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BIOM30002 > The Respiratory System and CF > Flashcards

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

1
Q

Airways are a series of branching tubes

Actual business of gas exhange happens at the _____

A

Acinus

*group term for alveoli and supporting cells

  • Respiratory bronchioles
  • Alveolar ducts
  • Alveolar sacs
  • Alveoli
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2
Q

Stages of Lung Development

  1. _____ (0-6 weeks gestation)
  2. _____ (6-16 weeks gestation)
  3. _____ (16-26 weeks gestation)
  4. _____ (26-36 weeks gestation)
  5. _____ (2 years to adult)
A
  1. Embryonic (0-6 weeks gestation)
  2. Pseudoglandular (6-16 weeks gestation)
  3. Canalicular (16-26 weeks gestation)
  4. Sacular/Alveolar (26-36 weeks gestation)
  5. Postnatal (2 years to adult)
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3
Q

Lung Development - Embryonic Stage

  • Lung bud appears day ______
  • Ventral _____ of the primitive _____
  • _____ origin
  • _____ branching of the airways into surrounding _____
A
  • Lung bud appears day 26-28
  • Ventral outpouching of the primitive foregut
  • Endodermal origin
  • Proximal branching of the airways into surrounding mesoderm
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4
Q

Lung Development - Pseudoglandular Stage

  • Weeks ___
  • Airways develop (branch) to the level of the ______ (pre-___ bronchi)
  • ___ generations of airways
A
  • Weeks 6-16
  • Airways develop (branch) to the level of the terminal bronchioles (pre-acinar bronchi)
  • 16 generations of airways
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5
Q

Lung Development - Canalicular Stage

  • Weeks ___
  • _____ region develops
  • Thinning of the ____ (allows gas exchange)
  • Type _____ develop (develop into 2 types of cells in alveoli)
A
  • 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)
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6
Q

Lung Development - Sacular/Alveolar Stage

  • Weeks ____
  • Sacules form into the ____ and ____
  • Marked ____ in ____ tissue
  • Sacules become ____ ______
  • Sacules and alveoli form ______ ______ of ______ by ______ (division)
A
  • 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

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7
Q

Functions of the lung

Q) Which functions of the lung are affected in CF?

A

1) Defence
2) Gas Exchange

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8
Q

Q) Physical (airway) vs Cellular (alveolar) defence mechanisms

A
  • 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
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9
Q

Q) What is the Mucociliary Escalator?

A
  • 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
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10
Q

What parameters are used to measure lung function? (3 points)

A
  • Volume (litres)
  • Flow (L/sec) = Volume over time
  • Pressure
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11
Q

Lung Volumes and Capacities

Summary slide

A
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12
Q

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?

A
  • 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
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13
Q

FEV1 vs FVC graph

A
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14
Q

Normal Flow-volume curve

TLC = total lung capacity

RV = residual volume

A
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15
Q

Intrathoracic airway obstruction

  • Obstructive lung disease
  • scooped out appearance which reflects obstruction within the airways
A
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16
Q

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
A
  • 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
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17
Q

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
A
  • 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
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18
Q

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_____
A
  • (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
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19
Q

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

A

Defective CFTR
>
Increased NA+/Cl- absorption
>
Increased H2O absorption
>
Dehydrated ASL

>>
impaired mucociliary clearance

>
Infection and inflammation
=
Lung disease

20
Q

Ion Transport in Normal Lung

CFTR coordinates modulation of ASL by:

  1. Inhibiting ENac
  2. 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

A

CFTR coordinates modulation of ASL by:

  1. Inhibiting ENac
    • Reduce Na+ absorbed into cell
    • Water follows Na+
    • ASL stays hydrated
  2. Secreting Cl-
    • Cl- ions secreted out into ASL
21
Q

Ion transport in CF lung

2 functions of CFTR lost:

  1. ENaC not inhibited
  2. Cl- ions not secreted

Elaborate/describe mechanisms

A

2 functions of CFTR lost:

  1. ENaC not inhibited
    • increased Na+ absorption into cell
    • water follows sodium (not salt)
    • ASL dehydrated
  2. Cl- ions not secreted
    • Increase Na+, Cl-, H20 absorption
    • ASL volume decreased
22
Q

ASL volume hyperabsorption has important consequences for both the Periciliary liquid (PCL) and mucus layer:

What are the consequences?

