The Respiratory System and CF Flashcards
Review - Normal Lung anatomy and development - Normal lung physiology - Lung function tests (spirometry) Pulmonary complications of CF Pathophysiology of lung disease in CF Microbial colonisation of the lung in CF
Airways are a series of branching tubes
Actual business of gas exhange happens at the _____
Acinus
*group term for alveoli and supporting cells
- Respiratory bronchioles
- Alveolar ducts
- Alveolar sacs
- Alveoli
Stages of Lung Development
- _____ (0-6 weeks gestation)
- _____ (6-16 weeks gestation)
- _____ (16-26 weeks gestation)
- _____ (26-36 weeks gestation)
- _____ (2 years to adult)
- Embryonic (0-6 weeks gestation)
- Pseudoglandular (6-16 weeks gestation)
- Canalicular (16-26 weeks gestation)
- Sacular/Alveolar (26-36 weeks gestation)
- Postnatal (2 years to adult)
Lung Development - Embryonic Stage
- Lung bud appears day ______
- Ventral _____ of the primitive _____
- _____ origin
- _____ branching of the airways into surrounding _____
- Lung bud appears day 26-28
- Ventral outpouching of the primitive foregut
- Endodermal origin
- Proximal branching of the airways into surrounding mesoderm
Lung Development - Pseudoglandular Stage
- Weeks ___
- Airways develop (branch) to the level of the ______ (pre-___ bronchi)
- ___ generations of airways
- Weeks 6-16
- Airways develop (branch) to the level of the terminal bronchioles (pre-acinar bronchi)
- 16 generations of airways
Lung Development - Canalicular Stage
- Weeks ___
- _____ region develops
- Thinning of the ____ (allows gas exchange)
- Type _____ develop (develop into 2 types of cells in alveoli)
- Weeks 16-26
- Acinar region develops
- Thinning of the peripheral epithelium (allows gas exchange)
- Type I and II pneumocytes develop (develop into 2 types of cells in alveoli)
Lung Development - Sacular/Alveolar Stage
- Weeks ____
- Sacules form into the ____ and ____
- Marked ____ in ____ tissue
- Sacules become ____ ______
- Sacules and alveoli form ______ ______ of ______ by ______ (division)
- Weeks 26-36
- Sacules form into the alveolar ducts and alveoli
- Marked decrease in interstitial tissue
- Sacules become thin walled
- Sacules and alveoli form futher generations of alveoli by septation (division)
*Before 30 weeks, no alveoli, but there are alveolar ducts so gas exchange can occur
Functions of the lung
Q) Which functions of the lung are affected in CF?
1) Defence
2) Gas Exchange
Q) Physical (airway) vs Cellular (alveolar) defence mechanisms
- Physical (airway)
- Upper airway filter (particularly in nose, filter out large particles
- Reflexes
- Sneeze
- Cough
- Mucociliary escalator*
- Cellular (alveolar)
- Phagocytes e.g. alveolar macrophages
- Immunological
Q) What is the Mucociliary Escalator?
- At airway surface epithelium, Airway surface liquid (ASL) has 2 layers
- Periciliary layer
- Mucus gel layer
- Mucus produced by secretory cells incl. Goblet cells
- Mucus propelled by cilia
- Beat 10-15 times per sec
- 5mm per min
What parameters are used to measure lung function? (3 points)
- Volume (litres)
- Flow (L/sec) = Volume over time
- Pressure
Lung Volumes and Capacities
Summary slide
Forced Expiration
Measured using a spirometer
Maximal inspiration followed by fast exhalation to residual volume
Q) What is FEV1 and FVC, and what do they tell us about the lung?
