Fibrosis & Scarring

Tissue Repair (Healing)

• Regeneration of injured tissue (replacement by normal cells of the same kind)• Replacement by fibrous tissue

(fibrosis, scarring)• Fibrosis : is the formation of excess fibrous

tissue in an organ or tissue in a reparative process.

•When one suffers a cut to the skin, the tissue is repaired by two methods: regeneration and fibrosis. • Regeneration replaces dead or damaged

cells with the same type of cell, thus restoring normal function. Fibrosis replaces damaged tissue with scar tissue, which holds the tissue together but does not restore normal function.

• Upon damage to the tissue, blood vessels bleed, and the blood pools in the cut. Mast cells release histamine, which promotes vasodilation.

• Vasodilation causes more blood to seep into the wound; however, it brings with it antibodies to help prevent infection, clotting proteins for clot formation.

• A clot forms in the tissue. The clot gently binds together the edges of the cut to keep and protect the healthy tissue. The surface of the clot forms a scab, while macrophages beneath the scab remove the damaged tissue.

• New blood capillaries grow into the wound. fibroblasts migrate into the wound. The macrophages remove the clot, and the fibroblasts produce collagen fibers, which will form the scar tissue. This is fibrosis.

• Eventually the scab loosens and falls off. As fibrosis continues, capillaries withdraw from the area.

Fibrosis progresses through four main stages:

• Angiogenesis•Migration and proliferation of

fibroblasts• Deposition of ECM• Remodeling of ECM

Angiogenesis

This process cannot be done without "Endothelial precursor cells" (EPCs)

Vessels

EPCs are in two places

Bone marrow

network of capillary plexus

Capillary sprouts

• Vascular endothelial growth factor (VEGF): is a protein that promotes the growth of new blood vessels by Angiogenesis process.

Important factors to increase the process

• VEGF forms part of the mechanism that restores the blood supply to cells and tissues.

• Hypoxia: is an inducing agent for VEGF.

• TGF(α-β ): Transforming growth factor.

Receptors of VEGF:

• VEGFR-1 Most common in the body.

• VEGFR -2 with the endothelial cells.

• VEGFR -3 with lymphatic endothelial cells.

Functions of VEGF

• Promotes angiogenesis.• Increases vascular permeability.• Stimulates endothelial cell migration.• Stimulates endothelial cell proliferation.

Migration and proliferation of fibroblasts

• Granulation tissue contains numerous newly formed blood vessels for transporting of new substances.

• As discussed previously,VEGF promotes angiogenesis but is also responsible for the increase in vascular permeability that leads to deposition of plasma proteins, such as fibrinogen and plasma fibronectin in the ECM and provides a provisional stroma for fibroblast and endothelial cell growth.

• Migration of fibroblasts to the site of injury and its proliferation are caused by multiple growth factors, including TGF-β, and the cytokines The sources of these growth factors and cytokines include platelets, is inflammatory cells and activated endothelium.

• We also have Macrophages are important cellular constituents , clearing extracellular debris, fibrin, and other foreign material at the site of repair.

• This factor -> TGF-β, helps in migration of fibroblasts.

• If the appropriate chemotactic stimuli are present, mast cells, eosinophils, and lymphocytes may also accumulate.

• TGF-β appears to be the most important because of the effects on fibrous tissue deposition in grannular tissue.

• TGF-β is produced by most of the cells in granulation tissue and causes fibroblast migration and proliferation.

• increased synthesis of collagen and fibronectin, and decreased degradation of ECM by metalloproteinases (discussed later).

• Increase the permeability of the vessels .• Increase the deposition of plasma protein .• Plasma protein will provide provisional

stroma for fibroblasts ingrowth• Megretion of fibroblasts made under

several factors .• Macrophages clear the extra cellular

debris, fibrin and some foreign materials

Summary

Deposition of ECM

Major Components of the ECM:

• Collagen• Elastic fibers• Proteoglycans • Fibronectin • Laminin • Integrins

• As repair continues, the number of proliferating endothelial cells and fibroblasts decreases.

• Fibroblasts progressively deposit increased amounts of ECM. Fibrillar collagens form a major portion of the connective tissue in repair sites and are important for the development of strength in healing wounds.

• collagen synthesis by fibroblasts begins within 3 to 5 days after injury and continues for several weeks, depending on the size of wound.

• Net collagen accumulation, however, depends not only on increased collagen synthesis but also on decreased degradation. Ultimately, the granulation tissue scaffolding is converted into a scar composed of spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components. As the scar matures, vascular regression continues, eventually transforming the richly vascularized granulation tissue into a pale, avascular scar.

Remodeling of ECM

• The replacement of granulation tissue with a scar involves transitions in the composition of the ECM.

• Some of the growth factors that stimulate synthesis of collagen and other connective tissue molecules also modulate the synthesis and activation of metalloproteinases, enzymes that degrade these ECM components.

• The balance between ECM synthesis and degradation results in remodeling of the connective tissue framework an important feature of both chronic inflammation and wound repair.

Thank You

Presented by:

Ahmed Kamal Abdallah Hammad

Ahmed Reda Mohamed EdreesAhmed Alaa El-Din Mokhtar

Ahmed Emad MofeedAhmed Emad Mounir

Reference : Tissue Repair and

healing, ROBBINS Chapter 3.