Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PATH30001 - Mechanisms of Disease > Lecture 21 - Fibrosing Disease of the Lung > Flashcards

Lecture 21 - Fibrosing Disease of the Lung Flashcards

1
Q

What is fibrosis?

When does it occur?

A

Fibrosis: abnormal deposition of ECM

Occurs in:
• Chronic obstructive diseases (Asthma, COPD: emphysema, bronchitis)
• Fibrosing disease of the lung

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the most common fibrosing disease of the lung?

What are some other aetiologies?

A
  1. IPF: Idiopathic pulmonary fibrosis
    • most common

Known causes:

2. Iatrogenic
 • antibiotics
 • anti-inflammatories
 • radiotherapy
 • chemotherapy
  1. Inhaled dust particles
    • Silicates
    • Asbestos

etc.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q 
Describe IPF:
 • Major features
 • Median age of diagnosis
 • Location of pathology
 • Risk factors
 • Epidemiology
 • Prognosis
 • Symptoms
A
  • Chronic & irreversible
  • Usually lethal
  • Unknown cause

Median age of diagnosis:
• 66 years

• Limited to the lungs

Risk factors:
• Cigarette smoking
• Wood & metal dust exposure
• Genetic transmission

Epidemiology:
• Men (predominantly)
• Rising incidence

Prognosis:
• about 3 year survival after diagnosis

Symptoms:
• Cough
• Progressive dyspnea

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Describe the progression of IPF

What are the different clinical phenotypes?

A

Progression:

  1. Asymptomatic period
    • Lasts years
    • Progressive degeneration of lung function
  2. Onset of symptoms
    3a. Rapid progressive course

3b. Slow progressive course
+ acute exacerbations which speed up the progression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

How is IPF diagnosed?

What are the major and minor criteria

A
  1. High resolution computed tomography
    • Heterogeneous gaps in tissue
    • Thickened septa between lobes (interstitial tissue)
  2. Surgical biopsy & high power histology

Fibroblastic loci:
• Observed as pale foci
• Full of fibroblasts

Histopathologic hallmark:
Heterogenous appearance:
 • Areas of fibrosis
 • Scarring
 • Honeycomb change
alternating with regions that are less affected.

Major criteria:

  1. Exclusion of other known causes if interstitial lung disease
  2. Abnormal lung function tests
  3. Abnormalities in chest radiographs
Minor criteria:
 • > 50 years
 • Insidious onset
 • Duration of more than 3 months
 • Crackles: breathing causes a crackling sound
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the histological and radiological pattern of IPF?

A

Usual interstitial pneumonia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Describe the gross appearance

A

Cobblestone:
• enlarged airspaces

Gross honeycombing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe the microscopic appearance

A

“Usual interstitial pneumonia”
• Patchy fibrotic reaction
• Spatial heterogeneity

Fibrotic foci
• Epithelial cells still present, but they have become cuboidal

  • Paucity of inflammation
  • Lack of uniform involvement
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Describe acute exacerbations in IPF
What are the pathological features?
What does it lead to in terms of clinical presentation?

A

Leads to rapid decline in lung function

Diffuse alveolar damage

Pathological features:
 • Type II pneumocyte hyperplasia
 • Oedematous alveolar septa
 • Hyaline membranes
 • Squamous cell metaplasia (in alveoli)
 • Thrmobi in pulmonary arteries
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

How may IPF be studied?

A
  1. Biopsies from patients
    • Dead tissue
    • Only can do observational studies or immunohistochemistry
  2. Cell line studies
    • However, the cell lines are not typical and representative of the disease
    • Different micro-environment
  3. Primary cell culture
    • Cells taken directly from the person
    • Cells retain the phenotype
    • More useful and representative
  4. Animal models
    • Bleomycin in mice
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What was Bleomycin originally?

A

A cancer drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Describe the Bleomycin model of IPF

Pros / cons

A

Bleomycin causes pulmonary fibrosis in the lung similar to IPF

The drug administered to mice
Mice get IPF

Drawbacks:
• Mouse lifespan & anatomy are different
• Lacks human chronicity
• Bleomycin releases free radicals and causes DNA damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the paradigm of IPF?

A

Formerly: Chronic inflammation

Now: Aberrant wound healing (disease starting at epithelial level)

  1. Injury of alveolar epithelial cells

– TGF-B induction –

  1. Activation of fibroblasts and myofibroblasts

– ECM deposition –

  1. Pulmonary fibrosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the genetic component of IPF?

A

Specific genes expressed in alveolar epithelial cells involved:

  • MUC5B: codes for mucin
  • TERT/TERC: telomere length
  • SPA & SPC: surfactant protein

Changes in these genes are observed in disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe the observation of ER stress

A

Alveolar epithelial cells observed to have ER stress

Unfolded protein response:

  1. Environmental insults or genetic predisposition (MUC5B etc.) → unfolded proteins
  2. Stress detected in cell
  3. Apoptosis and / or fibrosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are some environmental insults that lead to the UPR?

