Growth and repair
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Growth and Repair. dr. FAIRUZ QUZWAIN,SpPA,M.Kes Kepala bagian Patologi Anatomi FKIK-UNJA. Repair following inflammation: two simultaneous processes. Regeneration : replacement of injured/necrotic cells by cells of same type, often leaving no evidence of previous injury

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Growth and Repair

dr. FAIRUZ QUZWAIN,SpPA,M.Kes

Kepala bagian Patologi Anatomi

FKIK-UNJA


Repair following inflammation: two simultaneous processes

  • Regeneration : replacement of injured/necrotic cells by cells of same type, often leaving no evidence of previous injury

  • Repair : replacement of injured/necrotic cells by connective tissue, leaving a permanent scar (microscopic or macroscopic)


Control of cellular population


Cell Cycle

PHASES of Cell Cycle:

G1:

S:

G2:

M:

G0:


Correlation of Cell Cycle and Tissue Types

  • Continuously dividing (labile) cells:

    • Surface epithelium and excretory ducts of glands (skin, gi / gu mucosa, biliary tract, pancreas)

    • Marrow hematopoietic cells

    • Stem cells in multiple organs (immature, undifferentiated cells)

  • Quiescent (stable) cells in G0:

    • Organ parenchymal cells (liver, kidneys)

    • Mesenchymal cells (fibroblasts, smooth muscle, endothelium, chondrocytes, osteocytes)

  • Nondividing permanent cells (can’t re-enter cell cycle)

    • Neurons, skeletal & cardiac myocytes


Mechanism: control of cell cycle

Which cyclin ?

Which cyclin?

Cyclin-dependent kinase inhibitors


Modes of Intercellular Signalling

Autocrine

Paracrine

Endocrine


Surface Receptors: 3 classes

Receptors without intrinsic tyrosine kinase

Receptors with intrinsic tyrosine kinase

Seven transmembrane (G protein-coupled)


Consequences of Receptor Activation

  • Intrinsic-kinase activity receptors:

    • Irreversible commitment of cell to enter

      (proliferative response)

  • Receptors without intrinsic kinase activity (cytokine superfamily):

    • Activation cytosolic kinases to mediate functional response (not proliferative)

  • G-protein coupled (seven spanning) receptors:

    • Over 1500 receptors identified

    • Bind various ligands, producing specific intracellular response


Signal Transduction by Tyrosine Kinase Receptors

Growth factors: coming soon!

Clinical application: if mutant ras protein is permanently fixed in active GTP form, what pathologic process may result?


Transcription Factors

  • Definition: intracellular proteins that regulate gene expression, thereby controlling cell growth

  • Specific domains in transcription factors:

    • : permits factor to bind specifically to short

      sequences of DNA

    • : allows factor to increase transcription of DNA

    • :allows factor to decrease transcription of DNA

  • Transcription factors known to be operative in malignant neoplasms:

    • Growth promoting: c-MYC and c-JUN

    • Cell cycle inhibiting (tumor suppressor gene): p53


Growth Factors

  • Definition: proteins that bind to cell surface receptors with generating cascade response that signals cell to enter S-phase (cell division).

  • These factors can also modulate cell functions: locomotion, contractility, differentiation, etc.


Major growth factors / effects

EFFECTS

  • Mitogenic for epithelium & fibroblasts

  • Mitogenic for hepatocytes

     Mitogenic for endothelial cells

  • Mitogenic for monocytes, fibroblasts, smooth muscle cells; activates neutrophils

  • Angiogenesis, wound repair (mitogenic for both fibroblasts and keratinocytes)

FACTOR

  • EGF = epidermal

  • TGF-a = transforming

  • VEGF=vascular endothelial

  • PDGF= platelet-derived

  • FGF= fibroblast

  • FGF-1=acidic

  • FGF-2=basic


Tissue Regeneration

Liver from living donor before transplantation, outlining right lobe to be used for grafting into recipient

Liver of donor one week post-partial hepatectomy, showing marked growth of left lobe (compensatory hyperplasia) without regrowth of right lobe. Why didn’t right lobe regrow also?


