Healing and Repair

What is healing/repair?

restoration of tissue architecture and function after injury

The inflammatory process not only eliminates microbes but also puts what in motion?

process of repair

What are the two processes of repair?

regeneration and scarring

What is regeneration?

restores normal cells to original architecture and function; replacement of lost cells by their own kind, thereby returning tissue to normal structure and function

What is scarring?

damage is replaced connective tissue altering the architecture and causing a loss of function; when damaged tissue is incapable of regeneration or the ECM is severely damaged

Regeneration is dependent on what two elements?

cell proliferation and integrity of extracellular matrix (ECM); labile/stable cells and intact stroma and basement membranes

What role does cell proliferation have in regeneration?

cells need to be capable of diving or differentiated cells or tissue stem cells must be able to proliferate

What role does the integrity of the extracellular matrix have in regeneration?

provides signals along with growth factors to guide the proliferation process

What is labile?

continuously dividing; continuously lost and replaced by proliferation/differentiation of stem cells

What are examples of labile cells?

epithelia and hematopoietic cells

What is stable?

cells remain quiescent (G0 stage of cell cycle) but are capable of diving following damage; usually have limited regeneration capacity

What type of stable cells are the exception to the normal stable cells limited regenerative capacity?

liver

What are examples of stable cells?

liver and kidney

What is permanent?

cells are terminally differentiated and non-proliferative in post-natal life

What are examples of permanent cells?

cardiac muscle and neurons

What occurs to the regeneration process if the supporting stroma is damaged?

proliferation of connective (fibrous) tissue and deposition of collagen (scarring); fibrosis

When does scarring take place?

destruction of stroma, excessive exudation/infection, excessively large defects, necrosis of permanent cells

What are the steps of scarring?

inflammation → cell proliferation → formation of granulation tissue → deposition of connective tissue → remodeling of connective tissue

What occurs during the inflammation step of scarring?

inflammatory mediators and recruited cells (particularly monocytes) will initiate the process of repair

What occurs during the cell proliferation step of scarring?

several cell types proliferate to fill damage/wound (fibroblasts, endothelial cells, pericytes, epithelia)

What occurs during the formation of granulation tissue step of scarring?

proliferation and migration of fibroblasts and deposition of loss connective tissue with new vessels (angiogenesis) and scattered mononuclear leukocytes

What occurs during the deposition of connective tissue step of scarring?

granulation tissue progressively replaced by deposition of collagen (scar formation)

What occurs during the remodeling of connective tissue step of scarring?

degradation of collagen and other RCM components continue until the scar is stable

What is the macrophages role in repair?

M2 phenotype plays a central role in clearing microbes and necrotic cell debris, produce growth factors that tigger proliferation, and secrete cytokines that stimulate fibroblast proliferation and collagen deposition

What is angiogenesis?

process of new blood vessel development from existing vessels

What is angiogenesis stimulated by?

hypoxia and high lactate

What are the steps of angiogenesis?

proteolysis of basement membrane and matrix, migration of endothelial cells, proliferation of endothelial cells, maturation/stabilization, suppression of proliferation

What are the two steps of the deposition of connective tissue? (fibroplasia)

proliferation and migration of fibroblast then the synthesis and deposition of ECM

What is the proliferation and migration of fibroblasts triggered by?

predominantly by growth factors/cytokines produced by M2 macrophages

What are the growth factors produced by M2 macrophages for the proliferation and migration of fibroblasts?

TGF-b, PDGF, and FGFs

What are the characteristics of new vessels?

leaky; ooze fibrin and plasma fibronectin, temporary mesh for fibroblast adhesion and migration

What is the synthesis and deposition of ECM (mainly collagen) mainly stimulated by?

strongly stimulated by TGF-b

What is granulation tissue?

exuberant granulation tissue “proud flesh”

What are the main cell types in connective tissue?

fibroblasts, present in nearly every tissue

What is the function of fibroblasts?

deposit ECM within 3-5 days secreted as procollagens and polymerizes extracellularly

What inhibits collagen synthesis?

corticosteroids

Overall cellularity is _______ as ECM synthesis is increasing.

decreasing

During healing, some fibroblasts develop extensive myofibrils similar to smooth muscle cells. What are these fibroblasts called?

myofibroblasts

What is the function of myofibroblasts?

contract simultaneously with collagen deposition and are responsible for wound contraction then disappear with completion of healing

The outcome of the repair process is a balance between what?

synthesis and degradation of ECM

What mediates the degradation of collagen and other ECM components?

matrix metalloproteinases (MMPs)

What produces matrix metalloproteinases (MMPs)?

several cell types: fibroblasts, macrophages, and others

What can inhibit healing?

malnutrition, metabolic disease such as diabetes, glucocorticoids inhibit collagen synthesis, infections, neoplasia, etc