COD respiratory diseases Flashcards
What are basal cells?
Stem cells of the airways
Differentiate into ciliated and secretory cells
What are ciliated cells?
Airway clearance
Removal of debris and pathogens out of the airways
What are goblet cells?
Secretes mucous
Which protects the lining of the airways and traps pathogens
What is air-liquid interface (ALI)?
Model
Differentiation of basal cells to secretory and ciliated cells upon exposure to air
What is spheroids in Matrigel?
Model
Cell differentiation demonstrated by production of mucous
What is Co-Cultures organoids?
Powerful to look at cell-cell crosstalk
eg fibroblasts
What are some common respiratory diseases?
Obstructive lung diseases eg asthma
Restrictive lung diseases eg Pulmonary fibrosis
Lung cancer
What are obstructive lung diseases?
Difficulty getting air out of the lungs
eg asthma
cystic fibrosis
What are restrictive lung diseases?
Difficulty getting air into the lungs
eg pulmonary fibrosis
Sarcoidosis
What is the forced vital capacity FVC?
Total air volume you can exhale in one forced breath
What is forced expiratory volume in 1 sec FEV1?
Air volume you breath out in 1 sec
Obstructive or restrictive diagnosis?
FEV1/FVC ratio <0.7
Reduced speed of breathing out
Narrow airways
Obstructive
Obstructive or restrictive diagnosis? Normal FEV1/FVC ratio Reduced amount of air breathed in Normal speed breathing in Rigid/unable to expand lungs
Restrictive
Describe Chronic Obstructive Pulmonary Disease (COPD)
eg stats
Heterogenous disease with different clinical phenotypes and progression course
Usually affecting older people
1.2 million people live with COPD in the UK
3.17 million deaths in 2015
3rd cause of death worldwide but no effective therapy
What are some clinical phenotypes in COPD?
PINK PUFFERS
- (mostly) Emphysema
- Thin and cold
- Pink skin
- Minimal cough
- Barrel chest
- Severe breathlessness
BLUE BLOATERS
- (mostly) Bronchitis
- Overweight
- Cyanosis (blue lips)
- Chronic cough
- Crackle and wheeze
- Ankle swelling
Describe COPD as a Premature Aging Disease
Ageing lung features: loss of elasticity, enlargement of alveoli
Oxidative stress as key driver
- > telomere shortening
- > DNA damage
- > stem cell exhaustion & senescence
- > reduced repair & regeneration
Senescent cells secrete inflammatory mediators and proteases ->
senescence-associated secretory phenotype (SASP)
What has been proposed as a new approach for COPD as a Premature Aging Disease?
Targeting with anti-ageing drugs (senotherapies)
Awaiting clinical trials in patients
How do you diagnose COPD?
Spirometry
The lower the FEV1
is => the worse the COPD is going to be
Chest CT (computed tomography) may help identify emphysema
What could be a risk factor for COPD development?
Small lungs at birth
How is COPD managed?
Currently no cure
- Smoking cessation (quit)
- Bronchodilator inhalers: relax & open the airways making breathing easier
- Steroid inhalers: reduce airway inflammation, combined with bronchodilators (triple-therapy)
Pulmonary rehabilitation: exercise and education
Oxygen therapy often required in severe disease
Surgery: lung volume reduction, lung transplantation
What are the future directions for COPD?
Urgent need for sensitive COPD biomarkers
-> early diagnosis
Need for curative treatments
-> identification of disease drivers & novel regulators
Need for better disease education
-> earlier diagnosis and better management
Describe asthma
eg stats
Affects people of all ages, often starts in childhood, but can also develop in adults
5.4 million people live with asthma in the UK
420.000 deaths / year (2016)
Reversible disease involving narrowing of the airways (bronchioles)
What are some genetic and environmental risk factors associated with asthma?
- > allergens
- > pollutants
- > work exposures
- > cigarette smoke
- > medication (e.g. aspirin)
- > stress
- > exercise
- > cold air
- > viruses
- > obesity
What are the 2 asthma subtypes?
Atopic = allergic
Non-Atopic =Non- allergic
Describe Atopic asthma
Allergic Extrinsic (triggered by environment) Most common Begins in childhood Elevated IgE - antibodies produced by the immune system More favourable Family history
Describe Non-Atopic asthma
Non-allergic Intrinsic (no recognisable allergen) Non common Late onset Normal IgE -antibodies produced by the immune system More severe
What are the key features of asthma?
