dr.edati-25 march 2013-inflammation and repair

8/12/2019 Dr.edati-25 March 2013-Inflammation and Repair

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INFLAMMATIONDepar tment of Pathology Anatom y

Faculty of Medicine

GMU


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Overview of inflammation

Survival all organismsrequireseliminate foreigninvaders e.g. infectious pathogens and damage tissue

These functions are mediated by a complex hostresponse called : INFLAMMATION

Inflammation is a protective response intended toeliminate the initial cause of cell injury as well as thenecrotic cells and tissues resulting from the original insult

Inflammation accomplishes its protective mission bydiluting, destroying, or neutralizing harmful agents(microbes and toxins)


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INFLAMMATION

Local response to injury in a living tissue

Fundamentally a vascular phenomenon

it is is added to base to state condition:

myositis, arthritis, tendinitis, synovitis etc

4 ancient cardinal sign:

- tumorswelling

- ruborredness

- calorwarmth

- dolorpain

+ functiolaesaimpair of function


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Locomotor impaired function

due to :

Pain

Swelling Fibrosis


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Causes

Burns

Chemical irritants

Frostbite

Toxins Infectionby pathogens

Physical injury, blunt or penetrating

Immune reactions due to hypersensitivity

Ionizing radiation Foreign bodies, including splinters, dirt and debris
http://en.wikipedia.org/wiki/Burn_(injury)http://en.wikipedia.org/wiki/Irritationhttp://en.wikipedia.org/wiki/Frostbitehttp://en.wikipedia.org/wiki/Toxinhttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Pathogenhttp://en.wikipedia.org/wiki/Physical_injuryhttp://en.wikipedia.org/wiki/Hypersensitivityhttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Hypersensitivityhttp://en.wikipedia.org/wiki/Physical_injuryhttp://en.wikipedia.org/wiki/Pathogenhttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Toxinhttp://en.wikipedia.org/wiki/Frostbitehttp://en.wikipedia.org/wiki/Irritationhttp://en.wikipedia.org/wiki/Burn_(injury)


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Cardinal sign

The classic signs and symptoms of acute inflammation:

English Latin

Redness Rubor*

Swelling Tumor/Turgor*

Heat Calor*

Pain Dolor*

Loss of function Functio laesa**Virch

ow

All the above signs may be observed in specific instances, but no

single sign must, as a matter of course, be present.These are the

original, so called, "cardinal signs" of inflammation.*

Functio laesa is a bit of an apocryphal notion, as it is not really

unique to inflammation and is a characteristic of many disease

states.**

The first four (classical signs) were described

by Celsus(ca 30 BC38 AD), while loss of

function was added later by Galen[6]even

though the attribution is disputed and the

origination of the fifth sign has also been

ascribed to Thomas

Sydenham[7]and Virchow.[4][5]

Redness and heat are due to

increased blood flow at body core

temperature to the inflamed site;

swelling is caused by accumulation of

fluid; painis due to release of

chemicals that stimulate nerveendings. Loss of function has multiple

causes.

These five signs appear when acute

inflammation occurs on the body's

surface, whereas acute inflammation of

internal organs may not result in the fullset. Pain only happens where the

appropriate sensory nerve endings exist in

the inflamed area e.g., acute

inflammation of the lung (pneumonia)

does not cause pain unless the

inflammation involves the parietal pleura,

which does have pain-sensitive nerve

endings.

Celsus-- Aulus (Aurelius) Cornelius, a Roman physician and

medical writer, who lived from about 30 B.C. to 45 A.D.
http://en.wikipedia.org/wiki/Ruborhttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Heathttp://en.wikipedia.org/wiki/Painhttp://en.wikipedia.org/wiki/Functio_laesahttp://en.wikipedia.org/wiki/Aulus_Cornelius_Celsushttp://en.wikipedia.org/wiki/Galenhttp://en.wikipedia.org/wiki/Pneumoniahttp://en.wikipedia.org/wiki/Thomas_Sydenhamhttp://en.wikipedia.org/wiki/Thomas_Sydenhamhttp://en.wikipedia.org/wiki/Rudolf_Ludwig_Karl_Virchowhttp://en.wikipedia.org/wiki/Rudolf_Ludwig_Karl_Virchowhttp://en.wikipedia.org/wiki/Pneumoniahttp://en.wikipedia.org/wiki/Painhttp://en.wikipedia.org/wiki/Pneumoniahttp://en.wikipedia.org/wiki/Parietal_pleurahttp://en.wikipedia.org/wiki/Parietal_pleurahttp://en.wikipedia.org/wiki/Pneumoniahttp://en.wikipedia.org/wiki/Painhttp://en.wikipedia.org/wiki/Pneumoniahttp://en.wikipedia.org/wiki/Rudolf_Ludwig_Karl_Virchowhttp://en.wikipedia.org/wiki/Rudolf_Ludwig_Karl_Virchowhttp://en.wikipedia.org/wiki/Thomas_Sydenhamhttp://en.wikipedia.org/wiki/Thomas_Sydenhamhttp://en.wikipedia.org/wiki/Pneumoniahttp://en.wikipedia.org/wiki/Galenhttp://en.wikipedia.org/wiki/Aulus_Cornelius_Celsushttp://en.wikipedia.org/wiki/Functio_laesahttp://en.wikipedia.org/wiki/Painhttp://en.wikipedia.org/wiki/Heathttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Rubor


