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“Tracheobronchial” Clearance Fast clearance from the bronchi and bronchioles. J E Agnew Royal Free Hampstead NHS Trust and Royal Free & University College Medical School. The Lungs: Function, Diagnosis and Treatment What do the Lungs do? How do they do it?. Being Scientific

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tracheobronchial clearance fast clearance from the bronchi and bronchioles

“Tracheobronchial” ClearanceFast clearance from the bronchi and bronchioles

J E Agnew

Royal Free Hampstead NHS Trust and

Royal Free & University College Medical School

slide2

The Lungs: Function, Diagnosis and Treatment

What do the Lungs do?

How do they do it?

Being Scientific

Weighing-up Evidence

Making Models

Testing Ideas

Aerosol Clearance

Long-term

Retention

Mucus Clearance

Effect of Disease

Adverse

Effects

Diagnosis

Treatment

slide6

GI

tract

Clearance

Routes

from the

Respiratory

Tract

ET

based on

the ICRP

model

ICRP

Publication

66

BB

bb

AI

Lymph

Nodes

Blood

slide7

NCRP

Model

slide8

100 mins

Bronchi BB

Bronchioles bb

8 hours

ICRP reference BB and bb half-times

slide9

Timescales

for

Tracheobronchial

and Pulmonary

Clearance

as set out in

NCRP 1997

slide10

Aerosol Particles

  • Inert polystyrene particles
  • 5m diameter
  • Tc-99m labelled
  • Inhaled “slowly”
  • Retention measured 0-6h & 24h
  • Initial Gamma Camera Image
slide11

Peripheral zone clearance

Regional mucociliary

clearance in CF

“Measurement of mucociliary clearance in CF patients would seem to be a valuable outcome measure for clinical trials involving new pharmaceuticals and physical therapy designed to improve removal of secretions from the airway.”

Penetration Index

Inner zone clearance

0.60

50

0.40

40

30

0.20

20

0.00

10

Normal

CF-mild

CF-mod

CF-sev

Robinson et al. J. Aerosol Med. 13:73-86 : 2000

0

Normal

CF-mild

CF-mod

CF-sev

slide12

Tracheobronchial Clearance - intermediate and outer zones

%

19 patients

with mucus

hypersecretion

Hasani et al. 1994

Control FET

Control FET

Intermediate Zone Outer Zone

slide13

The

Lungs ?

slide16

Conductive Airways

“….Examination reveals that each bronchus divides into two distal bronchi. This pattern of branching is called dichotomy and is frequently observed in nature. The dichotomous branching may sometimes be obscured by considerable variation in the length of the elements. Nevertheless, of more than 1000 branchings analyzed…, all of them could be characterized as dichotomous. The irregularity in the dimensions of the elements is related to the shape of the lung. After four generations of airway branching… the basic shape of the lung appears to be outlined.”

Weibel and Gomez 1962

slide18

Branching

Structure

of the

Airways

Weibel,1991

original version

Weibel, 1963

slide19

The

‘Tracheo-bronchial’

tree

from

Contours of

Breathing (1980)

based on

Weibel (1963)

slide20

Bronchial

Epithelium

(seen in

cross-section)

Royal Free

slide21

This is what

cilia look like

???

Royal Free

slide22

Or

like

this

???

Royal Free

slide23

Or

like

this

???

Royal Free

slide24

Tracheal

epithelium

BC basal cells

TBC tall basal

cells

CC ciliated cells

GC goblet cells

IC intermediate

cells

Evans et al

Exp Lung Res 2001: 27: 401-5

slide25

Airway epithelium

  • protects submucosa
  • is metabolically active
  • synthesises and releases pro-inflammatory factors
  • influences inflammatory cells
  • - chemotaxis
  • - recruitment
  • - activation
  • - differentiation

Patel et al. Eur Respir J 2003: 22: 94-9

slide26

Airway epithelium

  • Following an inflammatory stimulus,
  • COPD bronchial epithelial cells:
  • show significant cytokine* response
  • response may be modified by inhaled steroids
  • *interleukin (IL)-6 and (IL)-8

Patel et al. Eur Respir J 2003: 22: 94-9

slide27

Bronchial

epithelium

(after hexadecane

stimulus)

MUC

mucus

GC

goblet cell

Green et al

in Particle-Lung

Interactions

ed. Gehr

and Heyder

Marcel Dekker

2000

slide28

Ciliary

Structure

(1)

Royal Free

slide29

Ciliary

Structure

(2)

