Block D Lecture 1 - Asthma and COPD Flashcards
What are 4 types of non-specific stimuli?
Exercise
Cold Air
Hyperventilation
Chemical Agents
(Slide 3)
What are 2 types of specific stimuli and what are they specific to?
Allergens - specific to asthmatics that respond to allergens
Aspirin - specific to patients which display hyper-responsiveness to aspirin
(Slide 3)
What are 4 characteristic asthma?
Answers Include:
Inflammatory Response (e.g Eosinophils, mast cells and neutrophils)
Hyper-responsiveness of smooth muscle to substances which cause contraction to smooth muscle (e.g acetylcholine)
Hypo-responsiveness of the smooth muscle to substances which relax smooth muscle (such as adrenaline)
Neuronal imbalance - overactive parasympathetic nervous system
Hyperplasia (an increase in the number of cells in a tissue or organ, leading to enlargement)
Hypertrophy ( an increase in the size of cells or tissues, often resulting in an increase in the overall size of an organ or part of the body, such as muscle tissue through exercise)
(Slide 4)
What is the early phase of asthma?
Where inflammatory cells are recruited into the interstitial fluid and smooth muscle, release constrictor mediators (from mast-cell bronchoconstriction), which activate vagal afferent to cause reflect bronchoconstriction
(Slide 7)
What is late phase asthma?
Eosinophils take up residence in the lung and release agents such as oxygen radicals, major basic protein and PAF.
This results in a potent killing and damaging effect upon epithelial cells and extensive damage to the epithelial lining is achieved
(Slide 7)
How are mast cells, eosinophils and neutrophils involved in asthma?
Mast cells: respond to the allergen and IgE by releasing histamine, TNF-α, LTC4 and LTD4 and various interleukins such as IL-1
Eosinophils: release PAF, TNF-α, oxygen, eotaxin, MBP, eosinophil peroxidase, IL-4, IL-5, il-1β, IL-6, which cause epithelial damage or activate other cells (such as leucocytes or smooth muscle cells)
Neutrophils: these cells release ROS species, neutrophil elastase, myeloperoxidase (damages epithelial cells)
(Slide 8)
Are most cases of asthma TH1 or TH2?
TH2
(Slide 9)
What is TH2 asthma?
A TH2 condition; TH2 cells cause B-cell production of IgE and binding of IgE to mast cell IgE receptors.
Pollen then cross links receptors and cause mast cell degranulation
Eosinophil migration and activation also occurs, triggering long term damage
(Slide 9)
What is TH1 asthma?
TH1 cells produce IFN-γ and TNFα
TNFα then activates neutrophils which results in the long term damage
(Slide 9)
What are 5 examples of structural changes / remodelling induced inflammation?
Epithelial damage
Goblet cell
Hyperplasia
Increased intraluminal secretions
Basements membrane thickening
Smooth muscle hypertrophy
Hyperplasia
(Slide 10)
What does airway smooth muscle do in patients with asthma when compared to healthy individuals?
Contracts more - due to an increased number of cytokines
Contracts more in response to methacholine - hyperresponsive
More stiffness - lack of breathing induced muscle softening
Increased muscle mass, leading to an increased force of contraction
In both normal as and asthmatic patients, the airway smooth muscle can release cytokines, which can worsen symptoms
(Slide 12)
What are 3 possible reasons why M3 induced contraction is more frequent / worse in patients with asthma when compared to healthy individuals?
Higher amounts of Rho kinase (due to cytokine mediated gene induction), which results in more sustained contraction
Higher levels of M3 receptors
Higher levels of signalling components, such as PCL or Gq
(Slide 15)
What 2 things are involved in airway muscle proliferation and what is it stimulated by?
Both hypertrophy (cell size) and hyperplasia (cell number) are involved
It is stimulated by multiple growth factors and mediators
(Slide 16)
What can the airway muscle release and what can this cause?
It can release its own mediators - which can result in an autocrine loop, which can amplify inflammation and contribute to airway restructuring.
These mediators can also effect other cells
(Slide 16)
Does airway muscle proliferate faster or slower in patients with asthma - how do we know this?
It proliferates faster, which we know as bronchial biopsies from patients proliferate more
(Slide 16)
What is the airway smooth muscle associated with in asthma?
Hyper responsiveness and increased stiffness
(Slide 16)
How does the MEK pathway contribute in asthma?
- In asthma, airway smooth muscle cells are exposed to a range of inflammatory mediators,
2.These activate receptor tyrosine kinases (RTKs) or G-protein coupled receptors (GPCRs) on the surface of airway smooth muscle cells
- When receptors are activated, adaptor protein grb2 is recruited to the receptor complex where it binds to Son of Sevenless (SOS)
- SOS acts as a guanine nucleotide exchange factor for Ras, and activates Ras by facilitating the exchange of GDP for GTP
- Ras then interacts with Raf1, a serine threonine kinase, activating it.
- Raf1 then phosphorylates MEK (map kinase kinase)
- MEK phosphorylates ERK (MAP kinase), a protein kinase which translocates to the nucleus.
- ERK then regulates the activity of transcription factors (such as NF-κB)), promoting genes that control cell proliferation, survival, and other important processes
Note: Bonus points for saying that binding to the RTK causes dimerization, and then RTKs undergo autophosphorylation via tyrosine residues and these phosphorylated RTKs then recruit Grb2
Above is stuff from last semester but it’ll count as extra reading for this class I think?
(Slide 17)
How does increased parasympathetic activity contribute to asthma?
Increased activity can occur due to defects in cholinergic innervation.
