1. Dr Arthur Chun-Wing Lau 刘俊颖 Intensive Care Unit, PYNEH Dec 2005
COPD Update 慢性阻塞性肺病
Dr Arthur Chun-Wing Lau 刘俊颖
Intensive Care Unit, PYNEH
Dec 2005

2. Definition of COPD (GOLD guidelines)
A disease state characterized by airflow limitation that is not fully reversible
The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases

3. Cigarette Smokers in Hong Kong
Thematic Household Survey 2003* (formerly called General Household Survey) by The Census and Statistics Department

4. Smoking accounts for most cases of COPD, but only …..
15% of long-term heavy smokers will develop COPD

5. Individual susceptibility
Angiotensin-converting enzyme (ACE) gene
Transcription factors (myogenic basic helix-loop-helix gene D (MyoD) and myocyte-enhacer factor (MEF)-2
Proteins related to histone acetylation/deacetylation

6. Inflammatory cell interactions in COPD and the role of histone acetylation
1. Oxidants in cigarette smoke deactivates HDAC2, leading to histone acetylation, which in turn promotes unwinding of DNA
2. Cigarette also degradates IK-KB, releasing NF-KB
Oxidant-modified HDAC will not interact with glucocorticoid receptor
Low-dose theophylline markedly induces HDAC transcription
Imp: ? Combination of steroid and theophylline as treatment can break the cycle (ref: Cosio BG et al. J Exp Med 2004)
4. Transcription of IL-8, TNF-alpha and MMP is promoted
3. Unwinding of DNA allows NF-Kb greater access to DNA promoter elements
Ito K et al, NEJM 2005 Shapiro SD, NEJM 2005
5. Leading to destruction of lung tissue

7. Anderson C et al, AJRCCM 2004

8. Decreased histone deacetylase activity in chronic obstructive pulmonary disease
HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages.
Whether there is a link between the severity of disease and the reduction in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity.
Results:
Specimens of lung tissue obtained from patients with increasing clinical stages of COPD had graded reductions in HDAC activity and increases in interleukin-8 messenger RNA (mRNA) and histone-4 acetylation at the interleukin-8 promoter.
The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease.
HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens
Conclusions:
Patients with COPD have a progressive reduction in total HDAC activity that reflects the severity of the disease.
Ito K et al, NEJM 2005

10. International COPD Genetics Network
Sponsored by GSK
Has enrolled 3500 patients
Aims:
to identify susceptibility genes for COPD to better define the manifestations of COPD
to help characterise intermediate phenotypes (with HRCT +/- inhaled hyperpolarised gas to produce 3-D images of the lung)

11. Respiratory system

12. Normal chest X-ray

14. Saber Sheath Trachea
Normal
COPD

15. Normal
COPD

16. Fig. 1.— Sequential images of the right lung in a 71-yr-old male patient with emphysema obtained during deep, slow inspiration (a–d). e) Measurement of diaphragmatic excursion.
Ventral part of the diaphragm moved upward during inspiration. In this case, excursion was –3.6 cm and displacement was 2.6 cm. The paradoxical movement ratio (Mpr) during deep breathing was 42.3%.
Ref: Iwasawa T. Magnetic resonance analysis of abnormal diaphragmatic motion in patients with emphysema
Eur Respir J 2002; 19:
normal

17. Decrease of inspiratory capacity (due to dynamic hyperinflation) in 16 patients with COPD at rest and after metronome-paced hyperventilation (HV) and after exercise (EXE), when the resting respiratory rate was doubled, both before (left) and after (right) administration of 54 mcg inhaled IB
Increases in EELV and EILV from the resting respiratory rate to after exercise and after hyperventilation, both before (left) and after (right) administration of 54 {micro}g aerosolized IB
Gelb, A. F. et al. Chest 2004;126:

18. Rapid shallow breathing pattern
As an adaptive physiological responses which lessen the risk of respiratory muscle fatigue and minimise breathlessness
Leading to hypercapnia
Hypercapnia increases sense of dyspnoea
Gorini M, Misuri G, Corrado A, et al. Breathing pattern and carbon dioxide retention in severe chronic obstructive pulmonary disease. Thorax 1996;51:677–683.[Abstract]

19. Smoking
Emphysema
Chronic bronchitis

20. The nature of small-airways obstruction in COPD
Methods:
N=159, GOLD stages 0 to 4
The small airways were assessed in surgically resected lung tissue
Results:
The progression of COPD was strongly associated with an increase in the volume of tissue in the wall (P<0.001) and the accumulation of inflammatory mucous exudates in the lumen (P<0.001) of the small airways
percentage of the airways that contained polymorphonuclear neutrophils (P<0.001), macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038), B cells (P<0.001), and lymphoid aggregates containing follicles (P=0.003) and the absolute volume of B cells (P=0.03) and CD8 cells (P=0.02) also increased as COPD progressed.
Hogg JC et al, NEJM 2004

22. Implications COPD is an inflammatory disease
Inflammation persists even after cessation of smoking, reason for the persistence unknown
Increased numbers of activated T lymphocytes, ?may include memory T cells that may perpetuate the chronic inflammatory response
? immunosuppressant therapies may be of value

23. Mechanisms of airflow obstsruction
Emphysema: alveolar attachments may have reduced elasticity
Peripheral airway disease: the airway wall may be thickened by an inflammatory-cell infiltrate, by structural changes, by lymphoid follicles.
Chronic bronchitis: the airway lumen may be occluded by mucous secretions

