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...
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
...
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 t...
Emphysematous Destruction Vs terminal bronchiolar loss

Terminal bronchioles are lost before emphysema becomes visible on ...
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)

Pare...
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Unpublished data Masaru Suzuki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...
Random Forest regression analysis of
prediction of Lm from histology
9 1011
8

10

4 56 7

5
0

Variable Tested
Vv.CD79A.a...
A

B

C
FEV1 (% of value at age 25)

Natural history of airflow limitation
100
75

Our working hypothesis is that the
decline in F...
Unpublished data courtesy of Tan et al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...
Summary
• The microCT analysis has shown that terminal bronchioles
are sharply reduced in number prior to the onset of
emp...
Do Airways Disappear in COPD?
Do Airways Disappear in COPD?
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Do Airways Disappear in COPD?

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  • Upper lobe tied to prevent the escape of the air, and died in the sun, the slice shows dilation of cells compared to normal lung
  • Add MicroCT image and quantitative histology image
  • 184mm3 in human
  • Figure 1 A) microCT Image of a terminal bronchiole dividing into 2 transitional bronchioles where where alveolar openings first appear. B) a lung lobule a defined by Millar as a group of terminal bronchioles (TB) and the acini they supply surrounded by a connective tissue septa ( arrow). C) A distal bronchogram demonstrating a lobule ( in box) as descibed by Reid where the branching paten changes from one where the branches occur roughly every cm to one where the branches are clustered only mm apart.
  • This graph shows the decline in FEV1 according with age. The curve from the top is represented by nonsmokers and the one from the bottom is represented by susceptible individuals.
  • Figure 4 A) Shows a normal lung lobule within the oval where several terminal bronchioles supply individual acini. B) Shows Leopold and Gough’s diagram of the primary lesion of centrilobular emphysema C) Shows a fully developed centrilobular lesion filled with contrast material D) Circuit diagram of the normal lung where R1 and R2 are terminal bronchioles and C1 and C2 the acini supplied by these terminal bronchioles E) Shows a circuit diagram of centrilubular emphysema where one terminal bronchiole (R1) has been destroyed and the second (R2) has survived with a thick wall and narrow lumen to supply a centrilobular emphysematous lesion that opens low resistance collateral pathway (R4) that supply normal alveoli in acinus C1 that has been isolated by the destruction of the normal terminal bronchiole R1
  • This graph shows the decline in FEV1 according with age. The curve from the top is represented by nonsmokers and the one from the bottom is represented by susceptible individuals.
  • Mention that total number of bacteria is small.
  • Do Airways Disappear in COPD?

    1. 1. Jim Hogg MD PhD Vancouver Canada Do Airways Disappear in COPD?
    2. 2. 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
    3. 3. Centrilobular Emphysema Air dried specimen of a human lung Courtesy of Dr Joel Cooper
    4. 4. 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
    5. 5. Evidence from lung Casts Weibel, 2009, Swiss Med Wkly
    6. 6. Evidence from Computed T0mograpy (CT) Courtesy Dr Dragos Vasilescu
    7. 7. Terminal Bronchiole N Engl J Med 2011
    8. 8. Measuring changes in small airways in relation to emphysema N Engl J Med 2011
    9. 9. 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
    10. 10. Emphysematous Destruction Vs terminal bronchiolar loss Terminal bronchioles are lost before emphysema becomes visible on a CT scan
    11. 11. How many terminal bronchioles in a human lung? Control Centrilobular A1AT N Engl J Med 2011 N Engl J Med 2013
    12. 12. Comparison of MicroCT to histology LEVEL 1 (specimen CT scan) Tissue Airspace LEVEL 2 (Whole mounts) Airways(AW) Parenchyma Unpublished data Masaru Suzuki
    13. 13. Bronchiolar tissue remodeling as a function Emphysematous Destruction Unpublished data Masaru Suzuki
    14. 14. 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
    15. 15. 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
    16. 16. A B C
    17. 17. 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.
    18. 18. Unpublished data courtesy of Tan et al No COPD
    19. 19. 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.
    20. 20. 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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