A

Viral infection

Smoking

17
Q

What is TGF-β?

How does it become activated?

What is the major source of it?

What processes does it bring about?

A

Key fibrotic cytokine

Inactive form:
• LAP (latency associated peptide) bound

During fibrosis, an integrin binds to the LAP and the TGF-β is released and becomes activated

Source:
• Epithelial cells

Function:
 • Increased collagen synthesis
 • Differentiation & stimulation of fibroblasts into myofibroblasts
 • Epithelial cell proliferation
 • EMT
18
Q

What is EMT?

What is the role in IPF?

A

Epithelial-mesenchymal transition

Transition:
Epithelial cell → fibroblast

Controversy:
• only demonstrated in vitro
→ not representative of the body

19
Q

List the profibrotic attributes of epithelial cells in IPF

A 
• ER stress
 • Genetic mutations:
- SPC & SPA
- MUC5B
- TERT
 • TGF-β
20
Q

Describe the role of external stressors in IPF

Give a specific example

A

Not solely genetic component, but also external insults

KO mice for the particular genes do not spontaneously develop pulmonary fibrosis, but can develop it with external stimuli

Examples:
 • Gastrointestinal reflux
- proteolytic enzymes, acid & food enter lungs
- damage to epithelial cells
 • Treatment: proton pump inhibitors
21
Q

What is the role of the mesenchyme in IPF?

A

Important role of mesenchyme & fibroblasts

Fibrocytes:
• secrete collagen

Increased presence of fibrocytes in circulation associated with poor prognosis and exacerbation

22
Q

What are myofibroblasts?

How are they produced?

A

Derived from common progenitor fibrocytes (from bone marrow)

Three paths of differentiation:
1. EMT: Epithelial cell → fibroblast → myofibroblast

  1. Fibrocyte in blood → fibroblast → myofibroblast
  2. Resident fibroblast → myofibroblast

TGF-β:
• Fibroblasts differentiate into myofibroblasts under TGF-β signalling
• Need constant signalling, otherwise they go away

23
Q

What are fibrocytes?

A

From the bone marrow

Present in the blood

Recruited to sites of injury

Precursor for fibroblasts and myofibroblasts

24
Q

How are fibrocytes recruited by the alveolar epithelium?

A

Fibrocyte: CXCR4

Alveolar epithelium: CXCL12

25
Q

What is special about the fibroblasts in IPF?

A
  • Resistant to apoptosis (pro-survival genes FoxO3a)
  • Remain in the lung for a long time
  • Hyper-proliferative
26
Q

Describe the similarity of IPF to cancer

A
  • Pro-survival genes
  • Invasive
  • Down regulation of apoptosis
  • Foci of fibroblasts are like little tumours
27
Q

Describe epithelial-mesenchymal cross-talk

A

Communication between epithelial cell and fibroblast

• Normally in close contact
• Epithelial cell releases products that stimulate fibroblasts:
- TGF-β
- GFs

  • Mesenchyme interacts with ECM
  • Aberrant ECM drives changes in fibroblast as well as epithelial cells
28
Q

What is the role of inflammation in IPF?

A

Macrophages:
• make most of the active TGF-β
• responsible for activating latent TGF-beta
• predominantly M2 macrophages

29
Q

What are the two types of macrophages?

A
  1. M1: Inflammatory
    • collagen turn over
  2. M2: Profibrotic
    • produces TGF-β
    • collagen production etc.
30
Q

Describe propagation of lung fibrosis

A
  1. Predisposition
    • Genetic factors
    • External stressors
    • Ageing
  2. Initiation
    • TGF-β activation
    • UPR activation
    • Fibrocyte recruitment
  3. Progression
    • Fibroblast differentiation
    • ECM remodelling
    • Epigenetic change
  • Still don’t know why IPF is so relentless, is controversial
  • External stressors may be important in propagation
  • ECM contains molecules that signal mesenchymal cells to secrete more ECM (vicious cycle)
  • “Feed forward auto amplified loop of matrix remodelling”
  • There may be a role of epigenetics
31
Q

What are some therapeutic strategies for IPF?

A
  1. Combination therapy of antioxidants & anti-inflammatories:
    • Prednisolone etc.
    • Slower decline in lung function
  2. Antifibrotic agents
    • IFN-gamma
  3. Endothelin receptor antagonists
  4. Lung transplant
    • only proven treatment
32
Q

What are the therapeutic challenges in IPF?

A

There is much redundancy in the pathways leading to the fibrosis

Simply knocking out one is not sufficient

Each pathway needs to be targeted

PATH30001 - Mechanisms of Disease (34 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions