People with cystic fibrosis on elexacaftor-tezacaftor-ivacaftor with high sputum neutrophil elastase exhibit worse pulmonary function and pro-inflammatory airway milieu Open Access

Abstract

Background: Cystic fibrosis (CF) is a genetic disorder characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), leading to multi-organ pathology and progressive respiratory failure. Neutrophil elastase (NE) activity, a critical component of the inflammatory response in CF, has been implicated in disease severity. The highly effective modulator therapy (HEMT) elexacaftor-tezacaftor-ivacaftor (ETI) has shown significant improvements in pulmonary function, but its impact on inflammation remains variable among patients.

Methods: We conducted a cross-sectional, single-center study involving 41 clinically stable individuals with CF, including 32 on ETI therapy and 9 not receiving any modulator treatment (NoHEMT). Sputum samples were analyzed for NE and myeloperoxidase (MPO) activities, pro-inflammatory cytokines, chemokines, and metabolites. Lung function was assessed using %FEV1_pred at collection date (GLI). Multivariate multiple regression models were employed to explore the relationships between NE activity and primary outcomes, with adjustments for multiple comparisons using the Bonferroni correction.

Results: NE activity was significantly higher in the NoHEMT group compared to the ETI group (p=0.0090). Within the ETI group, a bimodal distribution of NE activity was observed, distinguishing two sub-populations: high NE activity (NE^Hi) and low NE activity (NE^Lo). NE^Hi subjects exhibited significantly increased MPO activity (p=0.0002) and elevated levels of several cytokines, including IL-1β, IL-6, IL-10, TNF-α, and VEGF-A. Metabolomic analysis revealed 107 metabolites significantly associated with high NE activity, indicating broad neutrophil-driven pro-inflammatory metabolome disruption. Lung function was significantly lower in NE^Hi subjects both before and after ETI initiation (p=0.0117), with NE^Hi subjects showing worse lung function that was not fully rescued by ETI therapy.

Conclusions: Our findings highlight the heterogeneity in inflammatory responses among PwCF on ETI therapy. High NE activity is associated with increased inflammation and worse lung function, suggesting that additional inflammation-targeted therapies may be necessary to maximize the benefits of ETI in CF patients with advanced pro-inflammatory manifestations of lung disease. Further research is needed to understand the mechanisms underlying differential responses to ETI and to develop tailored therapeutic strategies.

Table of Contents

Table of Contents

Introduction. 1

Chapter 1: Differences in sputum inflammatory profiles of PwCF taking ETI or no HEMT.. 4

Chapter 2: NE activity distinguishes two populations of PwCF undergoing ETI therapy. 6

Chapter 3: Discussion. 8

Chapter 4: Materials and methods. 12

List of Tables and Figures

Table 1. Characteristics of PwCF, distributed by use of ETI therapy. 16

Table 2. Correlation between NE activity and lung function in the different groups of PwCF. 17

Table 3. Characteristics of PwCF on ETI, distributed by level of NE activity. 18

Figure 1. PwCF taking ETI present similar level of cytokine burden than PwCF not taking any HEMT. 19

Figure 2. PwCF taking ETI had lower NE activity driven by an activity low sub-population. 20

Figure 3. PwCF taking ETI with high NE activity have increased sputum MPO activity and pro-inflammatory cytokine burden. 21

Figure 4. Metabolomics reveals broad differences between NE^Hi and NE^Lo donors with strong evidence of neutrophilic involvement. 22

Figure 5. Forced expiratory volume in one second percent predicted (ppFEV1) is decreased in NE^Hi donors prior to the start of ETI and remains low. 23

References. 24

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Immunology Biology, Molecular Biology, General
Keyword	Lung function Lung inflammation Cystic Fibrosis CFTR modulators Sputum Neutrophil elastase
Committee Chair / Thesis Advisor	Jordan Kempker, Emory University
Committee Members	William M. Shafer, Emory University Rabin Tirouvanziam, Emory University

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