- FEV1 = Forced expiratory volume
- Volume exhaled in first second
- Tells us about the flow of the airways
- FVC = Forced vital capacity
- Total volume exhaled
- Tells you about the size of the lungs
FEV1 vs FVC graph
Normal Flow-volume curve
TLC = total lung capacity
RV = residual volume
Intrathoracic airway obstruction
- Obstructive lung disease
- scooped out appearance which reflects obstruction within the airways
Pulmonary Diease in CF
- Significant amount of ___ and ____
- _____ exacerbations
- increased cough and sputum production
- increased ____ - S.O.B
- Lethargy/poor appetite
- Reduced _____** (in ___, which is looked out for when testing)
- ______ decline in lung function
- Respiratory failure
- Death/transplatation
- Significant amount of morbidity and mortality
- Pulmonary exacerbations
- increased cough and sputum production
- increased dyspnoea - S.O.B
- Lethargy/poor appetite
- Reduced lung function** (in FEV1, which is looked out for when testing)
- Progressive decline in lung function
- Respiratory failure
- Death/transplatation
CFTR and lung disease
- CFTR mutations >>>>> Lung disease
- Exact mechanism unknown (how CF variants cause LD)
- Complex relationship between ___ and ___ that impacts on ___ production and ___ obstruction
- ___ infections may play a role in the initiation of these events
- Complex relationship between host defense and airway microbiology that impacts on sputum production and airflow obstruction
- Viral infections may play a role in the initiation of these events
CFTR and Lung Disease
CFTR expressed on several cell types
- (Highly expressed) ____ plasma membrane of ______ _____ cells in airways; regulates ion transport
- ____, ____
- _____ cells of submucosal glands
- Alveolar epithelial type ___ cells (produce ____)
- Cells of the ____ system
- Alveolar m_____
- N_____
- (Highly expressed) Apical plasma membrane of ciliated epithelial cells in airways; regulates ion transport
- chloride, bicarbonate
- Serous cells of submucosal glands
- Alveolar epithelial type II cells (produce surfactant)
- Cells of the immune system
- Alveolar macrophages
- Neutrophils
Airway Surface Dehydration
Widely held theory based on studies of cultured human airway epithelia (also mouse fibroblasts and dog kidney-cell lines)
Q) Give a brief outline of the theory
Defective CFTR
>
Increased NA+/Cl- absorption
>
Increased H2O absorption
>
Dehydrated ASL
>>
impaired mucociliary clearance
>
Infection and inflammation
=
Lung disease
Ion Transport in Normal Lung
CFTR coordinates modulation of ASL by:
- Inhibiting ENac
- Secreting Cl-
Describe/elaborate on the mechanisms
**crucial for modulating the viscosity and amount of fluid in that ASL that the cilia are surrounded by
CFTR coordinates modulation of ASL by:
- Inhibiting ENac
- Reduce Na+ absorbed into cell
- Water follows Na+
- ASL stays hydrated
- Secreting Cl-
- Cl- ions secreted out into ASL
Ion transport in CF lung
2 functions of CFTR lost:
- ENaC not inhibited
- Cl- ions not secreted
Elaborate/describe mechanisms
2 functions of CFTR lost:
- ENaC not inhibited
- increased Na+ absorption into cell
- water follows sodium (not salt)
- ASL dehydrated
- Cl- ions not secreted
- Increase Na+, Cl-, H20 absorption
- ASL volume decreased
ASL volume hyperabsorption has important consequences for both the Periciliary liquid (PCL) and mucus layer:
What are the consequences?
