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Physiology: References & Stats > Biology of Lung Disease > Flashcards

Biology of Lung Disease Flashcards

1
Q

Define pulmonary hypertension

A

Pulmonary arterial pressure >25mmHg

Normal is 14mmHg

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2
Q

What is the difference between pulmonary hypertension and pulmonary arterial hypertension?

A

Pulmonary arterial hypertension (pulmonary vasoconstriction) is a subgroup of pulmonary hypertension (high blood pressure in the lungs, multiple aetiologies)

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3
Q

What are the models of pulmonary hypertension?

A 
Classic = chronic hypoxic model
Monocrotaline model (MC) = inject it; it gets metabolised into MC pyrrole and causes vascular injury
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4
Q

Using the Dana Point classification, summarise the groups for pulmonary hypertension.

A 
1- PAH- idiopathic and heritable
1'- Venous/ capillary cause
2- Left heart pathology
3- Lung disease/ hypoxaemia
4- Chronic thromboembolic disease
5- Unclear/ multifactorial etiologies
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5
Q

What are the clinical stages of pulmonary hypertension?

A

I- no limitation in physical activity
II- mild limitation
III- marked limitation with less than ordinary activity
IV- can’t perform physical activity/signs of right ventricular failure at rest.

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6
Q

What is the pathophysiology of pulmonary arterial hypertension?

A

Neomuscularisation
Hypertrophy of large muscular arteries
Neointima - myofibroblast and extracellular matrix layer forms between endothelium and internal elastic lamina
Plexiform lesions containing endothelial cells, PASMCs, lymphocytes and mast cells.
Continuing thrombosis and vasoconstriction.

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7
Q

What are the problems with the animal models of PH and PAH?

A

Animal models of PH have all the classic symptoms except plexiform lesions.
In animal models of PAH, the main problem is vasoconstriction unlike human PAH where it is angioproliferation.

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8
Q

Why is the pulmonary endothelium thought to play a central role in the pathogenesis of pulmonary arterial hypertension?

A

Evidence of:
Abnormal endothelial cell function
Abnormal endothelial derived factors and markers
Role of cells in plexiform lesion formation
Current treatments target the endothelium derived factors

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9
Q

What is the role of endogenous nitric oxide synthase (eNOS) in vascular tone?

A

L-arginine activates eNOS which makes NO-> vasodilation

eNOS inhibition via ADMA or L-NMMA reduces NO -> reduced vasodilation -> vasoconstriction

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10
Q

What is the association between eNOS inhibitors and pulmonary arterial hypertension?

A

Too much ADMA in PAH patients - Pulamsett et al.

ADMA may not be cleared properly by DDAH

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11
Q

What are factors positively associated with pulmonary arterial hypertension?

A

Endothelium like factor 1 (ET-1)
bFGF
PDGF

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12
Q

What is the genetic basis of pulmonary arterial hypertension?

A

Familial: autosomal dominant mapped to chromosome 2
Reduced expression/ function of BMPR-2 which activates Smad proteins 1, 5, 7.
Mutations in ALK1 (which dimerises with BMPR2)
These mutations ultimately lead to loss of function of the receptors they code for.
Mutations increase risk of PAH by 10000.

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13
Q

What is proposed association between serotonin (5-HT) and pulmonary arterial hypertension?

A

Increased 5-HT (via drug administration) correlated with PAH, those drug side effects could have caused it too.
Eliminate 5-HT and it has a protective effect on PAH.
Excess 5-HT increases risk of PAH.

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14
Q

Describe the oestrogen paradox in pulmonary arterial hypertension

A

PAH seen more in younger women than older women.
Women with PAH survive longer than the male patients.
Decreasing oestrogen appears to protect against PAH (despite them being protective in animal models of PH as well as CVD).

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15
Q

Why may low oestrogen protect against pulmonary arterial hypertension (PAH)?

A

Oestradiol is metabolised into two CYPs:
CYP1B1 codes for 16alpha-OHE1 which is proliferative.
Other CYPs code for 2-OHE which is anti- proliferative

In PAH, the ratio of other CYPs to CYP1B1 is lower.
Wild-type CYP1B1 predisposes to PAH in those at risk of BMPR2.

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16
Q

How do plexiform lesions develop?

A

Increased blood pressure increases pulmonary artery (PA) sheer stress/ high sheer stress environment.
High stress increases endothelial cell apoptosis.
Some (abnormal) endothelial cells become resistant to apoptosis and these are capable of proliferating into lesions.

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17
Q

What are the roles of PPAR-gamma and caspase-3 in plexiform lesion formation?