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CLINICAL FEATURES OF

ACUTE INFLAMMATION


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Clinical features of chronic

inflammation


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ABSCES


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INCOMPLETE REPAIR/FIBROSIS


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Microscopic features of acute (left)

and chronic (right) inflammation


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Tissue and cell involvement in inflammatory

event

M h i f i d l


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Mechanisms of increased vascular

permeability in inflammation


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Vascular Leakage

Increased Vascular Permeability

15-30 minutes immediate transient response

(20-60 m)

Cytokines (IL-2, TNF, IFN-) also increase vascular permeabilityby inducinga structural reorganization of cytoskeleton endothelium retract from

one another


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Vascular Leakage

Increased Vascular Permeability

Leukocyte-mediated endothelial injury


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Vascular LeakageIncreased Vascular Permeability

Vesiculovacuolar organelle


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Vascular LeakageIncreased Vascular Permeability


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Acute Inflammation

is the immediateand earlyresponse to aninjurious agent.

Vascular phenomena play a major role :

Alterat ions in vascu lar caliberthat lead toan increase blood flow

Structu ral changesin themicrovasculaturethat permit the plasma

proteins and leucocytes to leave the circulation Emigrat ion of the leukocy tesfrom the

microcirculation and their accumulation in thefocus of injury


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The major local manifestations of acute

inflammation, compared to normal.

(1) Vascular dilation and increased bloodflow (causing erythema and warmth);

(2) extravasation and extravascular

deposition of plasma fluid and proteins

(edema);

(3)leukocyte emigration and accumulation

in the site of injury.


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Extravasation of leukocytethe Sequence of vents1.In the lumen: marginationrolling

adhesionto the endothelium (the

endothelium has to be activated to permit it to

bind leukocyte:as a prelude to their exit from

the blood vessels)

2.Transmigration across the endothelium (also

called diapedesis)3.Migrationin interstitial tissue toward a

chemotactic stimulus


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Sequence of leucocytic events in

inflammation


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Scanning electron micrograph of

moving leucocyte


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The Adhesion Receptors Involved in Leukocyte

Adhesion & Transmigration

1. SELECTIN

2.

THE IMMUNOGLOBULINFAMILY MOLECULES

3. INTEGRIN

4. MUCIN-LIKE GLYCOPROTEN


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Endothelial / leukocyte adhesion molecules

Endothelial Mol. Leukocyte Rec. Major role

P-Selectin Sialyl-Lewis X Rolling

PSGL-1

E-Selectin Sialyl-Lewis X Rolling, adhesion

ESL-1,PSGL-1

ICAM-1 CD11/CD18(integrin) Adh,arrest,transm

(LFA-1,Mac-1)

VCAM-1 alphaB1(VLA4) adhesion

(integrin)

alpha B7(LPAM-1)

GlyCam-1 L-selectin Lymphocytehoming

CD34 to high end.venules


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Cells of the inflammatory process

Neutrophilsphagocytize a foreign materiale.g.bacteria, and then attempt to oxidize anddigest it through oxidase and protease. To beseen particularly in acute phase

Eosinophilsalso phagocytic and posessmany enzymes of the neutrophil, also can

dispense antihistamine in an area of histaminerelease, and these cells is associated withallergic responses. It is seen in both acute andchronic inflammation


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Biochemical events in leucocyte activation


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Cells of the inflammatory process

Simple-appearing cells with varied and complexfunctions

Briefly, some lymphocytes are in the T-cell system and

produce various types of lymphokine, which have localeffect

Immunoglobulins or antibodiescan also be produced by

this cells as a B cells

Characterizes chronic inflammation, antibody productionis the function of the plasma cells, a specialized B cell. Itis particularly prominent in chronic inflammation involving

mucosal surfaces


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Cells in the inflammatory process . .cont

