Lung cell biology tutorial Flashcards
Describe the epidemiology of asthma
20% children
10% adults
Global increase
Describe the epidemiology of COPD
4th cause of death
5th cause of disability
Global increase
Which part of the airway is affected in asthma
Large & small airways
Airway hyper-
responsiveness
Increased mucus production
Which part of the airway is affected in COPD
Airways and lung
Very little AHR
iNCREASED Mucus
Which inflammatory cells and mediators are involved in asthma
Eosinophils
Mast cells
Th2 lymphocytes
IL-4, -5, cysLTs
Which inflammatory cells and mediators are involved in COPD
Neutrophils
Macrophages
Tc1 lymphocytes
TNF, IL-8, LTB4
Describe the treatment of COPD and asthma
Asthma- Bronchodilators -
Corticosteroids -
COPD cannot use these
What is the key difference between asthma and COPD
Asthma- reversible
COPD- irreversible
Summarise asthma pathology
Bronchoconstriction + mucus
Allergic induced airway inflammation results in:
smooth-muscle constriction
thickening of the airway wall (smooth-muscle hypertrophy and oedema)
basement membrane thickening
mucus and exudate in the airway lumen- mucus plug containing inflammatory cells- makes it hard to breathe.
What does the viscid mucous contain in asthma
Desquamated epithelial cells
Whorls of shed epithelium (Curschmann’s whorls)
Charcot-Leyden crystal ( eosinophil cell membrane)
Infiltration of inflammatory cells, particularly CD4+ T lymphocytes
Summarise the pathology of COPD
Chronic bronchitis- airway hyper mucous secretion
Tobacco smoke damages the lungs:
Inflammatory cell activation- stimulates epithelial cells, macrophages and neutrophils to release inflammatory mediators and proteases (neutrophil elastase)
oxidative stress- oxidants in cigarette smoke act directly on epithelial cells and goblet cells- causing inflammation
Impaired mucociliary clearance- leading to retained mucus secretions
What are the two main pathological processes in COPD
Alveolar destruction (emphysema) Mucus hypersecretion (chronic bronchitis)
Describe emphysema in COPD
Cigarette smoke and other inhaled noxious particles cause inflammatory cell activation within the lungs, inducing cells to release inflammatory mediators and proteases, the most important being neutrophil elastase
Normally, antiproteases will neutralise these proteases, but in COPD the volume of proteases produced is in excess
Unopposed action of neutrophil elastase destroys lung tissue
As the distal airways are held open by alveolar septa- destruction of alveoli causes the airways to collapse- resulting in airway obstruction.
Describe the consequences of emphysema
Destruction of parenchyma increases compliance of the lung and causes a V/Q mismatch Increased compliance (reduced elastic recoil) means that the lungs do not deflate as easily, contributing to air trapping As more alveolar walls are destroyed- compliance of the lungs increases and bullae (dilate air spaces >10mm) form which can rupture and cause pneumothoraces
Describe centriacinar (centrilobular) emphysema
septal destruction and dilation are limited to the centre of the acinus, around the terminal bronchiole and predominately affect upper lobes- seen in smoking
increasing damage further into the alveoli
Describe panacinar (panlobular) emphysema
The whole of the acinus is involved distal to the terminal bronchioles, and lower lobes are commonly affected- characteristic of alpha 1- antitrypsin deficiency
Describe chronic bronchitis (mucous hypersecretion in COPD)
Cigarette smoke causes hyperplasia and hypertrophy of mucus-secreting glands found in the mucosa of the large cartilaginous airways.
Mucous gland hypertrophy is expressed as gland:wall ratio or by the Reid index (normally <0.4)
Hyperplasia of the intraepithelial goblet cells occurs at the expense of ciliated cells in the lining epithelium and squamous metaplasia may occur
Small airways become obstructed by intraluminal mucus plugs, mucosal oedema, smooth muscle hypertrophy and peribronchial fibrosis.
Secondary bacterial colonization of retained products occurs
The effect of these changes is to cause obstruction, increasing resistance to air flow
mismatch in V/Q occurs- impairing gas exchange
Describe small airway disease (bronchiolitis)
Mucosal and peribronchial inflammation and fibrosis (obliterative bronchiolitis)
Why do the small airways collapse, become obstructed and stenosed in COPD
a. Collapse – alveolar attachments get digested away.
b. Obstructed – hyperplasia of goblet cells causing excess mucus production.
c. Stenosed – Fibrosis of the small airways.