A

PPAR-gamma is over expressed to reduce cell proliferation. Sheer stress inhibits PPAR-gamma, encouraging lesion formation.
Caspase-3 is a marker of apoptosis; abnormal cells in the lesion don’t die, so don’t release it.

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18
Q

What are signs and screening methods for pulmonary arterial hypertension?

A

Signs:
Split S2 with loud P2
Increased jugular venous pressure

Screening:
Right heart catheterisation is the gold standard for pulmonary artery pressure.
Echocardiogram
Cardiac MRI
Chest X-Ray
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19
Q

What are treatments for pulmonary arterial hypertension?

A

Diuretics
Supplementary oxygen
Prostacyclin inhibitors
Digoxin
Guanylate cyclase stimulator- helps produce more nitric oxide
Endothelin receptor antagonists- blocks ETA and ETB receptors

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20
Q

What are the features of COPD?

A 
Dyspnoea- progressive, limits exercise
Cough
Acute deterioration
This symptom burden gets worse with time.
Spirometry is 0.7 FEV1: FVC ratio
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21
Q

What are common causes of COPD?

A

Tobacco

Bio-mass fuel exposure

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22
Q

Describe the pathophysiology of sleep apnoea.

A

Weaker breathing muscles collapse
Closure during sleep
Hypoxia
Feedback to the brain
Muscles open the airway again (increasing oxygen concentration)
Reduced feedback results in muscle closure

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23
Q

What are the treatments of COPD?

A

Smoking cessation in smokers
Anti-muscarinics
Supplemental oxygen

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24
Q

What is the only known genetic cause of COPD?

A

Alpha-1-antytrypsin deficiency

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25
Q

What is the pathophysiology of alpha-1-antitrypsin deficiency?

A

Normally the protein functions as a monomer but in disease it mis-folds into a meta stable state
This abnormal state then polymerises and deposits itself in different organ systems.
Liver deposits -> cirrhosis

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26
Q

What are the functions of alpha-1-antitrypsin variants?

A

Pro-inflammatory
Chemotactic to neutrophils
ER stress

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27
Q

How does alpha-1-deficiency affect the lungs?

A

The lungs need a balance of proteases and anti-proteases.
alpha-1-antitrypsin deficiency reduces the number of functional proteases
Negative feedback triggers increase in proteases
This results in uncontrolled breakdown of elastic tissue & pro-inflammatory signalling cascades.

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28
Q

Why does emphysema contribute to COPD obstruction?

A

Radial tension keeps the airways open.
Disrupting the attachments to the pleura via tissue loss reduces this tension and makes it harder to keep the bronchi open.

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29
Q

What are treatments for alpha-1-antitrypsin deficiency?

A 
Alpha-1-antitrypsin replacement therapy
Stem cell (hIPSC) and gene-editing technology- alter the structure of the abnormal polymeric protein to correct the disease in vivo

Liver:
Healthy lifestyle since fat deposition is toxic
Smoking cessation

Lungs:
Inhaled steroids to reduce inflammation
Anti-pluggers (mucolytics)
Replace damaged lung (improves ventilation so V/Q ratio)
Pulmonary rehabilitation
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30
Q

Alpha-1-antitrypsin deficiency belongs to a family of serpinopathies. List diseases that share its nature.

A

Dementia - abnormal phosphorylated tau aggregates.
Thrombosis - antithrombin
Angio-oedema - C1 inhibitor
Emphysema - A1AC

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31
Q

What is asthma?

A

Chronic inflammation of the airways
Reversible airway obstruction
Airway hyper-responsiveness

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32
Q

List some non-allergic triggers of asthma

A 
Infections
Exercise
Cold air
Smoke/ dust
Air pollution
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33
Q

How does airway remodelling occur in asthma?

A 
Epithelial fragility/ loss
Airway smooth muscle accumulation
Reticular basement membrane thickening
Submucosal mucous gland hypertrophy
Increased vascularity
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34
Q

Explain the mediators involved in the delayed response of asthma

A

Allergen engulfed by dendrite -> APC
APC activates TH2 which can then release IL-4, IL-5 and IL-13.
These then stimulate fibrosis, recruitment of eosinophils, mucous production and airway hyper-responsiveness.

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35
Q

What are the observations made for PEFR for asthma?

A

Untreated:
Lower PEFR
Morning values lower than evening readings

Treated:
Higher PEFR
Smaller difference between morning & evening

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36
Q

How is reversibility of asthma measured?

A

> 12% and >200ml improvement in FEV1 after inhaled bronchodilators

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37
Q

What is the difference between direct and indirect challenge tests for asthma?

