Tissue repair (3&4 of 4)

What will we discuss today:

• Regeneration in tissue repair

• Scar formation

• Cutaneous wound healing

• Pathologic aspects of repair

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

…nephrectomy…contralateral compensatory hypertrophy and hyperplasia of

proximal duct cells

…the residual connective tissue framework needs to be structurally intact

examples: pancreas, adrenal, thyroid, lung…etc.

modified

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

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

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

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

Angiogenesis steps

• Vasodilation and permeability

NO VEGF

Proliferation of endothelial cells just behind the leading front of migrating cells

Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel

Suppression of endothelial proliferation and migration and deposition of the basement membrane

Robbins basic pathology 9th edition

VEGF

Induced by VEGF

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

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 the most important

-PDGF

-TGF-alpha

-TGF-beta

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

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

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

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

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

Cutaneous wound healing

•Occurs by 1st or 2nd intention according to wound nature and size

Healing by 1st intention, cont’d • Epithelial regeneration is the principal mechanism of repair

• Steps:

-within 24 hours: neutrophils & fibrin clot

-within 24-48 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

Healing by 2nd 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

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

Pathologic aspects of repair

Robbins basic pathology 9th edition

Name this condition ……

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: ……