Airway hyperresponsiveness to a range of stimuli / triggers Airway inflammation and structural remodelling -> obstruction Thickened airway wall Smooth muscle spasm Mucus hypersecretion Goblet cell hyperplasia Immune cells infiltration (inflammation)
Describe airway remodelling in asthma
Affects both large and small airways
Triggered by epithelial cells
Recruitment & prolonged activation of immune cells Th2, dendritic cells, macrophages
Increased smooth muscle cell mass & contractility, increased deposition of extracellular matrix
-> structural airway remodelling (thickening, fibrosis)-> obstruction
Activated fibroblasts & smooth muscle cells
Increased number of Goblet cells -> mucus production -> obstruction
How is asthma diagnosed?
Characteristic pattern of respiratory symptoms
Variable airflow limitation
Variability in lung function
-> peak expiratory flow measurement
Bronchial provocation test (e.g. inhaled methacholine/histamine or exercise stress challenge -> measures how the airways respond to
triggers, assesses airway hyperresponsiveness)
Allergy test (presence of atopy increases probability for asthma)
Describe Anti-inflammatory and bronchodilator inhalers
Reliever inhalers = bronchodilator eg salbutamol Dilate the airways Used occasionally During attack for immediate relief of symptoms
Preventer inhalers = anti-inflammatory
Used regularly eg daily
For prevention of symptoms
Reduces airway swelling
Severe asthma: monoclonal antibodies (e.g. IgE, IL-5, IL-4 receptor)
How do bronchodilators work?
Different classes & mechanism, but all open (dilate) the airways
▪ Short-acting or long-acting
Describe idiopathic pulmonary fibrosis
Affects mostly older people (>50 years), more common in males
5000 people diagnosed every year in the UK
30,000 living with IPF in the UK (2016)
Median survival: 2-4 years
Disease involving parenchymal remodelling and progressive ‘scarring’ of the lung
Difficulty breathing and getting oxygen into bloodstream
What does idiopathic mean?
Unknown cause
How do you diagnose IPF?
Difficult as symptoms resemble other respiratory diseases & there are many types of interstitial lung diseases (ILDs)
Multidisciplinary team of experts diagnose
Exclusion of other known causes
Spirometry to look for restrictive pattern
DLCO measurement (Lung ability to transfer
gas from inhaled air into
bloodstream (indicates
extend of damage))
What are the key features of IPF?
High-resolution chest CT scan -> Usual Interstitial Pneumonia pattern
Subpleural reticulation
Honeycombing
Collagen accumulation
Histology: Fibroblastic foci
Lung biopsy (if HRCT not clear)
How do you manage IPF
No cure
2 drugs approved in 2014 (side effects)
Pirfenidone Nintedanib
Oxygen therapy and pulmonary rehabilitation
What are the future directions of IPF?
Urgent need for sensitive ILD biomarkers
-> early & accurate diagnosis (potential for disease reversal)
-> identification of rapid progressors
Need for better & curative treatments
-> identification of disease drivers & novel regulators
-> discovery of new drugs without side effects & suitable for severe disease
Need for better disease education (patients & doctors)
-> earlier diagnosis & better management
Describe COVID-19
Affects people of all ages, but the most dangerous for elderly and vulnerable (associated chronic diseases)
123 million people have been infected worldwide (end of 2020)
2.7 Million deaths so far
Caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)
What are Key Lung Cells Expressing SARS-CoV-2 Entry Proteins?
ACE2 & TMPRSS2 expression: nose, oral mucosa, lung (heart, kidney, pancreas, eye, brain, testes) -> potential (but not proof) for infection
Describe the Different Expression of Entry Proteins with Age & Disease
Expression of ACE2 and TMPRSS2 in nasal and
bronchial airways relative to age and diseases status
children: lower expression than adults
increased expression in smokers, COPD, asthma
and hypertension
May explain differences in disease severity & susceptibility
What is fibrosis
Excessive scarring in the lung
occurring due to aberrant repair
What can we learn from receptor distribution in Covid?
Higher expression of receptors in the nose -> increased infectivity of the virus
viral transmissibility dependent on the spatial distribution of receptor accessibility along the respiratory tract
Presence of receptors may explain patients symptoms
eg
> gastrointestinal tract (small intestines): diarrhoea, viral sheading
respiratory tract: cough, pneumonia, acute respiratory distress syndrome
> brain: neurological symptoms: confusion, agitation, memory loss,
psychosis, brain inflammation and swelling, stroke)
Expression of ACE2 and TMPRSS2 in nasal and
bronchial airways is relative to age and diseases status
What does this mean for children and smokers?
children: lower expression than adults
increased expression in
smokers, COPD, asthma
and hypertension
what are the long term effects of covid?
SARS coronaviruses are fibrogenic exacerbates pulmonary fibrosis Fibrotic changes observed in patients who recovered from COVID-19 Fibrotic changes visible on CT scans eg micro-honeycombing