Macrophagphagocytosis of foreign

material and antigen processing

Communicates with immune system as a

part of antigen processing

Enzymes also present in the macrophage

to digest foreign material

Appear in late stages of acute

inflammation and are present during

chronic inflammation


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Mechanism of phagocytosis


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Cells of inflammation

CELL ACTIVITY PHAGOCYTOSIS INFLAMMATION

---------------------------------------------------------------------------------------------------------

NEUTROPHIL PROTEASES, OXIDASES + ACUTE

EOSINOPHIL ANTIHISTAMINE + ACUTE, CHRONIC

MACROPHAG ANTIGEN PROCESSING, + LATE ACUTE, CHRONIC

DIGESTION

LYMPHOCYTE LYMPHOKINES - CHRONIC

PLASMA CELL ANTIBODY PRODUCTION - CHRONIC


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TYPES OF INFLAMMATION ACUTEimmediate; short duration;

exudative;- Systemically may be

accompanied by fever, leucocytosisespecially neutrophil.

- Locally, it is vascular response

to injuryarteriolar

vasocontriction, followed by

vasodilatation and > vascular

permeabilities

CHRONIClong duration,

proliferative of cells


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Histopathology of acute inflammation


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Characteristics of transudate,

exudate and pus

FLUID TYPE CONDITION CONTENT SPECIFIC

GRAVITY

---------------------------------------------------------------------------------------------------------------------

TRANSUDATE INCREASED HYDROSTATIC LOW PROTEIN < 1.020

PRESSURE

EXUDATE ACUTE INFLAMMATION HIGH PROTEIN > 1.O20

PUS ACUTE INFLAMMATION HIGH PROTEIN + > 1.020

NEUTROPHILS


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Chemical Mediators


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Chemical Mediators Mediators originate either from plasma and from cells

Mediators perform their biologic activity by binding to specificreceptors on target cells. But some have direct enzymaticactivity or mediate oxidative damage

A chemical mediator can stimulate the release of mediators bytarget cells themselves

Mediators can act on one or few target cell types

Once activated and released from the cell, most of thesemediators are short-lived

Most mediators have the potential to cause harmful effects


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MEDIATOR OF ACUTE

INFLAMMATIONMEDIATOR VASODILATATION INCREASED PERMEABILITY CHEMOTAXIS OPSONIN PAIN

---------------------------------------------

IMMEDIATE SUSTAINED

--------------------------------------------------------------------------------------------------------------------------------------------------------------

HISTAMINE + +++ _ _ _ _

SEROTONIN(5-HT) + + _ _ _ _

BRADYKININ + + _ _ _ +++

COMPLEMENT 3a _ + _ _ _ _

COMPLEMENT 3b _ _ _ _ +++ _

COMPLEMENT 5a _ ++ _ +++ _ _

PROSTAGLANDINS +++ +++ + ? +++ _ ++

LEUKOTRIENES _ +++ + ? +++ _ _

LYSOSOMAL

PROTEASES _ _ ++ _ _ _

OXYGEN RADICALS _ _ ++ _ _ _

--------------------------------------------------------------------------------------------------------------------------------------------------------------


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MEDIATORS OF CHRONIC

INFLAMMATION

AGENT ACTION SOURCE

-----------------------------------------------------------------------------------------------

Migration inhibition Aggregation of Activated T

Factor (MIF) macrophages at lymphocytes

site of injuryMacrophage Increased Activated T

Activation factor phagocytosis by lymphocytes

(MAF) macrophages

Complement 5a Chemotactic for Complement

macrophages systemEosinophil chemo- Chemotactic for Mast cells and

Tactic factor of eosinophils in basophils

Anaphylaxis(ECF-A) metazoan infections


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Events in the resolution of

inflammation


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Summary of the acute inflammatory

response

Vascular phenomenaDilatation of arteriolar and capillary beds - increasedbloodflow to the injured area

Increased vascular permeabilityExudate

Leukocyte activityadhesion molecule,transmigrate, migrate to the site of injury;

phagocytosis of the offending agents

During chemotaxis and phagocytosis activated

leukocyte may released toxic metabolites andproteases extracellulary, potentially causing tissuedamage.