A

Direct:
Methacholine
Histamine

Indirect:
Exercise
Forced hypertension
Hypertonic saline
Mannitol
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38
Q

How are asthma patients treated?

A

Stepped care approach
Step 1 - SABA; beta 2 receptor agonist. Danger of over-reliance.
Step 2 - ICS; acts on intracellular glucocorticoid receptor.
Step 3 - LABA; beta 2 receptor agonist. Stick onto ICS.
Step 4- ‘lukast’; bronchodilating and therapeutic
Step 5 - AVOID regular oral steroids

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39
Q

Describe the different asthma phenotypes

A 
Allergic 
Intrinsic
Non-eosinophilic
Aspirin intolerant
Extensive remodelling (rare)
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40
Q

Describe the pathophysiology of intrinsic asthma.

A

PN/PE in sputum; suspected bacterial super-antigens

No sputum IgE markers.

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41
Q

Explain Witebsky’s postulates

A

Criteria for classifying a disease as autoimmune:

  1. Direct evidence from transfer of pathogenic body/ T cells.
  2. Indirect evidence based on reproduction of autoimmune disease in experimental animals.
  3. Circumstantial evidence from clinical clues
  4. Genetic architecture clustering with other autoimmune disease
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42
Q

What is the difference between ‘autoimmune’ and ‘immune’

A

Auto-immune damage to cells/ tissues caused by autoreactive antibodies/ immune cells; auto antigen is internal

Immune - antigen is external and triggers response which may cause damage

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43
Q

How can you treat respiratory conditions producing fluid in the lungs?

A

Extracorporeal membrane oxygenation (ECMO) - passes plasma through a membrane that filters out excess fluid where gas exchange takes place; while buys time for the immune system to overcome infection and keep the airways open.

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44
Q

What is the structure of a concept map for disease?

A
  1. Problem in the specific disease
  2. Mechanisms
  3. Current treatments/ prevention methods
  4. What problems remain unsolved
  5. Proposed approaches to solve remaining problems & difficulties
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45
Q

What is the immunological mechanism of allergy?

A 
−	Allergen capture
−	Allergen presentation
−	Th2 differentiation
−	Th2 ->B cell help
−	IgE production by B cells
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46
Q

What is sarcoidosis?

A

Autoimmune disease characterised by presence of granulomas in multiple organs.

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47
Q

How do granulomas form?

A

Deposit of immune cells; the centre has no access to oxygen so over time will die.
Build up scar of tissue which replaces parenchyma (the body tries to repair the tissue around the granuloma, increasing its size).
Insufficient gas exchange with increasing granuloma size.

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48
Q

What is the genetic architecture clustering observed in sarcoidosis?

A

TLR genes 10, 1, 6

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49
Q

Describe the IFN hypothesis

A

High IFN level may drive pathology of systemic lupus erythematosus.

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50
Q

What is the role of vitamin D in respiratory health?

A

Vitamin D helps mediate effective clearance of pathogens & control inflammation
Induces antimicrobial peptides/ mechanisms in innate & structural cells
Enhancement of tolerogenic pathways

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51
Q

According to Pfeffer et al, how does vitamin D affect inflammatory cytokines?

A

Inhibits Th1 & Th17 among others

Conflicting effects on Th2

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52
Q

What is the bioavailability of Vitamin D affected by?

A 
Sun
Diet
Skin colour
Obesity
Vitamin D receptor
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53
Q

What is the relationship between TB and vitamin D?

A

Deficiency reported among TB patients

Vitamin D suppresses intracellular growth of TB in vivo and induced expression of antimicrobial peptides

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54
Q

What did the RCT by Martineau et al establish about vitamin D with respect to TB?

A

% of culture containing smear positive TB decreased more in the group given antibiotics and vitamin D compared with just antibiotics (p=0.14)

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55
Q

How can vitamin D act as an antimicrobial in monocytes?

A

TLR2/1 signal to induce expression of CYP27B1 and vitamin D receptor.
Conversion of hydroxyvitamin D (25D) to active form (1,25D)
1,25 D binds to VDR -> promotion of transcriptional regulation

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56
Q

What are pathways that vitamin D could interact with in the cell?

A

Induction of antibacterial CAMP and DEFB4
Promotion of autophagy
Feedback regulation of TLR
Increased bacterial killing

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57
Q

What do studies say about vitamin D in respiratory health?

A

Increasing dose associated with decreased incidence of cold/influenza patients- Joliffe et al.
Rising prevalence with decreased exposure based on mouse and in vitro studies
Most studies suggest that in pregnancy it’s protective against asthma - Devereux et al.

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58
Q

What factors may contribute to the different findings of vitamin D studies?