A
  • Volume depletion of PCL
    • Failure of ciliary beating
  • Absence of lubrication
    • Adherent mucus plaque
  • >>>Promotes chronic infection
23
Q

Airway surface dehydration theory

Some conflicting studies:

  • Airway epithelia in newborn pigs, ferrets, and rats with CF do not hyperabsorb sodium
  • But…
A
  • Contradictory study of airway epithelia in humans with CF also showed no evidence of increased sodium absorption
24
Q

Reduced pH of ASL

  • CFTR also conducts bicarbonate (HCO3-)
    • so…
A
  • 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
25
Q

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
A
  • 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
26
Q

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
A

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
27
Q

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
A
  • 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
28
Q

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
A
29
Q

Dysregulated immune pathways in CF

Loss of CFTR function leads to

  • Increased activation of nuclear factor-kappa B (NFkB)
A

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
30
Q

Dysregulated immune pathways in CF

Loss of CFTR function leads to

    • Increased ROS production (and decreased antioxidant defense)
A
  • CF ASL contains high levels of ROS
    • Neutrophils major contributor
      • Released as part of respiratory burst
    • Airway epithelium
  • 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
31
Q

Dysregulated immune pathways in CF (Summary)

Loss of CFTR function leads to

      • ER stress response
    • *
A

ER sequestration of the misfolded F508del

  • Accumulation of abnormally folded CFTR in ER results in unfolded protein responses
    • Trigger ‘cell stress’ and apoptosis
32
Q

Dysregulated immune pathways in CF (Summary)

Loss of CFTR function leads to

        • Ceramide accumulation/cholesterol dysfunction
  • *
A

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
33
Q

Dysregulated immune pathways in CF (Summary)

Loss of CFTR function leads to

          • Abnormal basal lipid metabolism
            *
A

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
34
Q

Dysregulated immune pathways in CF (Summary)

Loss of CFTR function leads to

            • Defective interferon signaling
A

Blunting of interferon signaling

  • Defective type I INF response
    • Interferes with eradication of bacteria
    • increase susceptibility to viral infections
35
Q

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
A

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
36
Q

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
A
  • Expressed on a variety of cells
    • 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
37
Q

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)
A

3 main anti-bacterial weapons

  • Phagocytosis
  • Granule release (protease rich)
  • NET formation (DNA fibres that entangle, immobilise and kill pathogens)
38
Q

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):

A

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
39
Q

Role of other immune cells

  • Macrophages
  • Dedritic cells

ELABORATE for marks

A
  • 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
40
Q

Role of other immune cells

  • T cells
  • Invaraint natural killer T cells

Evaluate for marks

A
  • 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
41
Q

Vicious cycle of CF lung disease and respiratory failure

Summary slide

A
42
Q

Pathology of CF lung disease

Please describe for 3 marks

A
  • Infection, inflammation and obstruction of airways
  • lead to dilation and damage of airways
  • Bronchiectasis
    • Dilation of airways
    • Thickened airways obstructed by mucus
43
Q

Histology of CF lung disease

A

Photomicrograph shows:

  • endobronchial and peribronchial neutrophilic inflammation
44
Q

Computerised Tomography (CT)

Main takeaway??

A

Dilated bronchioles (bronchiectasis)

45
Q

Pathogens

*Fungi as well

  • aspergilis (pro-inflammatory)
  • candida (non-inflammatory)
A
  • 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
46
Q

FEV1 %predicted vs Age

*if you get 100% you are average

A

At FEV1 <30%, have 50% chance of dying in 2 years

>>>makes you eligible for lung transplant

BIOM30002 (20 decks)

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