9 - Pathogenesis of Fibrosis Flashcards
Two processes by which repair of injured tissue occurs
- Regeneration
- Scarring
Regeneration
- Growth of cells and tissues to replace lost/damaged structures
- Restoration of normal cells and cell function
Scarring
- Occurs in response to a wound, inflammation, necrosis
- Organs not able to regenerate
- Deposition of connective tissue
- ECM framework damaged
What are factors influencing repair of injured tissue based on
- Intrinsic capacity of cells within a tissue to proliferate (or presence of stem cells)
- Labile, stable or permanent tissue
Labile
- Continuously dividing cells
- e.g. Columnar epithelium GI
tract or hematopoietic cells in bone marrow
Stable tissue
- Quiescent cells (G0) that proliferate following damage
- e.g. parenchymal cells in liver
Permanent tissue
- Terminally differentiated cells
- eg. Cardiac myocytes in heart
Examples of factors influencing repair of injured tissue
- Extent of tissue damage
- Location of injury damage
- Duration of injurious agent
- Infection (delays healing, prolongs inflammation)
- Poor perfusion
- Mechanical stress
Requirements of regeneration
- Intact tissue scaffold
- Approptiate stem cells to be intact
Aberrant wound healing response
Fibrosis
Fibrosis
- Formation of excessive fibrous tissue
- Can adversely affect functional capacity
- eg. fibrosis following MI - compromised contractile function
Regulation of healing and repair
- Controlled by biochemical factors released in response to cell injury, death or trauma
- Cell responses regulated by intracellular signalling
Function of biochemical factors released in response to cell injury cell death, or mechanical trauma
- inducing resting cells to enter
cell cycle - Balance of stimulatory or inhibitory factors (determines overall effect)
- Shorten cell cycle
- Decrease rate of cell loss
Autocrine
Targets self
Paracrine
Targets nearby
Endocrine
Targets distant
Cellular source of TGF-β
- Platelets
- T cells
- Macrophages
Targets of TGF-β
- Chemotactic for many cells
- Stimulates angiogenesis
- TIMP synthesis
ECM
Non cellular component within all tissues and organs
Interstitial matrix
- Spaces between epithelial, endothelial and smooth muscle cells
- Connective tissue
- Fibrillar and non fibrillar collagen
- Elastin, Fibronectin, proteoglycans, hyaluronate
Basement membrane
- Produced by epithelial and mesenchymal cells
- Associated with cell surface
- Amorphous non-fibrillar collagen (type IV)
- Laminin, heparan sulfate, proteoglycan, glycoproteins
Major source of ECM components
- Fibroblasts
- As repair continues, proliferation decreases, increased collagen deposition
- Collagen synthesis starts 3-5 days after injury
Granulation tissue in scarring
- Becomes the scar (scaffold)
- Spindle-shaped fibroblasts
- Dense collagen
- Elastic tissue fragments
What causes scar to become pale
Vascular regression
4 main groups of biochemicals in ECM
- Complex polysaccharides
- Glycoproteins such as fibronectin, laminin
- Proteoglycans,
- Various types and amounts of structural and insoluble collagen fibres and flexible elastic fibres
Role of ECM
- 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)
Activities controlled by ECM
- Proliferation
- Migration
- Differentiation
- Apoptosis
Cutaneous wound healing process
- Inflammation to remove damaged and dead tissue
- Entry and proliferation of connective tissue and parenchymal cells
- Formation of new blood vessels
- Synthesis of new ECM proteins
- Tissue remodelling
- Wound contraction
- Acquisition of wound strength
Foreign body response
Fibrous encapsulation is a protective mechanism against foreign objects
Adhesions
The formation of fibrous bands between tissue surfaces that are not normally connected
Clinical impact of excessive collagen deposition
- Post operative adhesions
- Liver fibrosis
- MI
- Scleroderma
- Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis
- Lung disease of unknown cause
- A progressive and usually fatal lung disease
- Median survival of newly diagnosed patients is 3 years
- Limited treatment options
Characterisation of idiopathic pulmonary fibrosis
- Abnormal parenchymal tissue remodeling
- Re-epithelialization
- Increased collagen deposition
and angiogenesis - Loss of lung function
- Genetic and environmental susceptibility
Idiopathic pulmonary fibrosis possible causes
- Activation of inflammatory cells
- Dysregulation of mediator receptors/signalling
- Increased fibroblast numbers
How do we investigate the cause of fibrosis
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?
Models of fibrosis
- Pre-clinical animal models dermal, lung fibrosis
- Bleomycin
- Human cell cultures
Technical approaches to measure fibrosis
- μCT (Ex vivo imaging)
- Scar in a jar model (collagen deposition)
- HPLC
- Multicolour panel flow cytometry
- Confocal microscopy
Signalling pathways important in fibrosis
- Increased fibroblast number (proliferation)
- Increased fibroblast activity (collagen production, secretion)
- Myofibroblast differentiation
Increased STAT3 signalling
Increases the amount of fibrosis in mice
B cells in idiopathic pulmonary fibrosis
- 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
B cell ablation therapy
No effect on fibrosis
Process of developing new treatment for IPF
- 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
