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Translational Medical Sciences > Lung fibrosis > Flashcards

Lung fibrosis Flashcards

1
Q

What forms the basis of the mechanics of breathing

A
  • contraction and relaxation of intercostal muscles and diaphragm
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2
Q

What is fibrosis

A

excessive deposition of extracellular lung tissue

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3
Q

What is idiopathic lung fibrosis

A
  • most common lung disease
  • end stage of heterogenous group of interstitial lung diseases
  • lacy lung architecture is replaced by scar tissue, making it hard to breathe
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4
Q

What do interstitial lung diseases affect?

A

they affect the alveolar walls and spaces

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5
Q

What is the median survival for IPF

A

2-3 years

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6
Q

What are the symptoms of IPF

A
  • weight loss
  • clubbing
  • shortness of breath (dyspnoea)
  • coughing
  • physical examination of lung sounds are characteristic with:
    • velcro crackles
    • pleural rub
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7
Q

What diseases are velcro crackles in lungs associated with

A
  • IPF

- asbestos lung

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8
Q

What diseases are pleural rubs in lungs associated with

A
  • rheumatoid arthritis (some cases)

- SLE-associated Interstitial lung disease

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9
Q

What does the management of IPF depend on

A

an accurate and specific diagnosis of the disease

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10
Q

What are the key management decisions for a patient with IPF

A
  • Administration of pharmacological agents
  • Monitoring of disease
  • whether or not the patient is eligible for lung transplantation
  • whether the patient is on the end stage of the disease and unlikely to respond to therapies such that palliative care is the best option
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11
Q

How can IPF be monitored

A
  • Pulmonary functioning tests

- Thoracic imaging tests

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12
Q

Name some pulmonary functioning tests

A
  • 6 minute walk test
  • forced vitality test
  • FEV1/FEC1 ration
  • Diffusion capacity of lung for CO
  • Oxyhameoglobin saturation
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13
Q

Name a thoracic imaging test for IPF

A

HRCT to measure severity of fibrosis

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14
Q

What is the basic response to lung injury

A
  • fibroproliferative

- damage to lung creates abnormal processes

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15
Q

Outline the fibroproliferative response to lung injury in the alveolus

A
  • Epithelial lung damage
  • Activation of coagulation cascade
  • inflammation
  • Establishment of chemokine networks
  • Leukocyte infiltration and activation
  • AEC proliferation
  • Recruitment, proliferation and differentiation of fibroblasts
  • Loss of organ function
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16
Q

What are the uses of animal models in disease

A
  • Understanding cellular/molecular mechanisms of disease
  • Drug structure-activity relationship (PK/PD)
  • Drug safety
  • Dosage selection
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17
Q

What is the current regulation regarding drug safety

A
  • drug has to be safe in 1X rodent species and 1X non-rodent species
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18
Q

Name some features of the ideal animal model for IPF

A
  • mimics pathological features of human disease (fibroblastic foci)
  • progressive/fatal
  • possibly shows paucity of granulocytes
  • prone to acute exacerbations
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19
Q

Name some features of the ideal animal model for IPF drug discovery

A
  • a large therapeutic window
  • high thoroughput/reproducible
  • established across multiple species
  • low resource intensity
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20
Q

Name the main animal models for IPF

A
  • Bleomycin
  • Transgenic (pulmonary specific, virus targeted)
  • Irradiated
  • FITC
  • Silica
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21
Q

What are the general features of the most common model for IPF

A
  • Bleomycin
  • drug give intra-tracheally
  • can be done in multiple species, rats, mice or rabbits
  • flibrolytic response has a time frame of a few weeks
  • fibrolytic response consists of doubling of lung collagen
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22
Q

Define tissue repair

A

Replacement of damaged tissue by parenchymal cells of same type or connective tissue (scars)

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23
Q

What are the causes of tissue damage

A
  • Infection
  • Trauma
  • Physical and chemical factors (heat, acid)
  • tissue necrosis
  • foreign bodies (thorns or glass)
  • immune reactions (hypersensitivity)
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24
Q

What is the order of events during tissue repair/wound healing

A
  • Homeostasis
  • Inflammation
  • Proliferation
  • Remodelling
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25
Q

What does homeostasis consist of

A
  • fibrin plug
  • growth factors
  • cytokines
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26
Q

What cell types are involved in homeostasis

A

platelets

27
Q

What events are a part of homeostasis

A
  • platelet aggregation
  • clotting
  • release of pro-inflammatory cytokines
28
Q

What cell types are involved in tissue repair

A
  • Platelets
  • Macrophages
  • Monocytes
  • Neutrophils
  • Epithelial cells
  • Endothelial cells
  • fibroblasts
  • myoflibroblasts
29
Q

What does inflammation consist of

A
  • Cell recruitment

- wound debridement

30
Q

What cell types are involved in inflammation

A
  • neutrophils
  • macrophages
  • monocytes
31
Q

What events are a part of inflammation

A

diapederis

32
Q

What does proliferation consist of

A
  • re-epethlialisation
  • angiogenesis
  • ECM deposition
  • Fibroplasia
33
Q

What cell types are involved in proliferation

A
  • fibroblasts
  • endothelial cells
  • epithelial cells
34
Q

What events are a part of proliferation

A
  • alternatives to cell-cell and cell-matrix interactions
  • migration
  • ECM production
  • cross talk b/w MMPs, integrins and cells
  • growth factor and cytokine release
35
Q