This can result in:
Increased vagal tone (increased activity of the vagus nerve, the main parasympathetic nerve) - can lead to bronchoconstriction
Reflex bronchoconstriction
Increased acetylcholine release - which then binds to muscarinic receptors (specifically M3), causing bronchoconstriction
Increased post-synaptic muscarinic function - this means airway smooth muscle is more sensitive to acetylcholine, leading to stronger bronchoconstriction responses
(Slide 19)
What are 2 examples of classes of mediators can increase acetylcholine release, which can help contribute to asthma?
Tachykinins and thromboxanes
(Slide 19)
What are C-fibres?
Small, unmyelinated sensory nerve fibres that play a crucial role in detecting pain, temperature, and chemical irritants. They belong to the SNS.
(Slide 20)
How do C-fibres contribute to asthma?
- Irritants stimulate C-fibres receptors. Inflammatory cells can also release mediators which sensitive C-fibres
- C-fibres send signals via the nodose ganglion to the CNS
- This activates the vagus nerve, which is the major parasympathetic nerve.
- The vagus nerve sends signals to a parasympathetic ganglion, releasing acetylcholine
- Acetylcholine stimulates muscarinic receptors on airway smooth muscle, leading to bronchoconstriction
(Slide 20)
What is COPD?
It stands for Chronic Obstructive Pulmonary Disease (COPD) and is a chronic slowly progressive disorder characterised by airflow obstruction
(Slide 22)
What does COPD reduce and what does ratio does this affect?
It reduces FEV1 (the maximum amount of air a person can forcefully exhale in one second) which reduces the FEV1/VC ratio.
VC stands for total capacity and is the total amount of air a person can exhale after taking a full, deep breath
(Slide 22)
What are 3 features of the pathology of COPD?
Increased mucus gland thickness
Airflow Limitation
Circulatory Changes (only in advanced cases)
(Slide 23)
What are 3 ways which the air flow limitation of COPD can be caused?
Via mechanical obstruction / inflammation
Through loss of pulmonary elastic recoil
Reduction of the alveolar attachment around the walls of the small airways
(Slide 23)
What are 4 clinical features of COPD?
Answers Include:
Chronic Dyspnoea (shortness of breath or difficulty breathing)
Wheezing (breathing with a whistling or rattling sound in the chest)
Unintended Weight Loss
Cough and Sputum (a mixture of saliva and mucus coughed up from the respiratory tract)
Chest Tightness
(Slide 24)
What are 4 risk factors for COPD?
Smoking or second-hand smoke
Lung irritants (such as chemical fumes)
Family History (AATD gene linked to COPD)
History of respiratory infections as a child
(Slide 25)
What are chronic bronchitis and emphysema?
Different forms of COPD which affect the lungs in different ways
(Slide 26)
What causes chronic bronchitis and how does it affect the lungs?
Chronic bronchitis is caused by chronic inflammation and narrowing of the airways, leading to increased mucus production and difficulty breathing.
Symptoms include: A persistent cough, increased mucus production, shortness of breath and wheezing
(Slide 26)
What causes emphysema and how does it affect the lungs?
Emphysema is caused by Destruction of the alveoli (air sacs) in the lungs, leading to a reduction in the surface area for gas exchange.
Symptoms include: Shortness of breath, wheezing, and a feeling of not getting enough air (dyspnoea) ‘
(Slide 26)
What are the cellular mechanisms which lead to both chronic bronchitis and emphysema?
- Irritants (such as cigarette smoke) activate epithelial cells lining the airways and alveolar macrophages
- Both of these can activate neutrophils by releasing a variety of signalling molecules, such as pro-inflammatory cytokines or chemotactic factors
- Macrophages and neutrophils can release proteases, and neutrophils can also release other mediators such as reactive oxygen species (ROS)
4a. Proteases released breakdown elastin, a key component of the extracellular matrix in the alveolar walls, leading to the destruction of the alveolar walls, resulting in the loss of lung elasticity and alveolar collapse, leading to a decreased surface area for gas exchange (emphysema)
4b. Proteases released degrade structural proteins in the bronchial walls, such as collagen or elastin , which weakens the airways and contributes to inflammation and airway remodelling. These processes lead to thickening of the bronchial walls, narrowing of the airways, and increased mucus production (chronic bronchitis)
(Slides 27 and 28)
Why is the alpha 1 anti-trypsin gene important in COPD?
It encodes for alpha 1 anti-trypsin, which inhibits trypsin like proteases (“Pro elastin” in a way as it inhibits proteases which can break down elastin).
It is responsible for balancing the activity of elastin and other destructive enzyme proteases produced during an infection / immune challenge
Deletion of this gene results in a higher possibility of emphysema occurring
(Slide 29)
What is the first line of the innate response to irritants?
The epithelial / mucosal barrier
(Slide 30)
What are 3 immunological components which can be involved in COPD?
Epithelial / mucosal barrier being reduced over time
Enhanced TH-1 and TH-17 signals
CD8+ T cells doing direct damage through granzyme (a family of proteases) release
Damaged cells / degraded proteins functioning as antigens. Their DAMPs stimulate the innate and adaptive immune systems
M2 macrophages becoming dominant can lead to excessive healing, leading to excessive fibrosis and scar tissue forming
(Slide 30)
What is bronchodilator reversibility?
The percentage increase in FEV1 after bronchodilation
(Slide 31)
How is bronchodilator reversibility measured?
- FEV1 is measured using spirometry
- The patient is given a bronchodilator
- After a few minutes (usually 15 - 30 mins), FEV 1 is measured again
(Slide 31)
What is the criteria for bronchodilator reversibility to be considered significant?
An improvement in FEV1 of 12% or more after bronchodilator was administrated
(Slide 31)
