Tissue repair

Stages of wound healing

Hemorrhage

Inflammation

Granulation tissue (soft callus)

Scar – Fibrosis (hard callus)

Remodeling & Wound strength

Healing – replacement by connective tissue

Regeneration – Repair of injured tissue by parenchymal cells of the same type

Cell cycle

5 phases of cell cycle

G0( Quiescent phase)

G1( Pre synthetic phase)

S( phase of DNA synthesis)

G2( premitotic growth phase)

M( mitotic phase)

Transition between the phases regulated by cyclins and CDKs( cyclin dependent kinases)

The kinases on activation will phosphorylate proteins, form mitotic spindles, cause dissolution of nuclear membranes and chromosome condensation

CDK inhibitors like TP53 are important for buying time for DNA repair, or to induce apoptosis if the DNA cannot be repaired.

Proliferative Potential

Labile cells - continuously dividing

Epidermis, mucosal epithelium, GI tract epithelium etc

Stable cells - low level of replication

Hepatocytes, renal tubular epithelium, pancreatic acini

Permanent cells - never divide

Nerve cells, cardiac myocytes, skeletal mm

Polypeptide growth factors

Most Important Mediators affecting Cell Growth

Present in serum or produced locally

Exert pleiotropic effects; proliferation, cell migration, differentiation, tissue remodeling

Regulate growth of cells by controlling expression of genes that regulate cell proliferation

Angiogenesis: bFGF, VEGF

Scar formation: TGBβ, PDGF, FGF

Remodelling: metalloproteinases

Signaling

Types of signaling between cells:

Gap junctions

Autocrine signalling

Paracrine signalling

Endocrine signalling

Synapsis

Receptors of growth factors and cytokines:

Ion channels eg Ca++ channels

Receptors with intrinsic kinase activity, eg Ras, which activates the IP3/DAG pathway

G protein coupled receptors, which either increase or decrease the cGMP in the cell- Gs and Gi respectively

Repair by connective tissue

Occurs when repair by parenchymal regeneration alone cannot be accomplished

Involves production of Granulation Tissue

replacement of parenchymal cells with proliferating fibroblasts and vascular endothelial cells

Extracellular matrix

ECM, esp basement mb is very crucial to healing

ECM has collagen, elastin, proteoglycans and hyaluronan, which act as scaffolding for tissue repair

The collagen and laminin of basement mb, and the adhesive glycoprotein of the ECM like fibronectin and laminin hold the cells via integrins in the cell mb.

Note: proteoglycans are proteins linked to glycosaminoglycans( GAG) like dermatan sulphate and heparan sulphate while hyaluronan is not linked to any proteins.

Components of the process of fibrosis

Angiogenesis - New vessels budding from old

Fibrosis, consisting of emigration and proliferation of fibroblasts and deposition of ECM

Scar remodeling, tightly regulated by metalloproteinases like collagenase, elastase, etc and protease inhibitors

Epidermal Wound healing

Induction of acute inflammatory response by an initial injury

Parenchymal cell regeneration

Migration and proliferation of parenchymal and connective tissue cellsBasement membrane crucial to wound healing: collagen in the bm binds to cells via proteins like integrins, fibronectin and laminin.

Synthesis of ECM proteins

Remodeling of parenchymal elements to restore tissue function

Remodeling of connective tissue to achieve wound strength

Healing by First Intention

Focal Disruption of Basement Membrane and loss of only a few epithelial cells e.g. Surgical Incision

Chronological events in wound healing

24 hrs: neutrophils infiltrate, clot formation, increases mitosis in the basal cells which deposit new basement membrane and meet in the midline beneath the clot.

Day 3: macrophages replace neutrophils, granulation tissue formation, epithelial cell proliferation and collagen deposition

Day 5: neovascularisation and collagen deposition peaks, epithelium matures

2 weeks: the WBC and blood vessels decrease

1 month: tensile strength of the scar increased due to cross linking of collagen, wound contraction due to myofibroblasts dermal appendages like hair follicles and sweat glands are destroyed forever

Healing by Second Intention

Larger injury, abscess, infarction Process is similar but Results in much larger Scar and then CONTRACTION

Wound Strength

After sutures are removed at one week, wound strength is only 10% of unwounded skin (Walker’ Law)

By 3-4 months, wound strength is about 80% of unwounded skin (Walker’s Law)

Granulation tissue

Healing Skin wound