A 
Administration - UV light or oral supplementation
Duration of supplementation
Type - Vitamin D2 or D3
Dose
Outcome measure
Follow up length
Cohort
Baseline vitamin D status
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59
Q

What is the difference between vitamin D2 and D3?

A

Molecular structure
D2= ergocalciferol - Synthetically derived to treat hypoparathyroidism and hypophosphatemia (helps body absorb calcium and phosphorus)
D3= cholecalciferol - natural form we make with sunlight exposure

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60
Q

What are the clinical effects of vitamin D3?

A

Increases corticosteroid responsiveness
Decreases infections
Decreases airway smooth muscle mass
Decreases goblet cell hyperplasia

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61
Q

What are leukotrienes?

A

Lipid mediators generated via enzymatic reaction

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62
Q

What is the difference between leukotrienes and cytokines?

A

Leukotrienes - produced by many cells but only really act in one place
Cytokines - generated in one place in the body but can act in lots of places

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63
Q

How are leukotrienes made?

A

5-lipoxygenase (5-LO) pathway
5-lipoxygenase activating protein (FLAP)
cPLA2 and FLAP activate 5-LO
LTA4 can be converted into LTC4 by LTC4 synthase
Transport out of cell via MRP1
LTC4 -> LTD4 -> LTE4 where they can bind to LT receptors

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64
Q

What types of cells may produce leukotrienes?

A 
Via 5-LO pathway:
Granulocytes
Monocytes
Macrophages
Mast cells
B lymphocytes
Via transcellular metabolism of LTA4 (after it's synthesised in neutrophils):
Platelets
Erythrocytes
Endothelial cells
Epithelial cells
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65
Q

How do leukotrienes mediate chronic disease?

A 
Pro-inflammatory- help drive early atherosclerosis
Important in fibrotic diseases such as:
Asthma
Rhinitis/ sinusitis
Cancer
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66
Q

What have studies shown about leukotrienes?

A

LTC4 synthase knock out prevents asthma in knock outs - Kin et al.
LT antagonists inhibit bronchoconstriction, increasing FEV1 % change - Parameswaran et al

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67
Q

What role do leukotrienes play in asthma?

A

Inhalation of leukotrienes -> bronchoconstriction - Gauvreau and Snetkov

Cysteinyl leukotrienes can:
Vasodilate; induces blood vessel permeability
Play a role in chemotaxis
Increase mucous secretion
Increase eosinophil influx -> release of protein and epithelial cell damage.

68
Q

How are cysteinyl leukotrienes produces in asthma?

A

Produced in lungs of asthmatics by mast cells, eosinophils, basophils and macrophages
Important for dendritic cell migration to lymph nodes

69
Q

What is the main leukotriene to bind to the receptors (1, 2, 3)?

A

LTD4

70
Q

What did Gauvreau et al. discover about LTE4?

A

Inhale LTE4 and increase airway inflammatory cells

Asthmatic airways are hyper-responsive to LTE4 and this is increased in aspirin sensitive asthma.

71
Q

What did Maekawa et al conclude about cysteine leukotriene receptors?

A

There must be a third, CysLTER

Double knock-out of CysLT1 and CysLT2 receptors maintained LTE4 functionality compared to ‘sufficient’ mice

72
Q

What investigations could you run for asthmatic patients?

A 
Measure gene expression differences
RNA isolation and labelling to identify heterogeneity
RNA sequencing
PCR/qPCR
Manipulate RNA levels
Detect polymorphic variation
Whole genome sequencing
Exome sequencing
73
Q

What is the role of TH1?

A

Produces IL-2 and IFN-gamma -> phagocytosis

74
Q

What is the role of TH2?

A

Produces IL-5 and IL13 -> mucosal barrier

75
Q

What is the role of Treg (TR)?

A

Produces IL-10, TGF-beta -> regulation

76
Q

What is fluorescence activated cell sorting?

A

Antibody based recognition of cell surface markers
Couple an antibody to a dye
Separate cells via properties on the cell surface.

77
Q

Why isn’t DNA commonly used as a marker of disease?

A

It’s too robust

Easier to reverse transcribe RNA

78
Q

How is RNA sequencing performed?

A
  • Design oligonucleotides complimentary to the ones in the gene
  • Tag them with biotin (marks amino acids) and then avodin (fluorescent marker)
  • Take complimentary DNA (cDNA), melt it and then inject it into the gene chip
  • Individual cDNA will find the complimentary nucleotides and hybridise with them.
  • Shining a laser light on the GeneChip array causes hybridised DNA fragments to glow.
  • The more fluorescent the chip, the more biotin present.
79
Q

How is flow cytometry performed?

