Regeneration & Wound Healing

Outcome of Inflammation

• resolution: normal tissue homeostasis is completely restored

• regeneration: occurs when here is significant tissue damage, but basement membranes remain intact, and the tissue has regenerative capabilities

• repair by fibrosis: occurs when there is significant tissue damage, basement membranes are damaged or destroyed, or the tissue lacks the ability to regenerate

In order for regeneration to occur, the cells must be able to:

proliferate

What are the mechanisms of growth factors?

• soluble growth factors bind to appropriate receptors

• cells interact with the surrounding ECM

The mechanisms of growth factors result in:

• increased protein synthesis

• cell proliferation

• cell differentiation

• cell migration

Types of growth factors.

• autocrine: growth factors stimulate cell that produces it

  • hepatocellular regeneration, epithelial hyperplasia, and neoplasia

• paracrine: growth factor stimulates nearby cells

  • macrophages stimulate fibroblasts

• endocrine: growth factor carried from distant endocrine organ to target cell by the bloodstream

Intrinsic protein kinase activity receptor (GF)

When a ligand binds to the extracellular part of these transmembrane proteins, it activates an enzymatic domain on the intracellular side of the receptor, triggering a signaling cascade within the cell.

No intrinsic protein kinase activity reeceptors (GF)

Those that do not have their own enzymatic domain but rely on an associated cytoplasmic enzyme for signal transduction. After a ligand binds to the receptor, it recruits and activates a separate, non-covalently associated enzyme.

G-protein linked receptors (GF)

Also known as 7 transmembrane domain receptors that are coupled with an intracytoplasmic G protein.

Important growth factors.

• Vascular endothelial growth factor (VEGF)

• fibroblast growth factor (FGF)

• epidermal growth factor (TGF beta)

• platelet-derived growth factor (PDGF)

Mechanism of action for cell to extracellular matrix interactions

• integrin mediated

• binding of cell surface integrins with extracellular matrix proteins results in signal transduction from the cytoplasm to nucleus

• signal transduction is often mediated through the cytoskeleton

Structures pof the ECM

• structural proteins

  • collagen - strength to tissue

  • eleastic fibers - elasticity

• Adhesive glycoprotiens

  • fibronectin

  • laminin

  • integrins

• EC gell for tissue hydration

  • proteoglycans

  • hyaluronans

Collagen types and locations

I - skin, bone, tendon

II: cartilage

III: skin and muscle

IV: basement membrane

Cllagen synthesis steps

1. transcription ad translation to form pre-procollagen

2. in the RER, modifications like hydroxylation and glycosylation occur which requires vitmin C and cofactors

3. three chains twist into a triple helix forming procollagen which is secreted outside the cell

4. EC space the terminal ends are cleaved to form tropocollagen which forms crosslinks to form stable collagen fibrils

Angiogensis

RE-ESTABLISHMENT OF BLOOD FLOW FOR OXYGEN AND NUTRIENT DELIVERY TO HEALING TISSUES IS CRITICAL

What is the primary initiating signal for angiogenesis?

hypoxia inducing factor

Sequence of events for angiogenesis.

1. digestion: Proteolysis of basement membrane and extracellular matrix of parent vessels at the margins of wound

2. Migration: endothelial cells migrate through the digested point in the parent vessel

3. Proliferation: endothelial cells outwardly expand from the parent vessel to form solid endothelial tubes

4. Maturation: endothelial cells continue to mature with formation of a lumen

5. Cell-Cell adhesion: establishment of inter-endothelial gap junctions and receptors/ligands responsible for leukocyte adhesion cascade along luminal surface

6. Perivascular cell migration: recruitment of pericytes and smooth muscle cells to support final differentiation stages

What are the mediators of angiogenesis?

• vascular endothelial growth factor: mediator of angioblast production, endothelial cell proliferation and tube formation

• Angiopoietin: essential for stabilizing and vascular maturation

• Tie receptors serves as the angiopoietin receptor

  • Tie1: stimulatory receptor

  • Tie2: inhibitory receptor

What initiates repair by fibrosis?

macrophages

Fibrosis sequence of events?

1. fibroblasts migrate toward site of production of growth factors

2. fibroblasts proliferate

3. fibroblasts begin to synthesize and deposit collagen and other ECM proteins

4. tissue remodeling

How does TGF-b have a role in fibroblast activity and collagen deposition?

upregulates:

• macrophage chemotaxis

• fibroblast migration and proliferation

• synthesis of collagen and ECM protiens

What orientates the Fibrous CT correctly?

remodeling

What accomplishes tissue remodeling?

metalloproteinases

What are metalloproteinases produced by?

fibroblasts, macrophages, and neutrophils

What do metalloproteinases do?

degrade damaged tissue and then remodel the newly deposited collagen

Fibroblast proliferation amd migration

• FGF1 and 2

• PDGF

• EGF

• TGf-beta

Induce collagen production by fibroblasts

• FGF

• PDGF

• TGF-beta

• IL-13

Endothelial cell proliferation and basement membrane production

• FGF

• VEGF

• TGF-beta

• Angiopoietin

Primary intention wound healing

a process where the edges of a clean, surgical wound are brought together and closed, allowing for faster and more efficient healing

What are the conditions for primary wound healing?

clean wound edges, minimal tissue loss, mo infection present, and wound edges can be approximated.

Second intention wound healing occurs in:

septic wounds or gaping wounds with non-apposed edges

Common causes for impaired wound healing

• infection

• location

• foreign material

• blood supply

• nutrition

• corticosteroids

Osteogenesis imperfecta

impaired production of type 1 collagen that imapirs wound healing

Ehlers danlos

impaired synthesis, cross-linking, hydroxylation, or post-translational processing of collagen; delays wound healing

Exuberant granulation tissue

excessive granulation tissue projects above the epithelial surface and inhibits epithelization