What does remodelling consist of

A
  • Scar formation
  • ECM remodelling and degradation
  • Contraction
36
Q

What cell types are involved in remodelling

A

Fibroblasts

37
Q

What events are a part of remodelling

A
  • fibroblast to myofibroblast differentiation
38
Q

What are the two roles of the extracellular matrix

A
  • provides structure and support

- regulates movement and growth of cells

39
Q

Name the parts of the extracellular matrix

A
  • collagen
  • elastin
  • proteoglycans
  • adhesive glycoproteins
  • Integrins
40
Q

What role does collagen play in ECM

A

tensile strength

41
Q

What role does elastin play in ECM

A

elastic stretch and recoil

42
Q

What role do proteoglycans play in ECM

A
  • regulate ECM structure and permeability
  • bind growth factors
  • modulate cell growth
43
Q

Name some adhesive glycoproteins

A

fibronectin and laminin

44
Q

What role do integrins play in ECM

A
  • major cell surface receptor family

- modulate cell adhesion to ECM

45
Q

How many types of collagen are there

A

27

46
Q

Name the outcomes in the mechanism of injury that lead to scarring

A
  • Exudate organised
  • Cell necrosis in permanent tissue by stimulant not being completely destroyed/alleviated
  • Cell necrosis in labile/quiescent tissue when the framework is destroyed
47
Q

Name some examples of diseases involving tissue scarring

A
  • ulceration
  • liver cirrhosis
  • keloid scar
48
Q

Name some invasive diagnostic procedures for PF

A
  • BAL fluid analysis
    • visual inspection
    • cell count
    • microbiology
    • malignant cell staining
  • Endoscopic lung biopsy
    • histopathology
  • straining, immunochemistry
49
Q

What are the non-pharmacological treatments available for IPF

A
  • Self-care
  • Oxygen therapy
  • Pulmonary rehabilitation
  • Lung transplant
50
Q

What are the pharmacological treatments available for IPF

A
  • Tyrosine kinase inhibitors
  • anti-fibrotic agents
  • anti-viral therapy
51
Q

Name a tyrosine kinase inhibitor and outline how it works

A
  • Nintedanib

- inhibits PDGF receptors a and b, VEGF 1,2,3 and FGF receptors 1,2,3

52
Q

Name an anti-fibrotic agent and outline how it works

A
  • perfinodone
  • anti-inflammatory, anti-oxidant and anti-fibrotic properties
  • mechanism of action is not well understood
53
Q

Name an anti-viral agent and outline how it works

A
  • Ganciclovir

- Egan et al 2011 showed that 2 weeks of gancicolvir therapy temporarily attenuates disease progression

54
Q

What evidence is there for viruses in exacerbation of lung fibrosis

A
  • Immunohistological evidence
    • HHV8 and EP antigens localised in airway epithelial cells
  • PCR from lung tissue evidence
    • Human herpes simplex virus
      • HHV 7,8
      • EP virus
      • Cytomegalovirus
55
Q

What makes the structure of the herpes simplex virus special

A
  • complex structure
    • dsRNA in toroidal shape
    • icosohedral nucleo-capsid
    • tegument on the outside (protein filled region)
    • lipid bilayer envelope with a lot of glycoproteins
56
Q

What virus is most commonly associated with IPF

A

EP virus

  • specific for T/B lymphocytes
  • latency is demonstrated in lymphoid tissue
57
Q

Describe the latent herpes virus life cycle

A
  1. Primary site of infection: productive infection of epithelial cells
    - Infection by retrograde transport
  2. Secondary site of infection: sensory neurons
    - Minimal genetic expression
    - Episomal
    - Prevent immune recognition
    - Reactivation by by anterograde transport
    (Reactive stimuli: UV light, infections, stress, immunosuppression)
  3. Site of recurrent infection: productive infection of epithelial cells
58
Q

Illustrate some features of the lytic herpes virus life cycle

A
  • Nuclear dependance
  • Temporal gene expression
  • Importance of viral thymidine kinase
  • Direct cell lysis
59
Q

What aspect of the herpes life cycle does ganciclovir target

A

DNA replication of herpes virus

60
Q

Describe the immune response to a viral infection

A
  1. Virus infected cell present viral antigen to pre-cytotoxic CD8+ cell via MHC class I.
  2. This cell becomes activated and releases perforins and granzymes to induce apoptosis of the infected cell.
  3. Viral antigens are also phagocytosed by APCs which present viral antigen to CD4+ cells via MHC class II.
  4. These CD4+ then differentiate into Th1 cells and release cytokines (IL-2, IL-12, IFN-y, TNF-a) which enhance the proliferation of effect CD8+ cells.
  5. These CD4+ cells activated by APCs can also differentiate into Th2 cells. which produce cytokines (IL-4, IL-5, IL-6, IL-10, TGF-B) which facilitate differentiation of B cells.
  6. Viral antigen can also be detected by B-cells which present these to Th2 cells via MHC class II and co-receptor CD28. These activated B-cells also differentiate into Memory B-cells and Plasma B-cells responsible for immune memory and antibody production respectively.
61
Q

Name the techniques used for testing for viral infections

A

Direct
- Viral isolation using cell culture
- Genomic detection using PCR and gene extraction
- Antigen detection (immunohistological assays or rapid antigen detection tests)
Indirect
- Serology IgM and IgG tests in blood

62
Q

How does viral isolation work

A
  • Using cell culture
  • Centrifugation enhanced
  • Staining or immunoflourescence (can take up to 10 days)
63
Q

How long can genomic detection take

A
  • up to 24 hours
64
Q

What is the advantage of using rapid antigen detection tests

A
  • commercially available as ready made tests

- shows results within 30 minutes

Translational Medical Sciences (8 decks)

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