A

Similar to RNA sequencing
Adaptors = short nucleotides
Use known adaptors to capture different cDNA clusters
The clusters will be identical
Sequencing is performed via base complimenting.

80
Q

What is the function of polymorphic variation?

A

Where there’s variation, you can investigate if this is the cause of different severities, triggers etc.

81
Q

How can you present gene expression data?

A

Heat map: blue = less expression, yellow = more expression

Volcano plot: p value tells you how many similar people respond to the same stimulus
Fold change shows how much differential gene expression there is with added stimuli

82
Q

What is quantitative PCR (qPCR)?

A

Get representative number of individuals and find out which genes are expressed and how much - good for verifying differential gene expression

83
Q

How do siRNA/ microRNAs work?

A

When you know which genes are differentially expressed, it may be useful to work out the function of protein that they code for.
siRNA = small interfering (knock them out)
microRNA = non-coding RNA silences RNA and regulates gene expression post regulation

84
Q

What is the function of exome sequencing?

A

Sift through DNA and pick out the 2-3% that codes for proteins.
Means you have information on everything that actually functions.

85
Q

What are the functions of airway smooth muscle?

A

Contract and relax
Synthesis: secretion, migration and proliferation (contribute to inflammation and remodelling in asthma when they stop functioning normally)

86
Q

How do PKC and Rho kinase act to facilitate smooth muscle contraction?

A

Deactivate MLCP which stops MLC inhibition. This means it can be phosphorylated and activated, allowing for contraction.

87
Q

What role does airway smooth muscle play with respect to eosinophils?

A

Eotaxin expression increases with airway smooth muscle stimulation
Increased eosinophil viability

88
Q

How is SERCA2 affected in asthma?

A 
Down-regulation
Sarcoplasmic reticulum (SR) isn't affected because IP3 receptors remain unchanged
Less SERCA means less calcium for release and higher intracellular concentrations
89
Q

What did Mahn et al. find about SERCA defects?

A

Abnormal SERCA means reduced channel activity and therefore a decrease in concentrations of proteins that bind to it.

90
Q

What would you expect to see in calcium levels after SERCA knockdown

A

Lower transient peak (less calcium to move out of sarcoplasmic reticulum)
Higher basal effect (more calcium in muscle cell)
Less regulation of muscle contraction

91
Q

Why is increased/ faster proliferation observed with SERCA knockdown?

A

Proliferation of airway smooth muscle cells is calcium dependent (via CAMK & ERK).

92
Q

What changes in mitochondria are observed with asthma?

A

Increased mitochondrial biogenesis means increased mitochondrial mass.
This means increased proliferation and growth, allowing for airway remodelling

93
Q

What studies argue that SERCA isn’t important in asthma?

A

Sweeney et al. found no differences in calcium concentration with respect to to SERCA expression, bradykinin, IP3 production or rate of calcium sequestration after release

Normalising for Rho kinase results in no difference.

94
Q

What are arguments for Rho Kinase being the mediator of airway hyper-responsiveness?

A 
ARHGEF1 part of growth exchange factor family that activates RhoA
ARHGEF1 is unregulated in asthmatic airway smooth muscle -> increased Rho kinase
Actin cytoskeleton (containing Rho A) plays an active role in secretion, proliferation etc.
95
Q

What is breathlessness?

A

A subjective experience of breathing discomfort
Consists of a qualitatively distinct sensations that vary in intensity (increased work to breathe/ increased respiratory drive)
Derives from different factors and may induce secondary physiological and behavioural responses.

96
Q

What is the difference between breathlessness intensity and breathlessness quality

A

Intensity- respiratory drive

Quality- respiratory afferents and limbic processing

97
Q

How does breathlessness lead to a spiral of disability?

A

Breathlessness reduces activity which results in muscle de-conditioning.
Muscle de-conditioning means increased leg fatigue and weakness, so increased lactate/ CO2 production.
This sends afferents to the DRG -> increased respiratory rate (and therefore breathlessness).

98
Q

What are arguments for breathlessness being a better predictor of mortality than FEV1?

A

FEV1 is negatively correlated with breathlessness.

Breathlessness correlates to a greater degree of neuro-respiratory coupling

99
Q

What are problems with breathlessness as a symptom?

A

Not common symptom for patients to report with

100
Q

How do bronchodilators act to reduce breathlessness?

A

Bronchodilators reduce hyperinflation from increased functional residual capacity
They improve neuro-ventilatory coupling

101
Q

How does heart failure cause breathlessness?

A

Reduced lung compliance via pulmonary oedema

102
Q

How do cancer, neuromuscular disease and anaemia cause breathlessness?