1


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Outcomes of acute inflammation

1

2

3


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Chronic inflammation

Collection of inflammatory cells

(monocyte)lymphocytes ,

plasma cells

Tissue destruction

Replacement by connective tissue

accomplished by angiogenesis &fibrosis

Th h t i ti hi t l i


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Three characteristics histologic

pictures in chronic inflammation

M h l h t


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Macrophage-lymphocyte

interaction in chronic inflammation

Activated

lymphocytes and

macrophages

influence each other

and also release

inflammatory

mediators that affect

other cells


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Granulomatous Inflammation

is a distinctive pattern of chronic inflammationcharacterized by aggregates of activatedmacrophages that assume an epitheloid appearance.

Ex. : - TBC

- Leprosy- Syphillis

- Cat scratch disease

- Sarcoidosis

If granuloma develop in response to foreign bodies(suture or splinter), forming Foreign bodies granuloma

Granuloma chronic inflammation


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Granuloma, chronic inflammation

ex. TBC - TUBERCEL

Central necrosis

Epitheloid cells

Langhans type

giant cells

Lymphocytes

SUMMARY


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SUMMARYFeatures of Chronic Inflammation

Prolonged host response to persistent stimulus

Caused by microbes that resist elimination, immune

responses against self and environmental antigens, and

some toxic substances (e.g. silica)

Characterized by coexisting inflammation, tissue injury,

attempted repair by scarring, and immune response

Cellular infiltrate consists of macrophages, lymphocytes,

plasma cells, fibrosis is often prominent

Mediated by cytokines produced by macrophages and T

cell lymphocytestend to amplify and prolong

inflammatory reaction


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Nature of leukocyte infiltrates in inflammatory reactions.

The photomicrographs are representative of

- the early (neutrophilic) (A) and

- later (mononuclear) cellular infiltrates (B) seen in an inflammatory reaction in the

myocardium following ischemic necrosis (infarction).

- The kinetics of edema and cellular infiltration (C) are approximations.

M h l i P tt i t d


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Morphologic Patternsin acute and

chronic inflammation

Serous

Fibrinous

Suppurative or Purulent

Cattarhalis

Pseudomembrane

Sanguinis / haemorrhagic

Ulcers

S i fl ti


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Serous inflammation

Low power view of a cross section of askin- blister showing the epidermis

separated from the dermis by a focalcollection of serous effusion


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Fibrinous Pericarditis

A, Deposits of fibrin on the pericardium. B, a pink meshwork offibrin exudate (F) overlies the pericardial surface (P)


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Suppurative Inflammation

A, a subcutaneous bacterial abscess with collection of pus. B, the abscesscontains neutrophils, edema fluid, and cellular debris


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The morphology of an ulcer

A, chronic duodenal ulcer. B, low-power cross-section of duodenalulcer crater with an acute inflammatory excudate in the base.


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Systemic effectsof Inflammation Feveracute phase reaction ( Endocrine

and metabolic, Autonomic, Behavioral )

Leukocytosisesp. bacterial infection - neutrophilia. Leukocyte Increase ( N :

3.600

11.000 ) - 15.000

20.0000 cells/uL, extraordinary 40.000100.000 leukemoid reactions TNF & IL-1.

Viral infection : lymphocytosis,

Asthma, hay fever, parasite inf. - eosinophillia,

Typhoid, certain viral viruses, rickettsiae, certain protozoaleukopenia.

Other manifestation : increased heart rate & blood pressure,decreased sweating, shivering, chills, anorexia, somnolense, malaiseprobably cytokin in brain.

reactive, degenerative,septicaemia, pyaemia, bacteriamia


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TISSUE REPAIR


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TISSUE REPAIR

Restoration of normal structure

- occurs when the connective tissue

infrastructure remains relatively

intact

- requires that the surviving affected

parenchymal cells have the capacityto regenerate


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REPAIR

Two distinct processes:Regeneration

Replacement of injured cells by cells of the sametype

Fibroplasia / fibrosis

Replacement of injured cells by connective tissue

cell migrationcell proliferation & differentiation

cell-matrix interaction

repair

M h i l ti ll l ti


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Mechanism regulating cell populations


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Cell Cycle and Proliferative Potential

1. Labile cells

2. Stable cells

3. Permanent cells

Cell-groups based on the proliferative capacity


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Cell-groups based on the proliferative capacity

Continuously dividing cells (labile cells)

- Surface epithelia of the skin, oral cavity, vagina, cervix- The lining mucosa of the excretory ducts of glands:

pancreas, salivary glands, biliary tract

- Columnar epithelium of the gastrointestinal tract and

uterus

- Transitional epithelium of urinary tract- Cells of the bone marrow and hematopoietic tissue

Quiescent / stable cells (low level replication)- Parenchymal cells: liver, kidney, pancreas

