Do Airways Disappear in COPD?

Jim Hogg MD PhD

Vancouver Canada

He was able to correlate sounds he captured by his stethoscope to pathological changes in the chest

René Laennec, 1781 - 1826He described emphysema By inflating and air drying lungs

•the focal variations in Severity of emphysema• the persistent over inflation of the lung, and its decreased elastic properties• peripheral airways the primary site of obstruction

Air dried specimen of a human lung Courtesy of Dr Joel Cooper

Centrilobular Emphysema

Apex

Base

Microbiome Analysis

Quantitative Histology

MicroCT

Lung specimens that are:

1)inflated with air

2)held at a constant pressure

3) Frozen solid.

Metagenomics symposium 2013

Host Gene Expression Profiling

Methodology

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

Control Centrilobular A1AT

N Engl J Med 2011

How many terminal bronchioles in a human lung?

N Engl J Med 2013

Comparison of MicroCT to histology

LEVEL 1(specimen CT scan)

Parenchyma

Airways(AW)

Airspace

Tissue

LEVEL 2(Whole mounts)

Unpublished data Masaru Suzuki

Bronchiolar tissue remodeling as a functionEmphysematous Destruction

Unpublished data Masaru Suzuki

Vo

lum

e F

rac

tio

n t

o A

irw

ay

Wa

ll (

x 1

0-3

)

PMNs Macrophages CD4 CD8 B cells0

20

40

60

80

100

ControlLm ~ 600Lm 600 ~ 1,000Lm 1,000 ~*

*

*

*

*

Infiltration of Inflammatory Immune Cells into Bronchiolar Walls as a Function of Emphysema

Unpublished data Masaru Suzuki

Macrophage CD4 and B cell infiltration into bronchiolar wall tissue is associated with emphysematous destruction.

Random Forest regression analysis of prediction of Lm from histology

shadowMin Vv.NK.saw Vv.eos.saw Vv.CD79A.saw Vv.mp.alv.wall

-50

510

Attributes

Impo

rtan

ce

1 2 3

4 5 6 78

9 1011 Position on Graph Variable Tested Importance11 Vv.CD79A.alv.total 10.2610 Vv.CD79A.avg 10.189 Vv.Mp.alv.wall 8.658 Vv.CD4.alv.total 8.597 Vv.mac.avg 7.666 Vv.col1.alv 6.765 Vv.mp.alv.total 6.764 No.of.TB 6.623 Vv.CD4.avg 5.7222 Vv.eos.alv.total 4.041 Vv.CD79A.saw 3.95

Unpublished data Masaru Suzuki

Markers of B cells macrophages and CD4 cells are the best predictors of Lm

B

A C

Natural history of airflow limitation

50 7525

25

50

75

100

FE

V1 (

% o

f va

lue

at a

ge

25)

Age (years)

Death

Gold 2

Gold 4

Gold 1

Disability

Gold 3

Modified from Fletcher et al.

Our working hypothesis is that the decline in FEV1 in COPD is caused by progressive narrowing and loss of terminal bronchioles.

Our data show that emphysemadevelops after terminal bronchioles are lost

We postulate that emphysematous destruction collaterally ventilates normal alveoli whose terminal bronchioles are destroyed

No COPD

Unpublished data courtesy of Tan et al

Natural History of airflow limitation

50 7525

25

50

75

100

FE

V1 (

% o

f va

lue

at a

ge

25)

Age (years)

Death

Gold 2

Gold 4

Gold 1

Disability

Gold 3

The FEV1 declines in everyone with age

Modified from Fletcher et al.

Because we have demonstrated terminal bronchioles are destroyed prior to the onset of emphysematous detruction

We postulate that subjects who develop emphysema without COPD will subsequently develop a rapid decline in FEV1.

• 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.

Summary