A

Weak respiratory muscles -> have to work harder to breathe

103
Q

What are different ways to describe breathlessness?

A

Air hunger
Breathing more than usual (increased work/ effort)
Chest tightness

104
Q

How does COPD ruin respiratory dynamics?

A
  • Expiratory flow limitation
  • Neuro-mechanical and neuro-ventilatory uncoupling
  • As respiratory drive increases, so does near-mechanical uncoupling
  • Gas trapping, dynamic hyperinflation, reduced inspiratory reserve volume.
  • Lower respiratory reserve and higher residual capacity means that patients hit tidal lung volume wall quickly.
  • Destruction of elastin means that the lungs are more likely to collapse in on themselves
105
Q

What is a neurophysiological model of breathlessness?

A

Receptors:
Stretch, mechanoreceptors, chemoreceptors

Sensation:
Respiratory afferents from receptors

Perception:
Awareness of levels of respiratory drive to the respiratory muscles

106
Q

What is corollary discharge?

A

A sensory copy of the motor signal sent to higher centres.

This gives the brain feedback as to how much work was required to generate the respiratory output.

107
Q

What is the efferent-afferent mismatch theory?

A

= length- tension inappropriateness
Discrepancy between how hard a patient is trying to breathe (pressure = tension) and how much ventilation is occurring (tidal volume = length change)

108
Q

What are arguments in support of efferent- afferent mismatch?

A

Simulation of this mismatch (via a panic attack) results in disrupted ventilatory pattern -> breathlessness

109
Q

What are arguments against the efferent-afferent mismatch theory?

A

Gandevia et al. demonstrated that mechanoreceptor afferents aren’t necessary for breathlessness; in their absence, chemoreceptors take over
Jolley et al. showed that patients can still experience increased respiratory drive where there is no increased ventilation rate
This means that afferents don’t have to be mismatched to efferents to cause breathlessness

110
Q

How does cold air or a hand held fan help manage breathlessness?

A

Sensory trigeminal stimulation tricks the brain into thinking more air is being taken in.

111
Q

What is the importance of type I pneumocyte differentiation?

A

Loss of prelamellar vesicles, thinning and hollowing out process allows for future gas exchange

112
Q

What is the importance of type II pneumocyte differentiation?

A

Lamellar bodies become bigger, more numerous and packed with surfactant phospholipids and proteins.

113
Q

When does pneumocyte differentiation take place?

A

Canalicular phase - 16-24 weeks gestation

114
Q

How does surfactant reduce surface tension?

A

Surfactant forms an insoluble surface film which opposes the surface tension of the underlying liquid by exerting its own surface pressure.

115
Q

What are signs of respiratory distress syndrome?

A 
Respiratory rate > 60 breaths per minute
Indrawn sternum and intercostal spaces
Lower ribs during inspiration
Grunting during expiration
Cyanosis
Low functional residual capacity
Increased work of breathing
116
Q

What are the risk factors associated with respiratory distress syndrome?

A 
Gender - boys do worse as preterms
Race
C-section
Maternal diabetes- high insulin
Hypothyroidism
Hypothermia
Haemolytic disease of the newborn- high insulin 
Genetic predispositions
117
Q

How is respiratory distress syndrome managed?

A

Mechanical ventilation
Supplemental oxygen
Antenatal glucocorticoids

118
Q

What observations can be made in the alveoli of respiratory distress syndrome neonates?

A

Unsaturated surfactant
Surfactant monolayer buckles on compression during expiration
Small alveoli

119
Q

What is surfactant normally made of?

A

Phosphatidylcholine:
Saturated (50%)
Unsaturated (20%)

Phosphatidylglycerol - 8%
Other phospholipids - 6%
Neutral lipids 8%
Proteins 8%

120
Q

What are the functions of the different surfactant proteins?

A 
A & D = hydrophilic, immune
B & C = hydrophobic, surface action
A- Opsonin
B- Lamellar bodies formation
C- Lamellar body processing
D- Host defence
121
Q

What is SP-B deficiency?

A

Autosomal recessive disorder
Results in lethal respiratory failure
Treatment is limited to transplantation

122
Q

How is fluid secreted and absorbed in the lung during gestation?

A

Fluid = 4-6ml/kg

  • Active transport of chloride ions into lung lumen from interstitial space
  • Sodium and water travel via diffusion and osmosis
123
Q

How is fluid secreted and absorbed during labour and delivery?

A

20ml/kg at term

  • Increased epinephrine stops lung fluid secretion (reliant on thyroid hormone and cortisol)
  • Resorption occurs via activation and opening of sodium channels in apical surface of epithelium
  • Exposure to postnatal oxygen tensions increases sodium transport across pulmonary epithelium.
124
Q

Where can problems with fluid absorption occur?

