Open AccessBAL Cell Gene Expression in Severe Asthma Reveals Mechanisms of Severe Disease and Influences of Medications
Author(s) -
Nathaniel M. Weathington,
Maureen E. O’Brien,
Josiah E. Radder,
Thomas Whisenant,
Eugene R. Bleecker,
William W. Busse,
Serpil C. Erzurum,
Benjamin Gaston,
Annette T. Hastie,
Nizar N. Jarjour,
Deborah A. Meyers,
Jadranka Milošević,
Wendy C. Moore,
John Tedrow,
John B. Trudeau,
Hesper Wong,
Wei Wu,
Naftali Kaminski,
Sally E. Wenzel,
Brian D. Modena
Publication year - 2019
Publication title -
american journal of respiratory and critical care medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.272
H-Index - 374
eISSN - 1535-4970
pISSN - 1073-449X
DOI - 10.1164/rccm.201811-2221oc
Subject(s) - gene expression , medicine , agonist , asthma , immunology , cell , gene , regulation of gene expression , biology , receptor , genetics
Rationale: Gene expression of BAL cells, which samples the cellular milieu within the lower respiratory tract, has not been well studied in severe asthma. Objectives: To identify new biomolecular mechanisms underlying severe asthma by an unbiased, detailed interrogation of global gene expression. Methods: BAL cell expression was profiled in 154 asthma and control subjects. Of these participants, 100 had accompanying airway epithelial cell gene expression. BAL cell expression profiles were related to participant (age, sex, race, and medication) and sample traits (cell proportions), and then severity-related gene expression determined by correlating transcripts and coexpression networks to lung function, emergency department visits or hospitalizations in the last year, medication use, and quality-of-life scores. Measurements and Main Results: Age, sex, race, cell proportions, and medications strongly influenced BAL cell gene expression, but leading severity-related genes could be determined by carefully identifying and accounting for these influences. A BAL cell expression network enriched for cAMP signaling components most differentiated subjects with severe asthma from other subjects. Subsequently, an in vitro cellular model showed this phenomenon was likely caused by a robust upregulation in cAMP-related expression in nonsevere and β-agonist-naive subjects given a β-agonist before cell collection. Interestingly, ELISAs performed on BAL lysates showed protein levels may partly disagree with expression changes. Conclusions: Gene expression in BAL cells is influenced by factors seldomly considered. Notably, β-agonist exposure likely had a strong and immediate impact on cellular gene expression, which may not translate to important disease mechanisms or necessarily match protein levels. Leading severity-related genes were discovered in an unbiased, system-wide analysis, revealing new targets that map to asthma susceptibility loci.