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

Growth and Repair

dr. FAIRUZ QUZWAIN,SpPA,M.Kes

Kepala bagian Patologi Anatomi

FKIK-UNJA


Repair following inflammation two simultaneous processes

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

Control of cellular population


Cell cycle

Cell Cycle

PHASES of Cell Cycle:

G1:

S:

G2:

M:

G0:


Correlation of cell cycle and tissue types

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

Mechanism: control of cell cycle

Which cyclin ?

Which cyclin?

Cyclin-dependent kinase inhibitors


Modes of intercellular signalling

Modes of Intercellular Signalling

Autocrine

Paracrine

Endocrine


Surface receptors 3 classes

Surface Receptors: 3 classes

Receptors without intrinsic tyrosine kinase

Receptors with intrinsic tyrosine kinase

Seven transmembrane (G protein-coupled)


Consequences of receptor activation

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

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

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

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

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

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

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

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

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

Collagen: summary of major types

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

Genetic deficiency of type IV in:


Collagen synthesis

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

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

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

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

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

Summary: interactions cell-ECM

Major EC structural protein:

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


Overview repair after injury

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

Fibrosis (fibroplasia)

  • Four components:

    • : formation new blood vessels

    • of fibroblasts into damaged tissue

    • of extracellular matrix

    • Organization fibrous tissue =


Sequence of events in repair

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

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

Angiogenesis: 2 mechanisms


Ecm proteins affecting angiogenesis

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 fibroplasia1

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

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

Wound Healing

Healing by first intention

Healing by second intention


Summary phases of wound healing

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

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

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

Fibrosis: Summary


Overview inflammation repair

Overview: inflammation & repair


Conclusion

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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