Recommended
More Related Content
Similar to Fibrosis- Why and How?
Similar to Fibrosis- Why and How? (20)
More from Thi K. Tran-Nguyen, PhD
More from Thi K. Tran-Nguyen, PhD (20)
Recently uploaded
Recently uploaded (20)
Fibrosis- Why and How?
- 1. FIBROSIS -WHY AND HOW? PRESENTATION AND DISCUSSION SKILLS GRD 701 02/10/2016 Presented by THI TRAN-NGUYEN
- 2. Wound healing and Scar formation
- 4. FIBROSIS RESPONSES- THE GOOD • An attempt at wound healing. • Evolutionarily conserved process to protect the species: 1.Fibrotic scar prevents further blood loss 2.Fibrotic scar presents a barrier to pathogens. 3.Fibrosis responses facilitate the regeneration of the damaged epithelium.
- 5. Tubercle- The barricadeTubercle- The barricade
- 6. FIBROSIS RESPONSES- THE BAD • Fibrotic diseases contribute to an estimated 45% of all-cause mortality world wide. Lung: Pulmonary Fibrosis, Progressive massive fibrosis (coal workers). Liver: Cirrhosis Heart: Atrial fibrosis, endomyocardial fibrosis Skin: Keloid, Scleroderma/Systemic Sclerosis Bone marrow: Myelofibrosis
- 8. But why repair? Just regenerate…
- 9. FIBROSIS-HOW? Factors which drives persistent fibrotic responses 1) Persistence of pathogens/ antigens • Trypanosoma cruzi cardiac fibrosis • Latent viral infection associated with lung fibrosis • Noninfectious stressor: alcohol liver fibrosis, abestos fibers lung fibrosis 2) Autoimmune reactions • Loss of immune tolerance via epitope spread/ molecular mimicry • Autoreactive abs, T cells (enhance fibrotic responses) • E.g. high level of autoab to HSP70 associated with poor outcome in IPF patients.
- 10. Factors which drives persistent fibrotic responses 3) Impaired regeneration: • genetic/epigenetic: e.g. IPF association with protein folding/trafficking-> adversely affect regeneration of epithelium Epigenetic factors affect fibroblast differentiation • Aging : e.g. IPF is age-related disease (>50 y.o.) 4) Pleiotropic actions of genes involved in development and wound healing • Antagonistic pleiotropy theory, proposed by Williams in 1957: A gene beneficial in development but detrimental in old age is evolutionarily conserved. • E.g. NOX4 involved in myofibroblast differentiation, beneficial for wound healing in young subjects but causes fibrosis in aged subjects.
- 11. Fibrosis-How? Victor Thannickal et al. “Fibrosis: ultimate and proximate causes”. JCI Nov. 2015.
Editor's Notes
- 4:22
- Characteristics: Fibrosis results in loss of tissue architecture Progressive loss of function
- Characteristics: Fibrosis results in loss of tissue architecture Progressive loss of function
- Gross section of lung of IPF patient
- But why replacement over regeneration in complex organism? + energetic investment + risk of oncogenic transformation
- Trypanosoma cruzi, a well-known cause of cardiac fibrosis and cardiomyopathy . Protozoan. Viruses and other intracellular pathogens can cause apoptosis of alveolar epithelial cells, which is implicated in the pathogenesis of lung fibrosis. However, at present, it is unclear to what extent lung fibrosis that may be asso- ciated with viral or other infective agents is due to direct effects, rather than a secondary consequence of an injurious immune response provoked by these infection. The cascade of injury processes evoked by autoimmune responses can include direct cytotoxicities by autoantibodies or autoreactive T cells; elaboration of numerous proinflammatory, vasoactive, and profibrotic mediators (includ- ing IL-4, IL-13, and TGF-β); and recruitment and/or activation of other immune effectors and mesenchymal cells (18–20). The end result of many clinically distinct autoimmune syndromes is tissue fibrosis affecting one or more organs
- The first two relate to the host defense function of physiological fibrosis, and the last two to wound healing