Acute and Chronic Inflammation02

7/28/2019 Acute and Chronic Inflammation02

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Tissue Repair

Banun Kusumawardani

Dept. Biomedic-Faculty of Dentistry

Univ. Jember

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Assigned Reading

Chapter 3, Tissue renewal and repair in

Robbins and Cotran Pathologic Basis of

Disease, 7th Edition, p 87-118.

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Repair

Regeneration of injured cells by cells ofsame type as with regeneration of

skin/oral mucosa (requires basement

membrane) Replacementby fibrous tissue

(fibroplasia, scar formation)

Both require cell growth, differentiation,and cell-matrix interaction

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Tissue

response to

injury. Repair

after injurycan occur by

regeneration

, which

restores

normaltissue, or by

healing,

which leads

to scar

formation

and fibrosis

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Tissue Regeneration

Controlled by biochemical factors

released in response to cell injury, cell

death, or mechanical trauma Most important control: inducing resting

cells to enter cell cycle

Balance of stimulatory or inhibitory factors Shorten cell cycle

Decrease rate of cell loss5


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Mechanisms

regulating cellpopulations. Cell

numbers can be

altered by

increased ordecreased rates of

stem cell input, by

cell death due to

apoptosis, or by

changes in the

rates of proliferation

or differentiation

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Tissue-Proliferative Activity

Labile (always dividing) cells:

Replace dying cells

Epithelia: skin, oral cavity, exocrine ducts,GI tract, hematopoietic

Stable (quiescent) cells:

Usually G0 and low rate of division Driven into G1 and rapid proliferation

Liver, kidney, pancreas, endothelium,

fibroblasts 7


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Tissue-Proliferative Activity

(Contd) Permanent (non-dividing ) cells:

Permanently removed from cell cycle

Irreversible injury leads only to scar

Nerve cells, myocardium

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Normal cell proliferation and cell cycle

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Intercellular Signaling

3 pathways

Autocrine: cells have receptors for their

own secreted factors (liver regeneration) Paracrine: cells respond to secretion of

nearby cells (healing wounds)

Endocrine: cells respond to factors(hormones) produced by distant cells

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Growth Factors and Molecular

Events Polypeptide growth factors (e.G.,

PDGF, FGF, TGF-)with many

(pleiotropic) effects Proliferation, migration, differentiation,

remodeling (all part of wound healing)

Gene expression (protooncogenes) Sequence of events in factor signaling

Receptor binding (ligation)

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Molecular Events

Receptor activation: monomers >

dimerization > autophosphorylation

Signal transduction and secondmessengers (e.g., GTP-binding proteins,

phospholipases, MAP kinases)

Induce expression of transcription factor

genes (e.g., myc, fos, jun)

Cell cycle (growth) regulated by cyclins

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Extracellular Matrix (ECM)

ECM provides turgor, rigidity, support,

adhesion substrate, reservoir for factors

ECM must remain intact forparenchymal healing

Three ECM protein components

Collagens: most common; triple helix of

polypeptide chains; extracellular framework

of body

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ECM (Contd)

14 types

I-III: interstitial/fibrillar, most abundant

IV-VI: non-fibrillar, basement membranesAdhesive glycoproteins: e.g., Laminin,

fibronectin, thrombospondin, integrins

which bind ECM components to each

other, and to other cells

Proteoglycans: sugars linked to proteins;

influence ECM permeability and structure

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Major components of the extracellular matrix (ECM), including collagens,

proteoglycans, and adhesive glycoproteins. Both epithelial and mesenchymal

cells (e.g., fibroblasts) interact with ECM via integrins. To simplify the

diagram, many ECM components (e.g., elastin, fibrillin, hyaluronan,syndecan) are not included16


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Steps in collagen synthesis17


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Connective Tissue Repair

(Scar Formation) Loss of parenchyma andECM

Formation of new blood vessels

(angiogenesis), fibroblast migration andproliferation (lay down collagen) < 24 hr

Granulation tissue: pink, soft, granular

grossly

Maturation and organization

(remodeling) of fibrous tissue18


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Angiogenesis

Vessels derive from endothelial cell

precursors (angioblasts) or from

budding of pre-existing vessels BM degradation

Endothelial migration

Endothelial proliferation Endothelial maturation

Periendothelial cell recruitment (pericytes,

smooth muscle) 19


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Steps in the process of angiogenesis

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Fibrosis (Fibroplasia)

Occurs within the granulation tissueframework (new blood vessels and

loose ECM)

Proliferation of fibroblasts at site ofinjury

Growth factors (TGF-, PDGF, EGF,

FGF) Cytokines (IL-1, TNF-)

Deposition of ECM (collagen)

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Scar Remodeling

Remodeling to strengthen repair

Metalloproteinases (interstitial

collagenases, gelatinases, stromelysins) Produced by macrophages, neutrophils,

fibroblasts as inactive precursors

In response to local factors Debris carried away by phagocytes

(debridement)

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Phase of wound healing

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Wound Healing: Primary Union

Clean incision

Line of closure fills with clotted blood

Dehydration at surface creates scab

24 hr: neutrophils, mitoses of basal

epithelium

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(Contd) 1 - 2 days: epithelial basal cells grow

along cut dermis

3 days: neutrophils gone,

macrophages enter, granulationtissue forms

5 days: space filled with granulation

tissue and collagen fibrils bridge lineof closure, epidermis at pre-incision

thickness

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(Contd) Week 2: accumulation of collagen,

fibroblasts, and blanching begins

(edema and inflammation reduced) End of first month: connective tissue

devoid of inflammation; epidermis intact

Tensile strength increases to 70 - 80%of unwounded skin in 3 months

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Wound Healing: Secondary

Union Large tissue defect

More inflammation

More granulation tissue

Wound contraction - myofibroblasts

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Host Factors Influence

Inflammation and Repair

Nutrition

Steroids Infection

Mechanical factors

Blood supply

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Aberrations of Inflammation and

Repair Inadequate scar formation

Wound dehiscence

Ulceration

Hypertrophic scar/keloid

Exuberant granulation tissue - proudflesh

Wound contracture

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Summary

Wound healing as evolving, changing

process

Various mechanisms involved

Various mediators

Orderly movement, proliferation, and

differentiation of cells

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Development of fibrosis in chronic inflammation. The persistent stimulus ofchronic inflammation activates macrophages and lymphocytes, leading to the

production of growth factors and cytokines, which increase the synthesis of

collagen. Deposition of collagen is enhanced by decreased activity of

metalloproteinases

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Thank you

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Acute and Chronic Inflammation02