A

Chronic drainage -> pulmonary hypoplasia
More lung fluid travels from intrapulmonary space-> prolonged oligohydramnios
Loss of amniotic fluid
Amniocentesis
Transient tachypnoea- delayed foetal lung fluid clearance

125
Q

What is meconium aspiration?

A

Asphyxiated babies gasp and draw in meconium and amniotic fluid
Motilin levels increase

126
Q

What does ‘UF’ mean with respect to pollution?

A

Ultra fine particulate matter, anything smaller than 0.1 micrometers in diameter

127
Q

What does ‘PM2.5’ mean with respect to pollution?

A

Anything less than 2.5 microns in diameter

128
Q

Give examples of common types of pollution

A

Ozone
Nitrous oxides
Sulphur dioxide

129
Q

Where does pollution come from?

A 
Road traffic:
Carbonaceous material
Traffic generated dust (includes road, brake and tyre wear)
Coal combustion
Shipping (bunker fuel combustion)
Power generation (oil & coal combustion)
Metal industry 
Biomass combustion
Desert dust episodes
130
Q

What is the oxidant/ free radical theory of air pollution?

A

PM toxicity is related to the ability to cause oxidative stress
Where formation of free radicals is greater than radical elimination, oxidative stress occurs.

131
Q

What is alpha-tocopherol?

A

Vitamin E

132
Q

Why are oxidants both beneficial and dangerous in the lung?

A

Beneficial - able to kill any live pathogens
Dangerous - able to activate the same pathways that created them, making more oxidants with nothing but parenchyma to destroy.

133
Q

What is brittle asthma?

A

Rare yet severe form of asthma which is characterised by recurrent life-threatening asthma attacks

134
Q

Name examples of disorders thought to be influenced by environmental exposures.

A 
Asthma
Cancer
Acute respiratory distress syndrome 
Cystic fibrosis
Idiopathic pulmonary fibrosis
Scleroderma
Hypertension
135
Q

What did Kelly et al. learn about antioxidant production in asthma?

A

Mild asthmatics had less ascorbate compared to healthy controls

136
Q

What are the different types of vitamin C transport?

A 
Ascorbate
Dehydroascorbic acid (DHA; for glucose transport)
137
Q

What are the clinical differences between chronic bronchitis and emphysema?

A

Chronic bronchitis- chronic inflammation -> excess mucous and presence of chronic productive cough
Emphysema - damage to alveoli, shortness of breath

138
Q

Describe the pathogenesis of COPD

A

Pollutant exposure-> lung inflammation -> oxidative stress and proteinases

139
Q

What evidence is there associating COPD with environmental factors?

A

COPD triggered partially through recurrent oxidative insults at the air/ lung interface

140
Q

What evidence of oxidative stress is there for asthma?

A

Increased protein nitrosylation and exhaled hydrogen peroxide
Decreased vitamin C and E activity

141
Q

Give examples of antioxidants.

A

Ascorbate
Glutathione
Urate
alpha-tocopherol

142
Q

What is the difference between genetic and environmental based diseases with regard to onset?

A

Genetic - slow onset (genes don’t mutate quickly)

Environmental - faster onset

143
Q

What is allergy?

A

Disease caused by the presence of allergen specific IgE that triggers mast cell/ basophil degranulation

144
Q

What is the difference between sensitised and allergic patients?

A

IgE levels
Sensitised patients have had just an initial exposure to allergen
Allergic patients have had repeated exposures to the same allergen, increasing IgE levels

145
Q

What is the ‘allergic march’?

A

A succession of different allergies that flow a trend with the age at which they affect individuals.
1- After birth = eczema
2- 6 months - food allergy (declines at around 3-4 years)
3- Allergic rhinitis
4- Asthma

146
Q

What is the ‘hygiene hypothesis’?

A

Prevention of allergic diseases may be facilitated through transmission of unhygenic contact with siblings/ prenatal acquisition of diseases.
(We’re all currently too clean for our own good)

147
Q

What are arguments in favour of the hygiene hypothesis?

A 
Statistical epidemiologica correlations
With increased asthma prevalence:
- Family size has declined
- Lifestyle - improved cleanliness
- Lower frequency of (and therefore exposure to) childhood infections

Allergic disease prevalence is lower in:

  • Younger siblings
  • Larger families
  • Children’s early years in countryside
  • Maternal working with animals
148
Q

What are arguments against the hygiene hypothesis?

