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TMS > Pulmonary Fibrosis > Flashcards

Pulmonary Fibrosis Flashcards

1
Q

Name 5 cell types in the lungs and their functions

A

Goblet cells - secrete mucus
Ciliated cells - have cilia to waft mucus
Basal cells - type of stem cell, proliferate to replace lost tissue
Alveolar Type I cells - gas exchange
Alveolar Type II cells - secrete surfactant to reduce surface tension

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2
Q

What are the 4 steps of the breathing cycle?

A 
Diaphragm contracts (flattens)
External intercostals contract
Diaphragm relaxes
Internal intercostals contract (if forced exhalation)
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3
Q

Name 5 risk factors for IPF

A 
Air pollution
Workplace dust
Smoking
Respiratory viruses
Genetic predispositions
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4
Q

Name 5 symptoms of IPF

A 
Dyspnoea
Dry cough
Fever
Weight loss
Clubbing of fingers
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5
Q

What part of the lung does IPF affect?

A

The interstitium i.e. the tissue and space surrounding the alveolae

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6
Q

How is IPF diagnosed?

A

Look for symptoms
Respiratory crackles heard with stethoscope
Honeycombing pattern seen with HRCT
Lung function tests
Bronchoscopy to visualise airways
Lung biopsy
Analysis of BAL fluid to inspect cell count

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7
Q

How is the progression of IPF monitored?

A

Pulmonary function tests (spirometry) such as
-FVC
-DLco
-FEV1/FVC ratio
Oxyhaemoglobin saturation
6 minute walk test
Thoracic imaging with HRCT, X-ray or lung biopsy

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8
Q

What is FVC?

A

Forced Vital Capacity
Maximum possible breath
Tidal volume + Inspiratory reserve volume + Expiratory reserve volume

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9
Q

What is DLco and what does it measure?

A

Diffusion capacity of the lung for CO. Measures extent to which oxygen passes from the alveoli to the blood

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10
Q

What is FEV1 and what should the and what should the FEV1/FVC ratio be in healthy people?

A

Forced expiratory volume 1 - how much air you can forcefully breathe out in 1 second.
Ratio should be at least 80%

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11
Q

What is the general mechanism of the fibroproliferative response to lung injury?

A
  1. Epithelial cell injury
  2. Activation of extrinsic coagulation cascade
  3. Inflammation - release of ROS, cytokines and growth factors TGFbeta1 and PDGF
  4. Leukocyte infiltration
  5. Alveolar endothelial cell proliferation
  6. Fibroblast recruitment and proliferation
  7. Fibroblasts differentiation into myofibroblasts, generating collagen and extracellular matrix
  8. Alveolar walls thicken
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12
Q

How does the fibroproliferative response cause IPF?

A

Persistent lung injury repeatedly triggers the response. Alveolar walls get progressively thicker. Surface area for gas exchange reduces until the lungs cannot function

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13
Q

What is an exacerbation of IPF and what causes it?

A

Acute exacerbation is a sudden rapid decline in health. Often leads to death. Thought to be caused by viral infection

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14
Q

What methods can be used to detect viruses in the lungs of IPF patients?

A

Take blood sample, lung tissue biopsy or lung fluid sample with bronchoscopy
Use PCR/qPCR on liquid sample
Immunohistochemistry on tissue sample
Detection of viral IgG or IgM antibodies

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15
Q

Which viruses have been associated with acute exacerbations of IPF?

A

Herpes simplex virus
Epstein-Barr virus
Human herpes virus 7 and 8
Cytomegalovirus

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16
Q

What is the structure of the herpes virus?

A

dsDNA
Toroidal shape
Icosahedral capsid (20 faces)
Has a tegument - viral matrix between the capsid and envelope that is filled with proteins

17
Q

Describe the latent life cycle of the herpes virus

A
  1. Infection of epithelial cells
  2. Enters sensory neuron, retrograde transport up axon
  3. Viral DNA remains latent in cell body. Remains episomal
  4. Reactivation of virus by UV light, stress, immunosuppression
  5. Anterograde transport back down axon
  6. Recurrent infection of epithelial cells
18
Q

Describe the lytic life cycle of the herpes virus

A
  1. Infection of epithelial cells
  2. dsDNA transcribed into RNA and proteins
  3. Viral replication
  4. Cell lysis
19
Q

Describe the general immune response to a viral infection

A
  1. Viral antigens engulfed by APC and expressed on MHC II
  2. Naive T cell proliferates into Th1 and Th2
  3. Th1 secretes interleukins and interferons to activate cytotoxic T cells
  4. Cytotoxic T cells kill host cells expressing the viral antigen on MHC I
  5. Th2 cells activate B cells
  6. B cells differentiate into plasma cells that secrete antibodies
20
Q

In what ways can animal models be useful for studying diseases and drug development?

