“Tracheobronchial” Clearance

Fast clearance from the bronchi and bronchioles

J E AgnewRoyal 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 ScientificWeighing-up Evidence

Making ModelsTesting Ideas

Aerosol Clearance

Mucus Clearance

Effect of Disease

Diagnosis Treatment

Long-termRetention

AdverseEffects

The ICRP Respiratory Tract Model

ET

BB

bb

LymphNodes

Blood

GItract

AI

ClearanceRoutesfrom theRespiratoryTract

based onthe ICRP

model

ICRPPublication

66

NCRPModel

Bronchi BB

Bronchioles bb

100 mins

8 hours

ICRP reference BB and bb half-times

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itia

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Pulmonary Deposition

TracheobronchialDeposition

Timescalesfor

Tracheobronchialand Pulmonary

Clearance

as set out inNCRP 1997

Aerosol Particles

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

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Normal CF-mild CF-mod CF-sev

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Normal CF-mild CF-mod CF-sev

Regional mucociliaryclearance 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.”

Peripheral zone clearance

Inner zone clearance

Penetration Index

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

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Intermediate Zone Outer Zone

Control FET

Control FET

Tracheobronchial Clearance - intermediate and outer zones

Mean SEM%

19 patientswith mucushypersecretionHasani et al. 1994

TheLungs ?

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

BranchingStructure

of the Airways

Weibel,1991original version

Weibel, 1963

The‘Tracheo-bronchial’

tree

from

Contours ofBreathing (1980)

based on

Weibel (1963)

BronchialEpithelium(seen incross-section)

Royal Free

This is whatcilia look like

???

Royal Free

Or likethis???

Royal Free

Or likethis???

Royal Free

Trachealepithelium

BC basal cellsTBC tall basal

cellsCC ciliated cellsGC goblet cellsIC intermediate

cells

Evans et al Exp Lung Res 2001: 27: 401-5

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

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

Bronchialepithelium

(after hexadecanestimulus)

MUCmucusGCgoblet cell

Green et alin Particle-LungInteractionsed. Gehrand HeyderMarcel Dekker2000

Royal Free

Ciliary Structure(1)

Royal Free

Ciliary Structure(2)

Interaction of cilia and

mucus

seeKnowles and BoucherJ Clin Invest2002: 109: 571-7

+ other papers fromChapel Hill group

Maintaining Airway SurfaceLiquid Depth - ? Stationary or

Moving Periciliary Liquid Layer

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

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

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/secPCL 39.8 ± 4.2 m/sec

But if you take the mucus away:

PCL 4.8 ± 4.2 m/secMatsui et al. J Clin Invest 1998 102: 1125-31

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

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

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

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

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

Pulmonary Defence mechanisms - against chronic bacterial infection

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

IsotonicVolumeTransportModel

ActiveNa+

Absorption

Boucher. J Physiol 1999: 516: 631-8

IsotonicVolumeTransportModel

superficialairwaycells

Boucher. J Physiol 1999: 516: 631-8

IsotonicVolumeTransportModel

submucosalgland

glandductsabsorbNaClbut notwater

Boucher. J Physiol 1999: 516: 631-8

“Hypotonic ASL physiology” Boucher. J Physiol 1999: 516: 631-8

Restoration of water balance in ASL

Boucher. J Physiol 1999: 516: 631-8

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

AirwayEpithelialCulture

good/badindicatorof clearanceeffectivenessin real life ?

Clearance measurements dependon deposition distribution

Pavia 1985

ICRP 66based on Burri & Weibel 1973

Pavia 1985

Pavia 1985

Pavia 1985

Clearance restswhen you’re

asleep

The effect ofsleep rather

than inactivity

Pavia 1984

Mild asthmaticshave worse daytimeclearance thancontrol subjects

- their clearance during sleep is aboutas bad as that seenin control subjects

Effect of inhaling mannitol (patients with bronchiectasis)

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

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

The importance of cough

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

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Whole Lung"Background"

Measuring and calculating retention …………..

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Whole Lung

"Background"

Tracheobronch.

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Whole Lung

"Background"

Tracheobronch.Cough

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Whole Lung"Background"TBTB cough corr

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Whole Lung"Background"TBCough retn

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Whole Lung"Background"TBCough retnTB cough corr

34

0

.349

.122

.094

89.022

Count

Num. Missing

R

R Squared

Adjusted R Squared

RMS Residual

Regression SummaryDeltaAUC vs. DeltaAD

1 35151.886 35151.886 4.436 .0431

32 253597.055 7924.908

33 288748.941

DF Sum of Squares Mean Square F-Value P-Value

Regression

Residual

Total

ANOVA TableDeltaAUC vs. DeltaAD

-26.082 15.842 -26.082 -1.646 .1095

4.265 2.025 .349 2.106 .0431

Coeff icient Std. Error Std. Coeff. t-Value P-Value

Intercept

DeltaAD

Regression CoefficientsDeltaAUC vs. DeltaAD

-350

-300

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0

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150D

elta

AU

C

-15 -10 -5 0 5 10 15 20 25 30DeltaAD

Y = -26.082 + 4.265 * X; R^2 = .122

Regression Plot

Can we relate clearance (or clearance changes) todeposition distribution (or distribution changes) ?

p < 0.05

-60

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AU

Cdb

-40 -30 -20 -10 0 10 20 30 40 50R48db

Y = -5.77 + .383 * X; R^2 = .129

Regression Plot

-60

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-20

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AU

Cdb

-60 -40 -20 0 20 40 60PEFRdb

Y = -2.434 - .322 * X; R^2 = .068

Regression Plot

Effect of a long-acting bronchodilator on mucociliaryclearance measured by an aerosol method

Change in retention

Change in “R48” Change in PEFR

p = 0.06 p = 0.18

2 3705.352 1852.676 4.057 .0298

25 11415.274 456.611

27 15120.625

DF Sum of Squares Mean Square F-Value P-Value

Regression

Residual

Total

ANOVA TableAUCdb vs. 2 Independents

-3.709 4.241 -3.709 -.875 .3901

.459 .189 .430 2.424 .0229

-.431 .220 -.348 -1.960 .0613

Coeff icient Std. Error Std. Coeff. t-Value P-Value

Intercept

R48db

PEFRdb

Regression CoefficientsAUCdb vs. 2 Independents

Effect of a long-acting bronchodilator on mucociliaryclearance measured by an aerosol method - continued

Multiple regression: p = 0.03

Is this an appropriate new approach ?

Effectofamilorideon muco-ciliaryclearance

Sood et al.Am J Respir-Crit Care2003167: 158-63

1

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Asthma

Normal

Transit times through the bronchioles

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10000T

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in)

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Generation No.

Lee et al. '79

NCRP '97

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Smoker

Non-smoker

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

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Intermediate Zone Outer Zone

Control FET

Control FET

Tracheobronchial Clearance - intermediate and outer zones

Mean SEM%

19 patientswith mucushypersecretionHasani et al. 1994

Clearance - Mucociliary / Cough

Whole Lung / Tracheobronchial

Cough-corrected ( ? how)

Dependence on Deposition Distribution

Mucus / Salt and Water

Effects of Medication / Physiotherapy