Eosinophilic inflammation in chronic obstructive pulmonary disease

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease characterised by persistent airflow obstruction. Eosinophilic inflammation has been identified in a subset of COPD subjects, with peripheral blood eosinophil count being used as a surrogate marker to predict exacerbation frequency and response to corticosteroid treatment. The cytokine, interleukin-5 (IL5), is a key player in the differentiation, proliferation, maturation, and survival of eosinophils. Monoclonal antibodies targeting IL5 and the Interleukin 5 receptor alpha subunit (IL5Rα), have been shown to deplete eosinophils in clinical trials. However, these treatments have not reduced rates of exacerbations or improved lung function in COPD subjects with high blood eosinophils.
The aim of this thesis was to characterise COPD subjects with high eosinophils in blood, BAL and tissue to determine the association of the presence of these cells in different bodily compartments with clinical features of disease. A further aim was to determine IL5Rα expression in the lung tissue of COPD subjects to investigate the role of this receptor in the raised number of eosinophils in COPD. Additionally, to understand the possible drivers of tissue eosinophilia, the final aim was to investigate differential gene expression signatures in lung tissue associated with high eosinophils in COPD.
To achieve these aims, COPD subjects, healthy ex-smokers (HV-ES) and healthy never smokers (HV-NS) were recruited. COPD subjects were stratified into frequent and infrequent exacerbators and into high and low blood eosinophil groups, using blood, BAL and tissue eosinophil thresholds. All participants underwent pulmonary function tests, blood sampling, completed the St. George’s Respiratory Questionnaire (SGRQ), bronchoalveolar lavage and bronchial biopsy sampling for RNA sequencing and histology. Formalin fixed paraffin embedded (FFPE) bronchial biopsy samples were sectioned and stained for eosinophil cationic protein (ECP) and IL5Rα. In addition, RNA was extracted from bronchial biopsies and total RNA sequencing was used to quantify gene expression.
Tissue eosinophils were significantly upregulated in the lung tissue of COPD patients compared to healthy subjects. However, this increase in eosinophils in lung tissue was not correlated to peripheral blood or BAL eosinophil counts. Upon stratification of the COPD groups into high and low eosinophil groups, high eosinophil (>2%) COPD group had better SGRQ compared to the low eosinophilic COPD group. Eosinophil numbers and IL5Rα expression in tissue were shown to be correlated, however there was no increase in IL5Rα expression in the lung tissue of COPD patients compared to healthy subjects. However, IL5Rα expression was increased in frequent exacerbators in comparison to infrequent exacerbators. Eosinophils from peripheral blood did not indicate a difference in IL5Rα expression between healthy and COPD subjects. Transcriptomic analysis of bronchial biopsy samples did not indicate a clear eosinophilic gene signature associated with high eosinophil group.
The data in this thesis suggest that blood eosinophil count is not predictive of tissue eosinophil count in COPD. High eosinophil counts observed in COPD subjects may not be a sign of worsening disease, but rather of a milder disease phenotype. In lung tissue a relationship between eosinophils and IL5Rα was identified. A significant relationship was observed between IL5Rα and frequent exacerbators, warranting further exploration into the role IL5Rα in COPD.

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Identifiers

ORCID for Karl Staples: orcid.org/0000-0003-3844-6457

ORCID for Cosma Mirella Spalluto: orcid.org/0000-0001-7273-0844

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