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Fibrotic Diseases
- 1. Biology of disease 11/10/2015 Presented by Thi Tran-Nguyen Ph.D. student in immunology Fibrotic Diseases
- 2. Outline: I. Fibrotic disorder 1) Characteristics 2) How? 3) Why? II. Idiopathic Pulmonary Fibrosis 1) Clinical presentation and diagnosis 2) Clinical trials in IPF
- 5. Fibrosis: The good and the bad • Physiologic: Fibrosis is an evolutionarily conserved process to protect against pathogens and promote wound healing. • Pathologic: Fibrotic diseases contribute to an estimated 45% of all-cause mortality world wide.
- 6. Fibrosis- The good and the bad • Lung: Pulmonary Fibrosis, Progressive massive fibrosis (coal workers). • Liver: Cirrhosis • Heart: Atrial fibrosis, endomyocardial fibrosis • Skin: Keloid, Scleroderma, Systemic Sclerosis • Bone marrow: Myelofibrosis
- 7. Fibrosis- Wound-healing response to epithelial injury -Fibrotic scar benefits survival of species: prevent blood loss, barrier to pathogens, facilitates regeneration of damaged epithelium -But why replacement over regeneration in complex organism? + energetic investment + risk of oncogenic transformation
- 8. Why repair? Just regenerate…
- 9. Fibrosis- Host defense mechanism -Many cells and mediators of innate and adaptive immune responses contributes to fibrotic disorders. -Contain and prevent pathogen spread, e.g. fibrotic rims around granuloma which contain mycobacteria.
- 11. 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/ mimicry • Autoreactive abs, T cells (enhance fibrotic responses) • E.g. high level of autoab to HSP70 associated with poor outcome in IPF patients.
- 12. 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.
- 13. Fibrosis-How? Victor Thannickal et al. “Fibrosis: ultimate and proximate causes”. JCI Nov. 2015.
- 14. IPF-Idiopathic Pulmonary Fibrosis • Chronic lung disease caused by progressive scarring of the lung parenchymal • Histology: Usual interstitial pneumonia • Clinical manifestation: loss of lung function, median survival is 3 years after diagnosis • Mortality rate comparable to breast cancer’s • No animal model • No FDA approved therapies
- 17. IPF lung biopsy (H&E stain) shows quilt-like pattern of fibrosis
- 18. IPF lung biopsy (H&E stain)-fibroblast focus
- 19. . Traditional approaches: immunosuppressive drugs such as prednisone and cyclophosphamide, anti-coagulant such as warfarin • Clinical trials difficulty: -no animal model -No good measurable tool to evaluate drug effectiveness in individuals (FEV cannot distinguish between natural course of disease and drug efficacy) Treatment for IPF
- 20. Recent positive phase III- randomized controlled clinical trial • Pifenidone: compound with anti-fibrotic, anti- inflammatory, and anti-oxidant properties (precise mechanism not understood) • Nintedanib: inhibitor of multiple tyrosine kinases downstream of growth receptors such as PDGF-R, VEGF-R and FGF-R
- 21. Reference: 1. Victor Thannickal et al. “Fibrosis: ultimate and proximate causes”. JCI Nov. 2015. 2. Jason S. Zolak and Joao de Andrade. “Idiopathic Pulmonary Fibrosis”. Immunol Allergy Clin. N. Am. 2012. 1. Spaolo Spagnolo et al. “Pharmacological treatment of idiopathic pulmonary fibrosis: an update.” Drug discovery today. May 2015.
Editor's Notes
- Characteristics: Fibrosis results in loss of tissue architecture Progressive loss of function
- Characteristics: Fibrosis results in loss of tissue architecture Progressive loss of function
- risk of oncogenic transformation as an issue with repeated cell division in regeneration. This contrasts with the remarkable regen- erative capacity observed with limb amputation in amphibians, which rely on dedifferentiation of somatic cells at the wound mar- gins to initiate regeneration without scarring or cancer
- risk of oncogenic transformation as an issue with repeated cell division in regeneration. This contrasts with the remarkable regen- erative capacity observed with limb amputation in amphibians, which rely on dedifferentiation of somatic cells at the wound mar- gins to initiate regeneration without scarring or cancer
- Trypanosoma cruzi, a well-known cause of cardiac fibrosis and cardiomyopathy 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
- Gross section of lung of IPF patient
- Idiopathic pulmonary fibrosis. High-resolution CT showing a characteristic combination of peripheral, subpleural, and predominantly bibasilar reticular abnormalities with associated honeycomb change (arrows) and traction bronchiectasis. Traction bronchiectasis refers to an aetiological sub type of bronchiectasis where there is irreversible dilatation of bronchi and bronchioles within areas of pulmonary fibrosis or distorted lung parenchymal architecture.
- The tissue is stained with hematoxylin (purple dye) and eosin (pink dye) to make it visible. The pink areas in this picture represent lung fibrosis (collagen stains pink). Note the "patchwork" (quilt-like) pattern of the fibrosis.
- The white space to the left is an airspace. The pale area to the right is a fibroblast focus. It is an area of active fibroblast proliferation within the interstitium of the lung.
- Warfarin clinical trial failed because of high mortality in the warfarin arm… Forced expiratory volume (FEV) measures how much air a person can exhale during a forced breath. The amount of air exhaled may be measured during the first (FEV1), second (FEV2), and/or third seconds (FEV3) of the forced breath. Forced vital capacity (FVC) is the total amount of air exhaled during the FEV test
- NAC, a precursor of the endogenous antioxidant glutathione (GSH), has been used in IPF based on the assumption that an oxidant–antioxidant imbalance has a role in the pathogenesis of the disease