Tissue repair. (3&4 of 4)

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1 Tissue repair (3&4 of 4)

2 What will we discuss today: Regeneration in tissue repair Scar formation Cutaneous wound healing Pathologic aspects of repair

3 Regeneration in tissue repair Labile tissues rapid replacement basement membrane needs to be intact by proliferation of residual cells and differentiation of tissue stem cells for blood cells: proliferation of hematopoietic progenitors, driven by CSFs (colony-stimulating factors) Stable tissues usually limited except in the liver examples: pancreas, adrenal, thyroid, lung etc. nephrectomy contralateral compensatory hypertrophy and hyperplasia of proximal duct cells the residual connective tissue framework needs to be structurally intact modified

4 Robbins basic pathology 9 th edition..courtesy of R. Troisi, MD, Ghent University, Flanders, Belgium

5 Steps in scar formation 1- Tissue defect/inflammation 2- Angiogenesis 3- Migration and proliferation of fibroblasts + abundant vessels + WBCs = granulation tissue (pink granular appearance) 4- Extracellular matrix deposition 5- Reorganization of the fibrous tissue (remodeling) to produce the stable fibrous scar

6 Robbins basic pathology 9 th edition Robbins basic pathology 9 th edition

7 Angiogenesis Occurs in: -tissue repair -development of collateral circulations at sites of ischemia -tumors Primarily from existing venules There are therapies that are being developed to either augment or inhibit the process

8 Angiogenesis steps Vasodilation and permeability NO Induced by VEGF VEGF Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel Robbins basic pathology 9 th edition VEGF Proliferation of endothelial cells just behind the leading front of migrating cells Suppression of endothelial proliferation and migration and deposition of the basement membrane

9 Growth factors involved in angiogenesis The most important are VEGF & FGF-2 Among VEGF family, VEGF-A is the most important PlGF = placental growth factor also a member of the VEGF family For vessel development in the embryo: VEGF-B & PlGF Also important for lymphangiogenesis: VEGF-C & -D

10 Growth factors involved in angiogenesis, cont d The most important receptor for angiogenesis is: VEGFR-2 on endothelial cells a tyrosine kinase receptor *Of VEGF inducers: -hypoxia -PDGF -TGF-alpha -TGF-beta the most important

11 Growth factors involved in angiogenesis, cont d FGF: can bind to heparan sulphate and be stored in the ECM proliferation & migration of: -endothelial cells -fibroblasts -macrophages -epithelial cells Angiopoietins (Ang1 & Ang2): for the structural maturation (stabilization) of new blood vessels by recruitment of pericytes & SM cells deposition of connective tissue

12 Growth factors involved in angiogenesis, cont d Ang1 its receptor: Tie2 (a tyrosine kinase receptor) Also involved in stabilization process: -PDGF -TGF-beta Recruits SM cells endothelial cell proliferation & migration Production of ECM proteins

13 ECM enzymes Matrix metalloproteinases (MMPs): -Zinc-dependent -produced by many cell types -initially as inactive precursors activated by proteases (e.g., plasmin) -They degrade ECM and permit remodeling & extension of the vascular tube -of them: -interstitial collagenases -gelatinases -stromelysins

14 ECM deposition FGF, TGF-beta & PDGF are the most important TGF-beta: -mainly TGF-beta 1 -its receptor has serine-threonine kinase activity -transcription factors: Smads -functions: -production of collagen, fibronectin & proteoglycans - proteinase activity & activity of TIMP

15 ECM deposition, cont d PDGF: -Migration and proliferation of -fibroblasts -SM cells -Migration of macrophages IL-1 & IL-13: -collagen synthesis by fibroblasts -proliferation and migration of fibroblasts

16 Cutaneous wound healing Occurs by 1 st or 2 nd intention according to wound nature and size

17 Healing by 1 st intention, cont d Epithelial regeneration is the principal mechanism of repair Steps: -within 24 hours: neutrophils & fibrin clot -within hours: migration and proliferation of epithelial cells to form thin continuous epithelial layer beneath the scab -by day 3: -less neutrophils and more macrophages -granulation tissue in the incision space -thicker epithelial layer -collagen fibers present but still not bridging the incision -by day 5: -peak neovascularization -more abundant collagen beginning to bridge the incision -normal epidermal thickness is retained -with time: -less inflammation, edema, and vascularity -more collagen

18

19 Healing by 2 nd intention More tissue defect Large wounds Abscesses Ulcers Infarctions Larger clot/scab More inflammation More abundant granulation tissue and larger scar Wound contraction will follow very important here in reducing defect size

20 Wound strength By 1 week: 10% of original strength By 3 months: 70% to 80% then: mostly no further improvement This increase is due to: -more collagen synthesis than degradation in the first 3 months -gradual increase in cross-linking and fiber size of collagen

21 Pathologic aspects of repair Name this condition Robbins basic pathology 9 th edition

22 Pathologic aspects of repair, cont d Excessive collagen and other ECM components deposition in parenchymal tissues in chronic diseases = Fibrosis due to persistent tissue injury can lead to organ dysfunction examples: -lung (pulmonary) fibrosis -liver (hepatic) fibrosis its end stage is called:

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