Block D Lecture 1 - Asthma and COPD Flashcards
What is asthma?
A chronic respiratory disease which is characterised by the hyper-responsiveness of the airways
What are 3 symptoms of asthma?
Answers Include:
Wheezing
Coughing
Shortness of breath
Chest tightness / pain
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 characteristics of 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.
Mast cells release constrictor mediators which activate vagal afferent nerves, causing reflex 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 - cause bronchoconstriction in the early phase of asthma
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: 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 respond to an allergen by causing B-cell production of IgE and binding of IgE to mast cell IgE receptors.
Re-exposure to the allergen (such as 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 3 examples of structural changes / remodelling induced inflammation?
Epithelial damage
Goblet cell hyperplasia
Increased intraluminal secretions
Basements membrane thickening
Smooth muscle hypertrophy and hyperplasia
(Slide 10)
What are 3 things 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, but this can worsen symptoms for people with asthma
(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 PLC or Gq
(Slide 15)
What are hyperplasia and hypertrophy (2 things involved in smooth muscle proliferation) stimulated by?
Multiple growth factors and mediators which cause proliferation
(Slide 16)
How can the airway smooth muscle releasing cytokines worsen symptoms in patients with asthma?
It 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)
How does the MAPK pathway contribute in asthma? State the steps of the MAPK pathway
- In asthma, airway smooth muscle cells are exposed to a range of inflammatory mediators,
- 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 (growth factor receptor-bound protein 2) 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, inflammation and other important processes, which can contribute to asthma
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 can increased parasympathetic activity occur and how can it 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 sensory nervous system (SNS).
(Slide 20)
How do C-fibres contribute to asthma?
- Irritants stimulate C-fibres receptors. Inflammatory cells can also release mediators which sensitise 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 vital capacity and is the total amount of air a person can exhale after taking a full, deep breath
(Slide 22)
