Transcript The Effects of Airway Microbiome on Corticosteroid Responsiveness

The Effects of Airway Microbiome
on Corticosteroid Responsiveness in
Asthma
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL
CARE MEDICINE Nov 15, 2013
R2.최하나
INTRODUCTION
• Current guidelines recommend the use of corticosteroids to
control airway inflammation in persistent asthma.
• Clinical studies
– Up to 45% of patients responding suboptimally to inhaled
corticosteroids
– Up to 25% of patients do not respond to oral corticosteroids
• Corticosteroid-resistant (CR) patients
– Airway inflammation and remodeling
– Severe asthma phenotype
– Alternative treatment strategies are needed to improve asthma
control
• 16S rRNA gene sequence analyses of airway specimens →
diversified microbial communities in the airways of subjects
with asthma
• Compared with healthy patients
– Asthma patients : significantly higher bacterial burden and
diversity caused by expansion of pathogenic bacteria.
• Moreover, airway microbiome composition and diversity
correlate with bronchial hyperresponsiveness .
• CR asthma : pathogenic microbial communities residing in
the airways →inhibit cellular responses to corticosteroids
METHODS
• Study Subjects
baseline FEV1 < 85%
prednisone 20mg bid for 7days
CR : FEV1<10%
CS : FEV1>15%
• Specimen Collection :BAL
• BAL Differential Analysis
• Bacterial DNA Extraction, Quantitative PCR, and
Sequencing
• Bacterial Cultures
• Cell Cultures
RESULTS
• Clinical Characteristics
Macrophages are the major cell type in the airway lumen,
and produce an array of proinflammatory mediators that
control responses of various cell types, including T cells
and airway epithelium that are involved in host defense,
airway inflammation, tissue remodeling, and repair.
• Airway Microbiome in Subjects with Asthma
Subjects
with
asthma with
Subjects
with
CR CS
asthma
withbacterial
microbialexpansions
expansions(9 of 10
patients)
(24 of 29 patients)
• Unique Bacterial Genus Expansions in the Airways
of CR and CS Subjects with Asthma
• Effects of Bacteria from the Airways on Cell
Activation and Response to Corticosteroids in
Airway Macrophages
2uM
10uM
DISCUSSION
CONCLUSION
• A subset of subjects with CR asthma demonstrates airway
expansion of specific gram-negative bacteria, which trigger
TAK1/MAPK activation and induce corticosteroid resistance.
• TAK1 inhibition restored cellular sensitivity to corticosteroids.