Tracheobronchial Clearance Fast clearance from the bronchi and bronchioles

1
Tracheobronchial ClearanceFast clearance from
the bronchi and bronchioles

• J E Agnew
• Royal Free Hampstead NHS Trust and
• Royal Free University College Medical School

2
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
3
(No Transcript)
4
(No Transcript)
5
The ICRP Respiratory Tract Model
6
GI tract
Clearance Routes from the Respiratory Tract
ET
based on the ICRP model ICRP Publication 66
BB
bb
AI
Lymph Nodes
Blood
7
NCRP Model
8
ICRP reference BB and bb half-times
9
Timescales for Tracheobronchial and
Pulmonary Clearance as set out in NCRP 1997
10

• Aerosol Particles
• Inert polystyrene particles
• 5?m diameter
• Tc-99m labelled
• Inhaled slowly
• Retention measured 0-6h 24h
• Initial Gamma Camera Image

11
(No Transcript)
12
Tracheobronchial Clearance - intermediate and
outer zones

19 patients with mucus hypersecretion Hasani et
al. 1994
Control FET
Control FET
Intermediate Zone Outer Zone
13
The Lungs ?
14
(No Transcript)
15
(No Transcript)
16
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
17
(No Transcript)
18
Branching Structure of the Airways Weibel,1991 o
riginal version Weibel, 1963
19
The Tracheo-bronchial tree from Contours
of Breathing (1980) based on Weibel (1963)
20
Bronchial Epithelium (seen in cross-section)
Royal Free
21
This is what cilia look like ???
Royal Free
22
Or like this ???
Royal Free
23
Or like this ???
Royal Free
24
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
25

• 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
26

• 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
27
Bronchial epithelium (after hexadecane stimulus)
MUC mucus GC goblet cell Green et al in
Particle-Lung Interactions ed. Gehr and
Heyder Marcel Dekker 2000
28
Ciliary Structure (1)
Royal Free
29
Ciliary Structure (2)
Royal Free
30
Interaction of cilia and mucus
see Knowles and Boucher J Clin Invest 2002 109
571-7 other papers from Chapel Hill group
31
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
32
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
33
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
34
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
35
Mucus transport - as seen by time-lapse photos in
cell culture experiments
Tarran et al. J Gen Physiol 2001 118 223-36
36
Pulmonary Defence mechanisms - against chronic
bacterial infection
Knowles Boucher J Clin Invest 2002 109 571-7
37
Isotonic Volume Transport Model Active Na Abso
rption
Boucher. J Physiol 1999 516 631-8
38
Isotonic Volume Transport Model superficial air
way cells
Boucher. J Physiol 1999 516 631-8
39
Isotonic Volume Transport Model submucosal gland
gland ducts absorb NaCl but not water
Boucher. J Physiol 1999 516 631-8
40
Boucher. J Physiol 1999 516 631-8
Hypotonic ASL physiology
41
Restoration of water balance in ASL
Boucher. J Physiol 1999 516 631-8
42
Airway Epithelial Culture good/bad indicator of
clearance effectiveness in real life ?
Knowles Boucher J Clin Invest 2002 109 571-7
43
(No Transcript)
44
(No Transcript)
45
(No Transcript)
46
Clearance measurements depend on deposition
distribution
Pavia 1985
47
ICRP 66 based on Burri Weibel 1973
48
Pavia 1985
49
Pavia 1985
50
Clearance rests when youre asleep
The effect of sleep rather than inactivity
Pavia 1985
51
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
52
Effect of inhaling mannitol (patients with
bronchiectasis)
Daviskas et al. Am J Respir Crit Care Med 1999
159 1843-8
53
Daviskas et al. Am J Respir Crit Care Med 1999
159 1843-8
54
The importance of cough
Foster WM Pulm Pharmacol Ther 2002 15 277-82
55
Measuring and calculating retention ..
56
(No Transcript)
57
(No Transcript)
58
(No Transcript)
59
(No Transcript)
60
(No Transcript)
61
Can we relate clearance (or clearance changes)
to deposition distribution (or distribution
changes) ?
p lt 0.05
62
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
63
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 ?
64
Effect of amiloride on muco- ciliary clearance
Sood et al. Am J Respir- Crit Care 2003 167
158-63
65
(No Transcript)
66
(No Transcript)
67
(No Transcript)
68
Transit times through the bronchioles
69
The foot of the mucociliary escalator goes
deeper in smokers than in non-smokers
Smoker
Non-smoker
70
Tracheobronchial Clearance - intermediate and
outer zones

19 patients with mucus hypersecretion Hasani et
al. 1994
Control FET
Control FET
Intermediate Zone Outer Zone
71
(No Transcript)
72
Clearance - Mucociliary / Cough Whole Lung /
Tracheobronchial Cough-corrected ( ?
how) Dependence on Deposition Distribution Mucus
/ Salt and Water Effects of Medication /
Physiotherapy