Respiratory Disease (4) Chronic Obstructive Pulmonary Disease (COPD)

Question 1

Asthma-COPD Overlap (ACO)

Answer 1

Asthma and COPD
>Bronchiolitis (vital infection of small airways, inflammation and mucus buildup)

COPD
>Emphysema (damaged alveoli)
>Bronchitis (viral infection of large airways)

Question 2

COPD

Answer 2

> Ephysema
Bronchiolitis
Chronic Bronchitis

> 3rd leading cause of death in the world

Question 3

Normal values for peak expiratory flow (PEF)

Answer 3

Trajectories indicate that injury to lungs early in life greatly increase COPD risk
>Air pollution is now a major cause

> We have a lot of reserve of lung tissue, can surgically remove 1.5 lungs and still be alive
Quite a lot of lung tissue can be destroyed and PTs coming in with advanced emphysema leave doctors nothing left to work with therapeutically (major loss of lung tissue)

Question 4

Reduced growth of lungs, affecting FEV1

Answer 4

Those born through assisted reproduction, parents who smoke, poor nutrition, or exposed to cigarette smoke will start off with poor lung function
>if they do nothing at all with normative lung function, will develop COPD

This low start can be accelerated by irritants in susceptible people
>start low - add insult
>1/3 to 1/2 of all COPD, developmentally related, nothing to do with cigarettes, important for public policy

Question 5

Normal lung structure

Answer 5

(after 6th division of airways, no longer any cartilage in airways)

> Alveolar units at the end of air structures where gas exchange happens
Green bands = elastin fibres = elastic tissue that gives spring force
Yellow = nerves that project all the way down the alveolar units
Red bands = airway smooth muscle that can contract
also Arteries and Veins

Question 6

Role of elastin in airways

Answer 6

All of the elastin fibres are connected to the walls of the small airways
>pull out from the airways, from neighbouring airway units
>Act like springs, elastin pulls back on the alveolar units and keeps them open

COPD PTs emphysema = progressive loss of elastin fibres
>PTs can breathe in but not out
>When breathe out, force is reversed, if you have a lot of elastin fibres, airways kept open
>If dont have elastin, airways cannot keep open > closed like little valves

> Bronchodilators are used in COPD and asthma
But because airways are physically closed in COPD because of the physics of the lung structures, bronchodilators cannot work as well

> Once lung tissue is damaged, no technology to make them grow again in an organised manner in this radial traction structure
Doesnt provide the support needed to keep the airways open

Question 7

Progressive loss of elastin fibres in COPD

Answer 7

Destruction of the elastin fibres in the smallest airways, expansion of microemphysema
>Start out as small bubble and gets bigger
>starts out really deep in the lung

> use inhaled tantilum to visualise the human small airways in life and noticed little blebs of microemphysema forming

Question 8

Emphysema

Answer 8

Progression of emphysema
>over time, big holes in lungs form
>no tissue, nothing to treat
>advanced COPD = major destruction of lung tissue

Neuronal and non-neuronal ACh contribute to airflow limitation in emphysema
>as lung gets destroyed, nerves get irritated and release ACh
>ACh can also be produced in inflammed damaged tissue
>Small damaged airways still have smooth muscle, cause tightening because of ACh
(so we want to antagonise effects of ACh)

Question 9

3D reconstruction of intraparenchymal vasculature

Answer 9

Smallest airways are destroyed

Reduced number of branches and airways in COPD

Actual airways are destroyed and disappear, no known way of making them grow again

Question 10

COPD:

Emphysema, small airway disease, mucus

Answer 10

Without elastic recoil,
>airways collapse
>made worse by secretions in the airways (mucus)

Question 11

COPD linked to many other diseases

Answer 11

Many PTs in real world have symptoms of both COPD and asthma
>having asthma and allergy is strong risk factor for developing COPD

Irritants that cause damage (high concentration when breathed in) distribute throughout the body
>damaged lung tissue releases factors that travel throughout the body and cause co-morbidities

> > cancer
recurrent infections, attenuated vaccine response
Autoimmunity (RA main risk factor is COPD and smoking)
Endothelium in body is damaged by same processes, cardiovascular, musculoskeletal, endocrine and other comorbidities

Question 12

Systemic inflammation

Answer 12

Cardiovascular death is common in COPD
>using WBCs as biomarkers of lung infection
»lung is common site of infection, has systems to encourage WBC growth (release GCSF to stimulate WBC production in bone marrow)

> Marked increase in WBC, Hs-CRP, IL-6, Fibrinogen in COPD

Question 13

Factors that influence Emphysema

Answer 13

1) Developmental and in utero hypoalveolarisation
(growth problem - lungs too small or dont form enough alveolar units)

2) Epithelial dysfunction and EMT
(damaged epithelium changes nature, goes from being ciliated (clear pathogens) to producing excessive mucus which actually retains those particles)

3) Src, IL-13, IFNgamma,
>shown to physically cause emphysema by destroying elastin

4) Autoimmmunity
>accelerates emphysema

5) Physical shear/tear

6) Microcirculation death
>VEGF/IL-6/gp130
»apoptosis, autophagy, mitochondrial stress, unfolded protein

7) Oxidative and mitochondrial stress, nicotine addiction, inhibited catabasis, immunity and mucosal failure, sensesence