A

Can understand disease at cellular and mechanistic level
Target discovery and target validation
Uncover structure-activity relationships and PK/PD profile
Dose selection - allometrically scale up for humans
Test safety of a novel molecular entity

21
Q

What are the characteristics of an ideal IPF animal model?

A

Mimic key pathological features such as fibroblast proliferation
Disease should be progressive and eventually fatal
Prone to acute exacerbations
Should have relatively low grade granulocytic inflammation

22
Q

What is the most frequently used animal model of IPF and how is it made?

A

Bleomycin mouse
Chemotherapeutic treatment given intratracheally, with side effect of pulmonary fibrosis. After a few weeks the amount of lung collagen doubles. Can be seen using a microCT

23
Q

How can the bleomycin model be used to mimic acute exacerbations of IPF?

A

Injection of the murine gammaherpes virus on day 14. Confirm infection by measuring expression of viral genes gB, M3 and DNApol.

24
Q

What are some pros of general use of mice models for disease research?

A 
Widely accessible
Reproducible
Easier to perform large scale trials
Rodents share characteristics with humans, similar GI tracts and endocrine systems
Rodent genome completely mapped
Easy to genetically modify
High throughput
Can look at effects across multiple species
25
Q

What are some cons of general use of animal models for disease research?

A

Cannot take into account human genetic predispositions
Can only test one element of the disorder at a time
Method used to create model not same as pathogenesis in humans
Metabolic/systemic difference to humans

26
Q

Why have many of the compounds successfully tested on the bleomycin model not been successful in humans?

A

Bleomycin fibrosis is reversible, IPF is not
Bleomycin model lesions are bronchiolocentric rather than in the alveoli
Compounds were administered in early disease phase so may have been preventative rather than reversing the disease

27
Q

Name 4 other possible animal models for IPF and how they are made

A

Transgenic models - viral vectors used to control gene expression e.g. cause overexpression of TGFbeta1
FITC administered intratracheally, destroys lung architecture
Single whole body dose of irradiation induces lung fibrosis
Exposure to silica mineral fibres leads to development of fibrotic nodules

28
Q

What are the current treatments for IPF?

A

Steroids (not actually used anymore)
Palliative care
Self-care (stop smoking, flu vaccine)
Oxygen therapy to raise oxygen saturation
Pulmonary rehabilitation (breathing exercises, singing groups)
Lung transplant

29
Q

What are some potential pharmaceutical treatments that may be used for IPF in the future?

A

Nintedanib - tyrosine kinase inhibitor
Pirfenidone - anti-inflammatory, anti-oxidant and anti-fibrotic
Ganciclovir - anti-viral therapy that inhibits thymidine kinase to prevent viral DNA replication
N-acetylcysteine - precursor to the antioxidant glutathione

30
Q

What is Nintedanib and how does it work?

A

Small molecular tyrosine kinase inhibitor
Inhibits PDGF, VEGF and FGF receptors
Prevents fibroblast proliferation and differentiation into myofibroblasts

31
Q

What are the steps of tissue repair?

A
  1. Haemostasis/Coagulation cascade
  2. Inflammation by neutrophils and monocytes
  3. Proliferation of epithelial cells, endothelial cells and fibroblasts
  4. Remodelling - fibroblasts differentiate into myofibroblasts to form scar tissue
32
Q

What are the components of the extracellular matrix and their functions?

A 
Collagen - tensile strength
Elastin - elastic stretch and recoil
Proteoglycans - contains water and growth factors
Adhesive glycoproteins
Integrins - adheres cells to matrix
33
Q

What are some cons of the bleomycin model?

A

Fibrosis will not develop in all mice that the chemotherapy is administered to
The timeframe to create the model is long

34
Q

Name 1 pro and 1 con of the transgenic model of IPF

A

Pro: Gene expression can be tightly controlled, useful for understanding fibrosis pathogenesis
Con: Viruses can promote vigorous immune responses and they are highly trophic for epithelial cells

35
Q

Name 1 pro and 1 con of the FITC model of IPF

A

Pro: Can visualise and monitor the lung fibrosis using thoracic imaging
Con: Very expensive

TMS (12 decks)

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