A

No specific pathogen causing allergy has been identified
In some cases, infections are correlated with increased allergy
Other epidemiological correlations exist:
- Higher paracetamol consumption
- Higher consumption of polyunsaturated fats
- Vitamin D deficiency and increased allergy
- Maternal testosterone in pregnancy

149
Q

How would the hygiene hypothesis apply to allergy?

A

Living an unhygienic lifestyle, the presence of increased allergens and microbes means higher bacterial turnover (Th1 mediated) and therefore decreased risk of atopy.
Living a hygienic lifestyle, the opposite would happen (Th2 mediated).

150
Q

Why are antibiotics dangerous in the context of infection?

A

Antibiotics result in the non-specific destruction of bacteria

151
Q

Give examples of strategies aimed at influencing environmental factors for the prevention/ treatment of allergies

A

Avoid allergens

Early exposure to antigens

152
Q

What is a ‘Quasi-RCT’?

A

An observation of a massive environmental change (East/ West Germany at around 1989/1990)

153
Q

Why is an RCT the gold standard of clinical trials?

A
  • Covariates are distributed equally across groups at baseline
  • Randomising controls for measured and not measured variables
  • Risk of imbalance would be smallest with randomisation, limiting bias
154
Q

What are the pros and cons to allergen avoidance?

A

Pros:
Effective at avoiding IgE cross-linking to mast cells)

Cons:
Difficult to achieve outside the home, where individuals can be exposed to anything

155
Q

What are the pros and cons to early allergen exposure?

A

Pros:
Could induce tolerance to allergens
individuals would not have to worry about exposure to the allergen.

Cons:
Introduction of peanuts in the LEAP trial caused negative effects in siblings (increasing their sensitisation)
This was found to be less effective in those who were already sensitised

156
Q

What is the methodology behind randomisation?

A

Participants can be assigned to any arm of the intervention, it’s not determinable or predictable.

157
Q

What are the ethics allowing for randomised control trials?

A

Uncertainty- not knowing whether an intervention is superior to another within the professional community (if a physician thinks they know, they have to follow beneficence and can’t enter patients into this type of trial)

Equipoise- Intervention must be compared to gold standard with genuine uncertainty as to which is better; once an obvious difference becomes clear, the trial must be stopped

158
Q

Why would you choose a parallel study over a crossover?

A

A crossover would be more expensive

The medication cost has to pay back the cost of development, making the drug more expensive to consumers.

159
Q

What is the ‘nocebo’ effect’?

A

Subjects could report symptoms despite being given placebo, through increased awareness of the actual drug’s potential side effects

160
Q

What is stage IV of a randomised control trial?

A

Post marketing studies for consumers to better establish drug benefits, risks and optimal use.

161
Q

Why is EGFR not a true oncogene?

A

Though over-expressed in lots of cancers, its expression in wild type form does not guarantee cancer development.

162
Q

What are known resistance mutations for EGFR?

A

Exon 19 short in-frame deletions
Exon 20 in-frame insertions
Exon 20 point-mutations (e.g. T790M)
Exon 21 point- mutations (e.g. L858R)

163
Q

How does resistant non-small cell lung carcinoma come to exist?

A

HER is unable to interact with EGFR so instead interacts with MET which drives Akt activation
Molecular interactions ‘make do’ because their counterparts aren’t present

164
Q

How is host immunity linked to cancer?

A

Programmed death ligand 1 inhibitor (PD-L1) = checkpoint inhibitor
Normally PD-L1 and PD-1 interact, killing using T cells
Inhibition of this interaction would allow for activation of T cells

165
Q

What are the disadvantages of checkpoint inhibitors?

A

Side effects all autoimmune mediated
Not everyone responds to immunotherapy/ has a durable response
Checkpoint inhibitors cost thousands of pounds
PD-1 expression isn’t the best predictor of clinical benefit

166
Q

What are the difficulties in using human tissues and animals models for studying the processes underlying asthma?

A

Human:

  • Difficulty obtaining suitable tissue
  • Bronchoscopy and lung resections -> ethics
  • Tissue from old/diseased patients -> variability between patients

Animals:

  • Tissue easily available, in vivo studies with potential drugs, genetic models
  • Most animals do not exhibit asthma, so have to use sensitised models (ovalbumin, house dust mite).
  • Inflammatory pathways aren’t always the same, e.g. mice do not have neutrophils, chemokines, IL-8 etc. but instead functional equivalents
  • Sensitisation in animals may not mimic that in humans
167
Q

How do pollutants affect the respiratory tract?

A

All the major pollutants contain transition metals which can redox cycle.

Direct- challenging the antioxidant network
Indirect- instigation of an inflammatory cascade

Physiology: References & Stats (4 decks)

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