Published on February 20, 2014
Jim Hogg MD PhD Vancouver Canada Do Airways Disappear in COPD?
René Laennec, 1781 - 1826 He described emphysema By inflating and air drying lungs •t he f ocal var iat ions in Sever it y of emphysema • t he per sist ent over inf lat ion of t he lung, and it s decr eased elast ic pr oper t ies • per ipher al He was able to correlate sounds he captured byt his air ways he pr imar y sit stethoscope to pathological changes in the cheste of
Centrilobular Emphysema Air dried specimen of a human lung Courtesy of Dr Joel Cooper
Methodology Apex MicroCT Quantitative Histology Microbiome Analysis Base Lung specimens that are: 1)inflated with air 2)held at a constant pressure 3) Frozen solid. Metagenomics symposium 2013 Host Gene Expression Profiling
Evidence from lung Casts Weibel, 2009, Swiss Med Wkly
Evidence from Computed T0mograpy (CT) Courtesy Dr Dragos Vasilescu
Terminal Bronchiole N Engl J Med 2011
Measuring changes in small airways in relation to emphysema N Engl J Med 2011
Measuring the number of terminal bronchioles in relation to emphysematous destruction in COPD. 1)Specimen MDCT provides total lung volume 2) microCT provides number of terminal bronchioles / ml lung. 3) Measure the mean linear intercept (Lm) at 20 different levels in each tissue core
Emphysematous Destruction Vs terminal bronchiolar loss Terminal bronchioles are lost before emphysema becomes visible on a CT scan
How many terminal bronchioles in a human lung? Control Centrilobular A1AT N Engl J Med 2011 N Engl J Med 2013
Comparison of MicroCT to histology LEVEL 1 (specimen CT scan) Tissue Airspace LEVEL 2 (Whole mounts) Airways(AW) Parenchyma Unpublished data Masaru Suzuki
Bronchiolar tissue remodeling as a function Emphysematous Destruction Unpublished data Masaru Suzuki
Volume Fraction to Airway Wall (x-3) 10 Infiltration of Inflammatory Immune Cells into Bronchiolar Walls as a Function of Emphysema 100 * Control Lm ~ 600 Lm 600 ~ 1,000 Lm 1,000 ~ 80 * * 60 * 40 * 20 0 PMNs Macrophages CD4 CD8 B cells Macrophage CD4 and B cell infiltration into bronchiolar wall tissue is associated with emphysematous destruction. Unpublished data Masaru Suzuki
Random Forest regression analysis of prediction of Lm from histology 9 1011 8 10 4 56 7 5 0 Variable Tested Vv.CD79A.alv.total Vv.CD79A.avg Vv.Mp.alv.wall Vv.CD4.alv.total Vv.mac.avg Vv.col1.alv Vv.mp.alv.total No.of.TB Vv.CD4.avg Vv.eos.alv.total Vv.CD79A.saw Importance 10.26 10.18 8.65 8.59 7.66 6.76 6.76 6.62 5.722 4.04 3.95 -5 Importance 1 2 3 Position on Graph 11 10 9 8 7 6 5 4 3 2 1 shadowMin Vv.NK.saw Vv.eos.saw Vv.CD79A.saw Attributes Vv.mp.alv.wall Markers of B cells macrophages and CD4 cells are the best predictors of Lm Unpublished data Masaru Suzuki
A B C
FEV1 (% of value at age 25) Natural history of airflow limitation 100 75 Our working hypothesis is that the decline in FEV1 in COPD is caused by progressive narrowing and loss of terminal bronchioles. Gold 1 Gold 2 50 Our data show that emphysema develops after terminal bronchioles are lost Gold 3 25 Gold 4 Disability Death 25 50 We postulate that emphysematous destruction collaterally ventilates normal alveoli whose terminal bronchioles are destroyed Age (years) 75 Modified from Fletcher et al.
Unpublished data courtesy of Tan et al No COPD
FEV1 (% of value at age 25) Natural History of airflow limitation The FEV1 declines in everyone with age 100 75 Because we have demonstrated terminal bronchioles are destroyed prior to the onset of emphysematous detruction Gold 1 Gold 2 50 Gold 3 25 Gold 4 Disability We postulate that subjects who develop emphysema without COPD will subsequently develop a rapid decline in FEV1. Death 25 50 Age (years) 75 Modified from Fletcher et al.
Summary • The microCT analysis has shown that terminal bronchioles are sharply reduced in number prior to the onset of emphysematous destruction in COPD. • A quantitative histological analysis confirmed that the total volume of bronchiolar tissue is reduced and extensively remodeled in the very earliest stages of emphysematous destruction. • These early changes in bronchiolar tissue are associated with CD4 T-cell, B cell and Macrophage infiltration. • We conclude that a reduction in terminal bronchioles precedes the appearance of emphysematous destruction in COPD.
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