BAL Cell Gene Expression in Severe Asthma Reveals Mechanisms of Severe Disease and Influences of Medications

作者：Nathaniel M. Weathington, Michael 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 · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2019 · DOI：10.1164/rccm.201811-2221oc · 被引用次数：50 · 研究领域：Asthma and respiratory diseases、Delphi Technique in Research、Neonatal Respiratory Health Research

Abstract 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 ...