic protein. Effect on superoxide anion generation and lysosomal enzyme release

J Immunol

Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma

J Clin Invest

Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro

Am Rev Respir Dis

The mechanism of vascular leakage induced by leukotriene E4. Endothelial contraction

Am J Pathol

Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls

N Engl J Med

Identification of a chemotactic epitope in human transforming growth factor-beta 1 spanning amino acid residues 368–374

J Cell Physiol

Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis

Am J Respir Crit Care Med

Regulation of fibroblast procollagen production. Transforming growth factor-beta 1 induces prostaglandin E2 but not procollagen synthesis via a pertussis toxin-sensitive G-protein

Biochem J

Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway

Am J Respir Crit Care Med

Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma

J Exp Med

Inhibition of airway remodeling in IL-5-deficient mice

J Clin Invest

Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo

J Exp Med

A critical role for eosinophils in allergic airways remodeling

Science

Defining a link with asthma in mice congenitally deficient in eosinophils

Science