Question 14

Mclennan theory of tissue ripping

Answer 14

Biomechanical strain mapping
>When collagen and elastin fibres are weakened, disease can also progress independently of active biochemical disease processes due to mechanical tearing

> > proven to be true

Question 15

Emphysema (mouse lung micro-CT scans)

Answer 15

Emphysema lung is
>really large
>elastin tissues lost
>lung is always under traction when we breathe
>progressive hyperinflation
>>can breathe in but cant breathe out

Question 16

Process of COPD is slowly evolving

1) Early/Rapid
still largely reversible

Answer 16

Early/Rapid (prone to infections)
>Upon first cigarette
>Cilia that sweep the lungs stop working
>TLR and pattern recognition receptors are damaged, dont sense virus properly
>Antioxidants destroyed by smoke, so we lose defense
>Tissue starts to get damaged
>Catabasis
(macrophages will eat the damaged tissue and remove them from body before they can spill their internal contents)
»if cell ruptures through necrosis, very irritating to tissue and causes inflammation in their own right
»happens quite early, catabasis doesnt work properly
»Immune system that presents antigens doesnt work

> > > > Still largely reversible at this stage if stimulus (smoking) stops

Question 17

Process of COPD is slowly evolving

2) Dys-Homeostasis
hope that this can be reversed pharmacologically

Answer 17

Dys-homeostasis (Prone to colonisation)

After some exposure, we get permanent changes that dont naturally reverse

> Methylation pattern in DNA (epigenetic imprinting) alters gene patterns in lungs even before DNA is mutated

> Macrophages go down strange development pathways where they become inflammatory but dont carry out phagocytosis

> Iron normally cleared
microhaemmorahages of RBC cause iron accumulation
Iron catalyses oxidation, massively enhances formation of damaging oxidants through femtoreactions

> Iron also essential for bacteria to grow, they suck it from our cells and we normally limit that
This allows bacteria to proliferate and form biofilms (alginate)
Extremely difficult for antibiotics to clear the bacteria because they are protected by biofilm

> > > > All this leads to co-morbidities

Question 18

Process of COPD is slowly evolving

3) Late/Slow
Normally treat patients around here, but emphasis is now on treating COPD much earlier

Answer 18

Late/Slow (Can lead to pneumonia and cancer)

> Immune system damaged, particularly T cells (T cell exhaustion)
important for progression to cancer
Early mutated cells detected and destroyed by immune system, but once immune system is weak, cannot eliminate those early mutated cells
Enhances risk of cancer developing

> also autoimmunity

Question 19

Broadly, the same drugs used to treat asthma are also used in COPD

Answer 19

Bronchodilators
1) Long acting muscarinic antagonists (LAMAs)
>Anti-cholinergics
>Particularly effective in COPD compared to asthma because damaged tissues and nerves release ACh near the smooth muscle and cause constriction
>Effects are blocked by LAMAs
»E.g. Ipratropium, tiotropium

2) Long acting B2-agonists (LABAs)
>E.g. Salmeterol, Formoterol
»LABAs and LAMAs are frequently combined in fixed combinations

3) Methylxanthines: theophylline
4) PDE4 blockers, roflumilast: Bronchitic COPD
(inhibit mucus hypersecretion)

Steroids
>Immunosuppressants
>E.g. Budensonide, beclomethasone
»Common in COPD and is now contraversial because steroids inhibit aspects of inflammation but also really damage mucosal defense - increase rate of chest infection very strongly

> > > Steroids work best in patients with eosinophilic inflammation AND a history of recurrent exaccerbations
(only PTs with asthma feature (increase eosinophils - 40% of PTs) will respond well to steroids, the rest just get more chest infections)
Biomarker guided allocation for steroids now

Vaccinations recommended
>Influenza and haemophillus
»Immune attenuation in COPD means that most vaccines work poorly, but are still recommended

Question 20

Role of the parasympathetic system in airway obstruction due to emphysema

Answer 20

From The New England Journal of Medicine

> These results suggest that the two classes of agents (anticholinergic agents and adrenergic agents) produce bronchodilation through a common cholinergic pathway in emphysema, and support the concept that parasympathetic activity is the dominant reversible component of airway obstruction in this disease

Question 21

Nerve development in human fetal lung

Answer 21

During embryogenesis, the smooth muscle sets the pattern of formation of airways
>thus always have muscles and nerves all the way to the end of the ducts

> Muscle relaxation achieved with beta2-agonists
Anticholinergics block effects of ACh
Enhance each other by about 40%
(not synergy, synergy is 1+1=3)

Question 22

Lung cholinergic neuroeffector pathways

Answer 22

Overrepresentation of cholinergic nerves in small airways
>50% of all ACh in lungs isnt coming from nerves
>Extra or non-neuronal ACh produced by damaged tissue
>Provides extra rationale as to why LAMAs are used in COPD but not in asthma

Question 23

Muscarinic receptors

Answer 23

Anticholinergics not very selective for M2/M3
>M2 and M3 receptors recently developed from each other, active site really similar

> When ACh released, M3 receptor causes muscle contraction
M2 is autoinhibitory receptor, tells nerve to stop releasing ACh
>LAMAs not very selective
>If can make a M2 agonist/M3 antagonist, a lot of money