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PATH3308 > 9 - Pathogenesis of Fibrosis > Flashcards

9 - Pathogenesis of Fibrosis Flashcards

1
Q

Two processes by which repair of injured tissue occurs

A
  • Regeneration
  • Scarring
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2
Q

Regeneration

A
  • Growth of cells and tissues to replace lost/damaged structures
  • Restoration of normal cells and cell function
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3
Q

Scarring

A
  • Occurs in response to a wound, inflammation, necrosis
  • Organs not able to regenerate
  • Deposition of connective tissue
  • ECM framework damaged
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4
Q

What are factors influencing repair of injured tissue based on

A
  • Intrinsic capacity of cells within a tissue to proliferate (or presence of stem cells)
  • Labile, stable or permanent tissue
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5
Q

Labile

A
  • Continuously dividing cells
  • e.g. Columnar epithelium GI
    tract or hematopoietic cells in bone marrow
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6
Q

Stable tissue

A
  • Quiescent cells (G0) that proliferate following damage
  • e.g. parenchymal cells in liver
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7
Q

Permanent tissue

A
  • Terminally differentiated cells
  • eg. Cardiac myocytes in heart
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8
Q

Examples of factors influencing repair of injured tissue

A
  • Extent of tissue damage
  • Location of injury damage
  • Duration of injurious agent
  • Infection (delays healing, prolongs inflammation)
  • Poor perfusion
  • Mechanical stress
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9
Q

Requirements of regeneration

A
  • Intact tissue scaffold
  • Approptiate stem cells to be intact
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10
Q

Aberrant wound healing response

A

Fibrosis

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11
Q

Fibrosis

A
  • Formation of excessive fibrous tissue
  • Can adversely affect functional capacity
  • eg. fibrosis following MI - compromised contractile function
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12
Q

Regulation of healing and repair

A
  • Controlled by biochemical factors released in response to cell injury, death or trauma
  • Cell responses regulated by intracellular signalling
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13
Q

Function of biochemical factors released in response to cell injury cell death, or mechanical trauma

A
  • inducing resting cells to enter
    cell cycle
  • Balance of stimulatory or inhibitory factors (determines overall effect)
  • Shorten cell cycle
  • Decrease rate of cell loss
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14
Q

Autocrine

A

Targets self

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15
Q

Paracrine

A

Targets nearby

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16
Q

Endocrine

A

Targets distant

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17
Q

Cellular source of TGF-β

A
  • Platelets
  • T cells
  • Macrophages
18
Q

Targets of TGF-β

A
  • Chemotactic for many cells
  • Stimulates angiogenesis
  • TIMP synthesis
19
Q

ECM

A

Non cellular component within all tissues and organs

20
Q

Interstitial matrix

A
  • Spaces between epithelial, endothelial and smooth muscle cells
  • Connective tissue
  • Fibrillar and non fibrillar collagen
  • Elastin, Fibronectin, proteoglycans, hyaluronate
21
Q

Basement membrane

A
  • Produced by epithelial and mesenchymal cells
  • Associated with cell surface
  • Amorphous non-fibrillar collagen (type IV)
  • Laminin, heparan sulfate, proteoglycan, glycoproteins
22
Q

Major source of ECM components

A
  • Fibroblasts
  • As repair continues, proliferation decreases, increased collagen deposition
  • Collagen synthesis starts 3-5 days after injury
23
Q

Granulation tissue in scarring

A
  • Becomes the scar (scaffold)
  • Spindle-shaped fibroblasts
  • Dense collagen
  • Elastic tissue fragments
24
Q

What causes scar to become pale

A

Vascular regression

25
Q

4 main groups of biochemicals in ECM

A
  • Complex polysaccharides
  • Glycoproteins such as fibronectin, laminin
  • Proteoglycans,
  • Various types and amounts of structural and insoluble collagen fibres and flexible elastic fibres
26
Q

Role of ECM

A
  • Provides a scaffold for cells
  • Provides spatial and locational information to cells
  • Controls activities
  • Acts as a sink for various growth factors (TGF) and cytokines (Oncostatin M)
27
Q

Activities controlled by ECM

A
  • Proliferation
  • Migration
  • Differentiation
  • Apoptosis
28
Q

Cutaneous wound healing process

A
  1. Inflammation to remove damaged and dead tissue
  2. Entry and proliferation of connective tissue and parenchymal cells
  3. Formation of new blood vessels
  4. Synthesis of new ECM proteins
  5. Tissue remodelling
  6. Wound contraction
  7. Acquisition of wound strength
29
Q

Foreign body response

A

Fibrous encapsulation is a protective mechanism against foreign objects

30
Q

Adhesions

A

The formation of fibrous bands between tissue surfaces that are not normally connected

31
Q

Clinical impact of excessive collagen deposition

A
  • Post operative adhesions
  • Liver fibrosis
  • MI
  • Scleroderma
  • Idiopathic pulmonary fibrosis
32
Q

Idiopathic pulmonary fibrosis

A
  • Lung disease of unknown cause
  • A progressive and usually fatal lung disease
  • Median survival of newly diagnosed patients is 3 years
  • Limited treatment options
33
Q

Characterisation of idiopathic pulmonary fibrosis

A
  • Abnormal parenchymal tissue remodeling
  • Re-epithelialization
  • Increased collagen deposition
    and angiogenesis
  • Loss of lung function
  • Genetic and environmental susceptibility
34
Q

Idiopathic pulmonary fibrosis possible causes

A
  • Activation of inflammatory cells
  • Dysregulation of mediator receptors/signalling
  • Increased fibroblast numbers
35
Q

How do we investigate the cause of fibrosis

A

Through research of indicators of mediator important in disease:
- Increased in patients with disease?
- Does it induce cell responses in vitro consistent with disease?
- Can responses be inhibited by blocking factor in vitro?
- Does overexpression in an animal model induce disease?
- Does inhibition in an animal model prevent or reverse the
disease?

36
Q

Models of fibrosis

A
  • Pre-clinical animal models dermal, lung fibrosis
  • Bleomycin
  • Human cell cultures
37
Q

Technical approaches to measure fibrosis

A
  • μCT (Ex vivo imaging)
  • Scar in a jar model (collagen deposition)
  • HPLC
  • Multicolour panel flow cytometry
  • Confocal microscopy
38
Q

Signalling pathways important in fibrosis

A
  • Increased fibroblast number (proliferation)
  • Increased fibroblast activity (collagen production, secretion)
  • Myofibroblast differentiation
39
Q

Increased STAT3 signalling

A

Increases the amount of fibrosis in mice

40
Q

B cells in idiopathic pulmonary fibrosis

A
  • Abnormal adaptive immune response
  • Characteristic of immunological disorders
  • B cell aggregates in lung
  • Similar to SLE and Ra due to high circulating autoantibodies, increased B cells, immune complexes
41
Q

B cell ablation therapy

A

No effect on fibrosis

42
Q

Process of developing new treatment for IPF

A
  • Use macromolecular crowding assay to test suitable drugs
  • Investigate the differential response of human IPF fibroblasts to drug treatment in vitro
  • B cell phenotyping and auto-antigen screening (which patients for which treatments)
  • Testing immunotherapy for lung fibrosis in mouse models

PATH3308 (8 decks)

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