What are the changes in epithelial cell profile and secretions during bronchitis?
a. Profile – hyperplasia of goblet cells and hypertrophy of submucosal glands.
b. Secretions – more mucus produced and cilia become destroyed and beat asynchronously.
Describe the proportion of cells in healthy individuals and those with COPD
Healthy
Macrophages- 70
Neutrophils- 30
COPD- reverses
mucociliary escalator not working- lots of dead neutrophils- macrophages come to clear these away- numbers still increase but neutrophils have a larger increase- mucous- infection- therefore increase
Describe the proportion of cells in the alveoli in healthy individuals and compare that to COPD patients
Healthy:
Macrophages- 90
Neutrophils- 10
COPD- same ratio but numbers increase- 5-10 fold increase
problem when pathogens enter the peripheral lungs- an increase in neutrophils by greater than 30% is problematic
Describe the bronchiolar lavage
inspects activity of the proteases in the lavage, need to see if the drug is effective
uses saline to wash mucus, cells and proteases away for sampling
mucus should decrease in response to treatment
What should be found in the lavage in response to the drugs (It can inhibit the activity of serine proteinases as well as matrix metalloproteases)
less IL-8, IL-1, TNFa
More defensins, anti-proteases and IL-10 as these are anti-inflammatory and so will put inflammation in balance
Describe the use of CT scanning
COPD lungs- full of gas and air- hyperinflated lungs
gas looks black on the X-ray- lungs look very dark- but won’t see much change
CT- contrast can differentiate between different types of tissue more easily- different shades of white to black
CT- pixels- measure the number and size of holes in the lungs to measure the level of emphysema.
Do drugs reduce the number of holes
No- destruction is an irreversible process
Compare neutrophil elastase and metalloproteinases
NE- active enzymes in storage granules- released upon recruitment, hydrolyses elastin
MMP- metal ion (zinc) as its active site- released in latent form- Zn releases/frees active site- MMPs can then break down connective tissue and collagen (cement of lungs)- which are not healed properly
Compare the activities of the different anti-proteases
AAT; also called alpha-1 proteinase inhibitor- inhibits NE
tissue inhibitor of metalloproteases (TIMP)- INHIBIT MMPS
What is important to remember about the proteases
NEs degrade TIMPS
MMPs degrade AATs
So we get a protease soup- imbalance in proteases- walls dissolve- alveolar destruction
MMPs and NEs activate growth factors and other molecules- important in homeostasis of tissues
Describe AATs
acute phase protein- irreversibly inactivate NEs
Neutrophils make free radicals which activate NEs
Cigarette smoke has millions of free radicals
Summarise small airway disease
Elastic walls disappear- mucous builds up- stenosis
Fibrosis adds to the stenosis
Why do we need to inhale the drugs
Deactivated by free radicals and the proteases themselves
Thus we need to inhale the drug to get it directly to where it is needed
Why do we need a dual inhibitor
Two classes of proteases
But inhibiting MMPs increases the risk of cancer- thus we need to deliver the drug locally
Why is it hard to deliver the drug
Lungs are blocked and stenosed- can be hard to inhale
Give mucolytic which is coughed up- freeing the airways
Describe the use of bronchodilators in COPD patients
a. Not really as COPD doesn’t affect bronchoconstriction. If he has a co-morbidity of asthma, it might affect him.- if they feel better- keep them on it
Describe the asthma- COPD overlap
Asthma-COPD overlap (ACO): smokers with asthma leading to wheezy bronchitis - overlap of two conditions
Describe a schema for the pathophysiology of COPD
Epithelial cells producing TGBbeta to activate fibroblasts leading to fibrosis and chronic bronchiolitis
Smoke activates macrophages- autocrine effect of MCP-1, activation of proteases, Neutrophil chemo-
tactic factors
(eg IL-8, LTB4)
and activating CTLs
Neutrophils release oxidants and proteases
CTLs lead to alveolar destruction
Oxidants lead to mucous hypersecretion and alveolar destruction, proteases have the same effect
Antioxidants inhibits oxidants
Anti-proteases inhibit proteases
Describe the findings from Flethcher et al
lung function measured in people >25 till age 80 to study how changes over lifetime; identified non-smokers had limited decline (~25%), and non-susceptible smokers had an almost identical decline; susceptible smokers had a much more severe decline that led to symptoms, disability and then death; if stopped smoking then led to reduced rate of decrease so longer prognosis, but older you stop the less the recovery
Function in terms of FEV1 (% predicted at age 25)
Symptoms at 50% predicted
Disability at around 30%
Death- 15%