Royal Free

slide30

Interaction of cilia and mucus

see

Knowles and Boucher

J Clin Invest

2002: 109: 571-7

+ other papers from

Chapel Hill group

slide31

Maintaining Airway Surface

Liquid Depth - ? Stationary or

Moving Periciliary Liquid Layer

Matsui et al. J Clin Invest 1998 102: 1125-31

Model 1: NaCl transepithelial transport Model 2: NaCl and water transport

slide32

Airway Surface Liquid

= Mucus + Underlying watery periciliary liquid (PCL)

Used to be thought that PCL was ~ stationary

Now cell culture studies show PCL movement

Mucus 39.2 ± 4.7 m/sec

PCL 39.8 ± 4.2 m/sec

But if you take the mucus away:

PCL 4.8 ± 4.2 m/sec

Matsui et al. J Clin Invest 1998 102: 1125-31

slide33

Airway Surface Liquid

“The cephalad movement of PCL along airway epithelial surfaces makes .. mucus-driven transport an important component of salt and water physiology in the lung in health and disease.”

Matsui et al. J Clin Invest 1998 102: 1125-31

slide34

Active ion transport regulates ASL height ... feedback between ASL and epithelia governs rate of ion transport and volume absorption. [?]

Red = ASL, green = mucus (attached fluorescent beads)

Change osmolality (of bath) and layers shrink or swell.

Conclusion: “liquid is being donated from the mucus layer to the PCL and vice versa in a spongelike fashion…”

Tarran et al. J Gen Physiol 2001: 118: 223-36

slide35

Mucus transport - as seen by time-lapse photos in cell culture experiments

Tarran et al. J Gen Physiol 2001: 118: 223-36

slide36

Pulmonary Defence mechanisms - against chronic bacterial infection

Knowles & Boucher J Clin Invest 2002: 109: 571-7

slide37

Isotonic

Volume

Transport

Model

Active

Na+

Absorption

Boucher. J Physiol 1999: 516: 631-8

slide38

Isotonic

Volume

Transport

Model

superficial

airway

cells

Boucher. J Physiol 1999: 516: 631-8

slide39

Isotonic

Volume

Transport

Model

submucosal

gland

gland

ducts

absorb

NaCl

but not

water

Boucher. J Physiol 1999: 516: 631-8

slide40

Boucher. J Physiol 1999: 516: 631-8

“Hypotonic ASL physiology”

slide41

Restoration of water balance in ASL

Boucher. J Physiol 1999: 516: 631-8

slide42

Airway

Epithelial

Culture

good/bad

indicator

of clearance

effectiveness

in real life ?

Knowles & Boucher J Clin Invest 2002: 109: 571-7

slide46

Clearance measurements depend

on deposition distribution

Pavia 1985

slide47

ICRP 66

based on Burri & Weibel 1973

slide50

Clearance rests

when you’re

asleep

The effect of

sleep rather

than inactivity

Pavia 1985

slide51

Mild asthmatics

have worse daytime

clearance than

control subjects

- their clearance

during sleep is about

as bad as that seen

in control subjects

Pavia 1984

slide52

Effect of inhaling mannitol (patients with bronchiectasis)

Daviskas et al. Am J Respir Crit Care Med 1999: 159: 1843-8

slide53

Daviskas et al.

Am J Respir Crit Care Med

1999: 159: 1843-8

slide54

The importance of cough

Foster WM Pulm Pharmacol Ther 2002: 15: 277-82

slide61

Can we relate clearance (or clearance changes) to

deposition distribution (or distribution changes) ?

p < 0.05

slide62

Effect of a long-acting bronchodilator on mucociliary

clearance measured by an aerosol method

Change in retention

Change in “R48” Change in PEFR

p = 0.06 p = 0.18

slide63

Effect of a long-acting bronchodilator on mucociliary

clearance measured by an aerosol method - continued

Multiple regression: p = 0.03

Is this an appropriate new approach ?

slide64

Effect

of

amiloride

on muco-

ciliary

clearance

Sood et al.

Am J Respir-

Crit Care

2003

167: 158-63

slide69

“The foot of the mucociliary escalator goes deeper in smokers than in non-smokers”

Smoker

Non-smoker

slide70

Tracheobronchial Clearance - intermediate and outer zones

%

19 patients

with mucus

hypersecretion

Hasani et al. 1994

Control FET

Control FET

Intermediate Zone Outer Zone

slide72

Clearance - Mucociliary / Cough

Whole Lung / Tracheobronchial

Cough-corrected ( ? how)

Dependence on Deposition Distribution

Mucus / Salt and Water

Effects of Medication / Physiotherapy