- Volume depletion of PCL
- Failure of ciliary beating
- Absence of lubrication
- Adherent mucus plaque
- >>>Promotes chronic infection
Airway surface dehydration theory
Some conflicting studies:
- Airway epithelia in newborn pigs, ferrets, and rats with CF do not hyperabsorb sodium
- But…
- Contradictory study of airway epithelia in humans with CF also showed no evidence of increased sodium absorption
Reduced pH of ASL
- CFTR also conducts bicarbonate (HCO3-)
- so…
- Loss of CFTR-dependent bicarb secretion
- pH of airway-surface liquid decreases, resulting in impaired antibacterial activity
- lower pH (more acidic environment) = promote bacterial growth
Abnormal Mucus
- Mucus produced in ____ glands = CFTR ____
- defective _____ ____ alters property of mucus
- In porcine model, defective CFTR prevents the ____ of ____ ____ from glands
- ____ of mucus to gland ducts, hindering ____ ____
- Contents of degraded _____ (elastases, proteases, DNA and oxidases) increase the _____ of the mucus, further affecting its transportability
- Mucus produced in submucosal glands = CFTR abundant
- defective bicarbonate secretion alters property of mucus
- In porcine model, defective CFTR prevents the release of mucus strands from glands
- tethering of mucus to gland ducts, hindering mucociliary transport
- Contents of degraded neutrophils (elastases, proteases, DNA and oxidases) increase the viscosity of the mucus, further affecting its transportability
Abnormal Microenvironment
Due to an _____ environment, resulting from:
- Thick mucus plaques adherent to epithelial surface
- increased ____ _____ by CF epithelia (cilia fail to beat so beat harder)
Lead to higher risk of infection because of:
- Ideal environment for growth of certain bacteria
- Pseudomonas converts to _____ _____ mode of growth
Due to an anaerobic environment, resulting from:
- Thick mucus plaques adherent to epithelial surface
- increased oxygen consumption by CF epithelia (cilia fail to beat so beat harder)
Lead to higher risk of infection because of:
- Ideal environment for growth of certain bacteria
- Pseudomonas converts to anaerobic biofilm mode of growth
CF and Inflammation
- CFTR dysfunction promotes ____ ____ infection
- Results in ____, predominantly ____ inflammation
- CFTR dysfunction may also directly affect airway immunity
- _______ immune pathways
- Increased production of ________ mediators
- CFTR dysfunction promotes chronic airway infection
- Results in exaggerated, predominantly neutrophilic inflammation
- CFTR dysfunction may also directly affect airway immunity
- Dysregulated immune pathways
- Increased production of pro-inflammatory mediators
Dysregulated immune pathways in CF (Summary)
Loss of CFTR function leads to
- Increased activation of nuclear factor-kappa B (NFkB)
- Increased ROS production (and decreased antioxidant defense)
- ER stress response
- Ceramide accumulation/cholesterol dysfunction
- Abnormal basal lipid metabolism
- Defective interferon signaling
Dysregulated immune pathways in CF
Loss of CFTR function leads to
- Increased activation of nuclear factor-kappa B (NFkB)
Increased activity of transcripton factors e.g. Nuclear factor-kappa B (NFkB)
- Increase secretion of pro-inflammatory cytokines e.g. IL-8, IL-6, TNFa, IL-1B
- Constituently active NFkB
- Enhanced IL-8 production
Dysregulated immune pathways in CF
Loss of CFTR function leads to
- Increased ROS production (and decreased antioxidant defense)
- CF ASL contains high levels of ROS
- Neutrophils major contributor
- Released as part of respiratory burst
- Airway epithelium
- Neutrophils major contributor
- Exacerbated by decreased antioxidant defense
- e.g. decreased glutathione metabolism
- Oxidative stress invigorates/creates a proinflammatory environment (defective autophagy) and correlates with inflammatory markers (TG2) in CF
Dysregulated immune pathways in CF (Summary)
Loss of CFTR function leads to
- ER stress response
- *
ER sequestration of the misfolded F508del
- Accumulation of abnormally folded CFTR in ER results in unfolded protein responses
- Trigger ‘cell stress’ and apoptosis
Dysregulated immune pathways in CF (Summary)
Loss of CFTR function leads to
- Ceramide accumulation/cholesterol dysfunction
- *
Ceramide accumulation/cholesterol dysfunction
- Ceramide accumulation may further augment pulmonary inflammation by
- inducing apoptosis with subsequent deposition of DNA in airways
- Ceramide is a breakdown product of sphingomyelin found in plasma membrane and in endolysosomal compartments
