Michael D Evans1, Stephane Esnault2, Loren C Denlinger2, Nizar N Jarjour3. 1. Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wis. 2. Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis. 3. Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis. Electronic address: NJarjour@uwhealth.org.
Abstract
BACKGROUND: Various clinical, biologic, or physiologic markers of asthma have been used to identify patient clusters and potential targets for therapy. However, these identifiers frequently overlap among the different asthma groups. For instance, both eosinophil and neutrophil counts are often increased in the airways of asthmatic patients despite their typical association with type 2 and type 17 immune response, respectively. OBJECTIVES: We sought to determine whether inflammatory gene expression is related to patterns of airway inflammation and lung function and identify molecular markers for neutrophilic asthma. METHODS: Expression levels of 17 genes characterizing type 1, type 2, and type 17 lymphocytes were measured in sputum samples from 48 participants with asthma. The relationships between gene expression levels and sputum cell differentials or measures of pulmonary function were examined by using partial least squares regression. RESULTS: Gene expression levels were strongly associated with cell differentials, explaining 71% of variation in eosinophil counts and 64% of variation in neutrophil counts. The 3 genes with the strongest relationships to sputum neutrophil counts were IL1R1 (standardized regression coefficient [β] = +0.27, P = .005), IL1RAP (β = +0.32, P = .0004), and IL4R (β = +0.29, P = .002). Higher expression levels of IL1R1, IL1RAP, and IL4R were associated with reduced FEV1/forced vital capacity ratio (β = -0.11, -0.08, and -0.10; P = .005, .07, and .05). CONCLUSION: IL-1 receptor appears to be a marker of neutrophilic inflammation and airflow obstruction in patients with asthma, who have a wide range of disease severity. The IL-1 pathway might contribute to airway neutrophilia and is a potential therapeutic target in patients with neutrophilic asthma.
BACKGROUND: Various clinical, biologic, or physiologic markers of asthma have been used to identify patient clusters and potential targets for therapy. However, these identifiers frequently overlap among the different asthma groups. For instance, both eosinophil and neutrophil counts are often increased in the airways of asthmatic patients despite their typical association with type 2 and type 17 immune response, respectively. OBJECTIVES: We sought to determine whether inflammatory gene expression is related to patterns of airway inflammation and lung function and identify molecular markers for neutrophilic asthma. METHODS: Expression levels of 17 genes characterizing type 1, type 2, and type 17 lymphocytes were measured in sputum samples from 48 participants with asthma. The relationships between gene expression levels and sputum cell differentials or measures of pulmonary function were examined by using partial least squares regression. RESULTS: Gene expression levels were strongly associated with cell differentials, explaining 71% of variation in eosinophil counts and 64% of variation in neutrophil counts. The 3 genes with the strongest relationships to sputum neutrophil counts were IL1R1 (standardized regression coefficient [β] = +0.27, P = .005), IL1RAP (β = +0.32, P = .0004), and IL4R (β = +0.29, P = .002). Higher expression levels of IL1R1, IL1RAP, and IL4R were associated with reduced FEV1/forced vital capacity ratio (β = -0.11, -0.08, and -0.10; P = .005, .07, and .05). CONCLUSION:IL-1 receptor appears to be a marker of neutrophilic inflammation and airflow obstruction in patients with asthma, who have a wide range of disease severity. The IL-1 pathway might contribute to airway neutrophilia and is a potential therapeutic target in patients with neutrophilic asthma.
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