24. YAMAGUCHI K et al. AJRCCM. Volume 156, Number 1, July 1997, 86-93
Inhomogeneities of Ventilation and the Diffusing Capacity to Perfusion in Various Chronic Lung Diseases A
A. Emphysema
B. Emphysema and chronic bronchitis
C. Peripheral airway disease
D. Peripheral airway disease and chronic bronchitis
VA/Q  and D/Q distributions in COPD (MIGET technique)
( A) Chronic pulmonary emphysema (CPE) only - bimodal V A/ Q   distribution with high V A/Q   regions. There were no low D/Q   regions.
( B) Both CPE and chronic bronchitis (CB) components; inhomogeneity along the V A/ Q   axis, but no low D/Q regions.
( C  Peripheral airway disease (PAD) only; bimodal V A/Q  distribution in combination with low VA/Q. There were no regions with low D/   ratios.
( D) Both PAD and CB features; bimodal abnormality in the V A/ Q   distribution with low V A/Q areas. No low D/Q regions were found.
N = 25
YAMAGUCHI K et al. AJRCCM. Volume 156, Number 1, July 1997, 86-93

25. Gas transport mechanisms for coupling of cellular (internal) to pulmonary (external) respiration

32. Circulating inflammatory cytokines
TNF (DiFrancia et al AJRCCM 1994, 150: 1453 – 1455
IL-6 (Degigare et al, Chest, 2003, 124: 83 – 89)
Cause and effect to be established in skeletal muscle dysfunction

33. Pathogenesis of nutritional depletion in COPD: a multicomponent disease

34. Malnourishment and cachexia
Cachexia (COPD)
Fat TG content ↓
Skeletal muscle protein content
Origin
↓ Intake ?
Response to dietary supplementations
Good
Poor

35. Weight loss
Causes: Inc VO2 in resp and non-resp muscles, beta-2 agonists, theophylline, tissue hypoxia, inc activity of cytochrome oxidase (the mitochondrial enzyme that consumes oxygen)
Loss of skeletal muscle mass (main cause of weight loss), loss of fat mass (lesser extent) – Schols AMWJ et al, AJRCCM 1993)
An independent prognostic factor, in addition to FEV1 and PaO2

38. Poor relationship between exercise and FEV1
Correlation between normalised FEV1 and normalized peak VO2 is low, accounting for <25% of the variability (Bauerle et al. J Appl Physiol 1995)

39. Reduced peak power output and VO2
Contractile properties of the vastus lateralis are preserved (Debigare et al ERJ 2003, – 278)
Strength/muscle X-section area was not different (Bernard et al AJRCCM 1998, 158: 629 – 634)
Small muscle mass peak VO2 same as in controls (Richardson et al, AJRCCM 2004, 169: 89 – 96)

40. Early blood lactate accumulation
Of course (Maltais et al, JAP 1998, 84: 1573 – 1580)
But typical of deconditioning (and hypoxemia)

41. Reduced muscle oxidative enzyme capacity
Citrate synthase in the legs (Maltais et al, Thorax 2000, 55: 848 – 853)
But typical of deconditioning
Normal enzymes in deltoid muscles (GEA et al, ERJ, 2001, 17: 939 – 945)

42. Scheme of the major biochemical pathways for ATP production
Anaerobic glycolysis (Pathway B) occurs when there is inadequate O2 flow to mitochondria

43. Gas exchange during aerobic (A) and aerobic plus anaerobic (B) exercise
The acid-base consequence of (B) is a net increase in cell lactic acid production.
Buffering of lactic acid is predominantly by bicarbonate.

44. Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD
Methods: Nine COPD patients (age = 62 +/- 5 yr, mean +/- SD, FEV1 40 +/- 9% of predicted) and in nine normal subjects of similar age (54 +/- 3 yr). Following a transcutaneous biopsy of the vastus laterialis, each subject performed a stepwise exercise test on an ergocycle up to his or her maximal capacity
Aim to determination:
Glycolytic enzymes: lactate dehydrogenase, hexokinase, and phosphofructokinase
Oxidative enzymes: citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HADH) levels (at vastus lateralis)
Serial lactate measurement during exercise
Maltais F et al AJRCCM 1996

45. Results
No difference was found between the two groups for the glycolytic enzymes.
Activities of the oxidative enzymes was significantly lower in COPD than in control subjects for both citrase synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HADH)
Increase in lactic acid was steeper in COPD (b = 4.3 +/- 2.0 versus 2.1 +/- 0.2 for normal subjects, p = ).
Conclusion: In COPD the increase in arterial La during exercise is excessive, the oxidative capacity of the skeletal muscle is reduced, and that these two results are interrelated.

46. Muslce histological differences: type II vs I fibers
Probably explains high VO2/power output
But may be due to long-term & extreme inactivity (Larsson et al, Muscle and Nerve, 1985, 8: 714 – 722)
Whittom, MSSE, 1998, 30: 1467 – 1474
Maltais ERJ 1999, 13, 850 – 854
Richardson et al, AJRCCM 2004, 169:

49. Reduced anabolic hormones
Testosterone
IGF-1
Cause and effect in causing muscle dysfunction to be established
Kamischke et al, ERJ 1998, 11: 41-45
Debigare et al, Chest 2003, 124:

50. Other potential systemic effects
Cardiovascular system
Nervous system effects
Osteoskeletal effects