“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

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. 100 mins Bronchi BB Bronchioles bb 8 hours 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. 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

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 ?

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

18. Branching Structure of the Airways Weibel,1991 original 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+ Absorption Boucher. J Physiol 1999: 516: 631-8

38. Isotonic Volume Transport Model superficial airway 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

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 you’re asleep The effect of sleep rather than inactivity Pavia 1985