Extracellular matrix 1

  • Definition: macromolecules outside cells, formed by local secretion and assembled into network surrounding cells

  • Functions:

    • Sequester H2O for turgor; minerals for rigidity

    • Reservoir for growth factors

    • Scaffolding within which cells adhere, migrate, and proliferate


Extracellular matrix (ECM) 2

  • Groups of macromolecules in ECM:

    • Fibrous structural proteins: 2 major families are:

    • Adhesive glycoproteins

    • Gel proteins in intercellular junctions and cell surfaces: proteoglycans & hyaluronic acid


Extracellular matrix (ECM) 3

  • Macromolecules of ECM assemble into two types of organizational structure:

    • : fills spaces between cells

    • : closely associated with cell surfaces


Collagen: summary of major types

Skin (80%), bone (90%), tendons

Genetic deficiency of type IV in:


Collagen synthesis

Nutrient required for hydroxylation of alpha chains:

Deficiency of this nutrient causes poor wound healing in disease called:

Inherited disorders of collagen synthesis, leading to defective fibers:


Elastic Fibers

  • Definition: fibers capable of stretching and recoiling to original size

  • Present in tissues requiring elasticity:

  • Structure:

    • Central core protein:

    • Peripheral microfibrillary network:

    • Inherited defect synthesis of peripheral microfibrillary network: abnormally weakened elastic fibers. Syndrome?

Skin, lung, uterus, ligaments, large blood vessels


Adhesion molecules 1

Function: attach cells to ECM matrices; 2 glycoprotein chains held together by disulfide bonds; produced by fibroblasts, endothelial cells, & monocytes. Name?


Adhesion molecules 2

Most abundant glycoprotein in basement membranes; it spans basal lamina and binds to both cell surfaces and ECM components:


Adhesion molecules 3

Transmembrane glycoproteins with alpha and beta chains that bind to fibronectin, laminin, & collagen. This family of surface receptors mediate attachment of cell membranes to ECM:

These also mediate adhesion of which cell type to endothelium?


Summary: interactions cell-ECM

Major EC structural protein:

Fig. 3-16, Pathologic Basis of Disease, 7th ed, Elsevier 2005


Overview: Repair after injury

ACUTE AND CHRONIC INFLAMMATION

Damage to parenchymal cells and interstitial framework

Regeneration of parenchymal cells whenever possible

Replacement of non-regenerated damaged tissue by what?


Fibrosis (fibroplasia)

  • Four components:

    • : formation new blood vessels

    • of fibroblasts into damaged tissue

    • of extracellular matrix

    • Organization fibrous tissue =


Sequence of events in repair

24 hrs: proliferation of fibroblasts & endothelial cells

Within 3-5 days:

Permanent result (weeks later)

Little mature collagen

Proliferation of young fibroblasts

blue-staining collagen (trichrome stain)

New capillaries


Angiogenesis

  • Definition: pre-existing vessels send out capillary sprouts to form new vessels

  • cf. vasculogenesis: the primitive vascular network established during embryogenesis

  • Clinical importance:

    • Repair post-inflammation

    • Formation collateral circulation (post-MI)

    • Support growth of neoplasms (therapeutic implications)


Angiogenesis: 2 mechanisms


ECM proteins affecting angiogenesis

  • Integrins: formation and maintenance new vv.

  • Matrix proteins which destabilize cell-matrix interactions, promoting angiogenesis:

    • Thrombospondin

    • SPARC

    • Tenascin C

  • Proteases that remodel matrix

    • Plasminogen activators

    • Matrix metalloproteinases

  • Fragment of collagen that inhibits endothelial proliferation and angiogenesis, with therapeutic application in neoplasia?


Fibrosis (fibroplasia)

  • Emigration and proliferation of fibroblasts at injury site, triggered by multiple growth factors produced by cells in granulation tissue, most important of which is:

  • ECM deposition by fibroblasts: fibrillar collagen synthesis enhanced by growth factors and cytokines, thus converting

Into a


Tissue remodeling

  • Conversion granulation tissue into scar involves changes in composition of ECM.

  • : enzymes which degrade ECM components for remodeling. These enzymes are dependent on ions for activity.


Wound Healing

Healing by first intention

Healing by second intention


Summary: phases of wound healing

Wound tensile strength: 10% of normal at 7 days; 70-80% of normal at 3 months


Factors influencing wound healing

  • Local Factors

    • : most important single cause of delay

    • Mechanical: too early motion can delay

    • Foreign bodies: may impede or cause abscess

    • Location: speed of healing proportional to richness of blood supply:

      face > trunk > extremities

    • Type of wound: primary intention heals faster than secondary intention


Pathologic complications, 2

  • Excessive formation of repair components:

    • Excessive granulation tissue

    • Desmoid tumor (aggressive fibromatosis)

      • Best viewed as low grade neoplasm with stubborn tendency for recurrences


Fibrosis: Summary


Overview: inflammation & repair


Conclusion

  • Physicians stand in wonder at the amazing capacity of the body to restore itself after injury, usually without loss of normal function.

  • This represents an advanced kind of engineering and self-regulated maintenance function that humbles human technology.


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