- Results in:
- Abnormal lysosome function
- Abnormal receptor signalling
Dysregulated immune pathways in CF (Summary)
Loss of CFTR function leads to
- Abnormal basal lipid metabolism
*
- Abnormal basal lipid metabolism
Abnormal basal lipid metabolism
- Fatty acid metabolism skewed towards
- increased production of arachidonic acid (AA) and leukotriene B4 (LTB4)
- Decreased docosahexaenoic acid (DHA) and lipoxin A4 (LXA4)
- Thus get impaired resolution of inflammation
Dysregulated immune pathways in CF (Summary)
Loss of CFTR function leads to
- Defective interferon signaling
Blunting of interferon signaling
- Defective type I INF response
- Interferes with eradication of bacteria
- increase susceptibility to viral infections
Innate immunity abnormalities
Pathogens in the airway are sensed in the airway by the innate immune system
- Innate immune system senses ____ ____ ____ using pattern recognition receptors
- ____ ____ (TLRs)
- ______ receptors
- ___ receptors
- ___________________ (NOD)-like receptors
Pathogens in the airway are sensed in the airway by the innate immune system
- Innate immune system senses conserved molecular patterns using pattern recognition receptors
- Toll-like receptors (TLRs)
- Complement receptors
- Fc receptors
- Nucleotide-binding oligomerization domain family (NOD)-like receptors
Toll-like Receptors
- Expressed on a variety of cells
- especially _____ cells, ______
- Majority recognise bacterial patterns
- TLR4 senses _____ (LPS)
- TLR5 senses ____ (predominant in B cepaciae)
- May be modifier gene as may change response to PsA and BC
- ___ poorly displayed on surface of CF cells and ______________ to stimulation
- Expressed on a variety of cells
- especially dendritic cells, neutrophils
- especially dendritic cells, neutrophils
- Majority recognise bacterial patterns
- TLR4 senses lipopolysaccharide (LPS)
- TLR5 senses flagellin (predominant in B cepaciae)
- May be modifier gene as may change response to PsA and BC
- TLR4 poorly displayed on surface of CF cells and fails to respond well to stimulation
Neutrophils are first and main inflammatory cell found in CF airways
3 main anti-bacterial weapons
- ______
- ____ release (protease rich)
- ___ _____ (DNA fibres that entangle, immobilise and kill pathogens)
3 main anti-bacterial weapons
- Phagocytosis
- Granule release (protease rich)
- NET formation (DNA fibres that entangle, immobilise and kill pathogens)
Neutrophils are first and main inflammatory cell found in CF airways
Release proteases which may be harmful to our underlying cell structure (3 types proteases):
Release:
- Serine proteases
- e.g. elastase
- Physiological role in tissue remodelling, chemotaxis, microbial killing
- Are tightly regulated by protease inhibitors e.g. alpha-1-antitrypsin
- Matrix mettaloproteases
- Calgranulins: proinflammatory proteins
- Increased in CF sputum
Role of other immune cells
- Macrophages
- Dedritic cells
ELABORATE for marks
- Macrophages
- increased numbers
- TLR
- altered function: impaired efferocytosis (removal of dying cells)
- Intrinsic effects
- Dendritic cells
- TLR
- reduced APC function
- Decreased levels of MHC Class II receptors
- *expression is dependent on TLR signalling
Role of other immune cells
- T cells
- Invaraint natural killer T cells
Evaluate for marks
- T cells
- Skewed towards Th2/Th17 immune response
- Counter-regulatory T cells (Tregs) may be reduced in CF
- Invaraint NK T cells
- Dysregulated in C, those which kils its own cells
- Upregulated in absence of CFTR
Vicious cycle of CF lung disease and respiratory failure
Summary slide
Pathology of CF lung disease
Please describe for 3 marks
- Infection, inflammation and obstruction of airways
- lead to dilation and damage of airways
- Bronchiectasis
- Dilation of airways
- Thickened airways obstructed by mucus
Histology of CF lung disease
Photomicrograph shows:
- endobronchial and peribronchial neutrophilic inflammation
Computerised Tomography (CT)
Main takeaway??
Dilated bronchioles (bronchiectasis)
Pathogens
*Fungi as well
- aspergilis (pro-inflammatory)
- candida (non-inflammatory)
- S. Aureus
- common pathogen envountered in life
- P. aeruginosa
- converts to anaerobic biofilm mode of growth
- Unusual
- Not very common pathogen
- Increases during childhood, then significantly increases during adulthood
FEV1 %predicted vs Age
*if you get 100% you are average
At FEV1 <30%, have 50% chance of dying in 2 years
>>>makes you eligible for lung transplant