- Mesenchymal cells: fibroblast, smooth muscle- Vascular endothelial cells

Nondividing / permanent cells- Neurons, skeletal muscle, heart, muscle

M l l E t i C ll G th


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Molecular Events in Cell Growth

Cell Signaling (autocrine, paracrine, endocrine)

Cell Surface Receptors

- Receptors with intrinsic kinase activity

- Receptors without intrinsic catalytic activity

- G Protein-Linked Receptors

Signal Transduction System

- MAP-kinase pathway

- PI-3 kinase pathway

- IP3pathway

- cAMP pathway

- JAK/STAT pathway

Cell surface receptors and principal signal


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Cell surface receptors and principal signal

transduction pathways

G l P tt f I t ll l Si li


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General Patterns of Intracellular Signaling


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Cell-matrix interaction

Intimate contact with ECM cells grow, move,

and differentiate

3 groups of macromolecules ECM

1. fibrous structural proteins: collagens &elastins

2. diverse group of adhesive glycoprotein:

fibronectin, laminin3. gel of proteoglycans and hyaluronan


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ECM & GF cell growth motility differentiation


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ECM & GFcell growth, motility, differentiation,

protein synthesis


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Repair by Connective Tissue

1. Formation of new blood vessels(angiogenesis)

2. Migration and proliferation of fibroblast

3. Deposition of ECM4. Maturation and organization of the fibrous

tissueremodeling

Angiogenesis


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Angiogenesis


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Granulation tissue

Regulation of vascular morphogenesis by receptor tyrosine


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kinases and their ligands


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WOUND HEALING

W d H li


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Wound Healing:a complex but orderly phenomenon involving a number of processes

Induction of an acute inflammatory process by the

initial injury

Regeneration of parenchymal cells

Migration and proliferation of both parenchymal andconnective tissue cells

Synthesis of ECM proteins

Remodeling of connective tissue and parenchymalcomponents

Collagenization and acquisition of wound strength

Wound Healing


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Wound Healing

Penyembuhan primer


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yContoh : Insisi bedah yang bersih dan tidak terinfeksi di sekitar jahitan bedah

24 jamneutrofil pd tepi insisi, migrasi menuju bekuan fibrin,sel basal pada tepi irisan epidermis mulai mitosis

2448 jam sel epitel kedua tepi irisan migrasi dan proliferasi

sepanjang dermis dan mendepositkan MB. Sel tsb

bertemu di garis tengah dibawah keropeng permukaan

menghasilkan lapisan epitel tipis yg tidak putus

Hari ke 3neutrofil digantikan makrofag , jar. Granulasi terbentuk

kolagen muncul vertikal, proliferasi epitel berlanjut

Hari ke 5Neovaskularisasi, jar. Granulasi mengisi ruang insisi

Serabut kolagen berlimpah menjembatani ruang insisi

Epidermis mengembalikan ketebalan normal dg deferensiasi

Minggu ke 2penumpukan kolagen dan proliferasi fibroblas berlanjutinfiltrasi lekosit dan vaskularisasi telah amat berkurang.

deposisi kolagen dan regresi pembuluh darah

Akhir bulan pertamaJaringa parut td. Jaringan ikat tanpa sel radang ditutupi

epidermis normal

Penyembuhan Sekunder


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Penyembuhan Sekunder

Jika luka luas, destruksi jaringan banyak, proses penyembuhan menjadi

lebih kompleks

Regenerasi parenkhim saja tidak dapat mengembalikan arsitektur asal.

Akibatnya : terjadi pertumbuhan jaringan granulasi luas ke arah dalam dari

tepi luka, diikuti penumpukan ECM serta pembentukan jaringan parut.

Bentuk ini disebut sebagai penyatuan sekunder, atau penyembuhansekunder.

Secara intrinsik, kerusakan jaringan luas membuat debris nekrotik, eksudat,

dan fibrin yang lebih banyak yang harus disingkirkan

o Jaringan granulasi akan terbentuk lebih luas, lebih besar

o Penyembuhan sekunder menimbulkan fenomena kontraksi lukadlm 6mgg kerusakan kulit luas dapat berkurang 5-10% ukuran semula, terutama

melalui kontraksioleh karena adanya miofibroblas

K k t L k


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Kekuatan Luka

Luka yang dijahit cermat70% kekuatan semula

Jika jahitan dilepas (1 mgg ) kekuatan luka menjadi 10%dari kekuatan kulit yang tidak terluka, tetapi kekuatan inimeningkat cepat dalam waktu 4 mgg berikutnya

Pemulihan kekuatan regangan diakibatkan sintesiskolagen yang melebihi degradasinya selama 2 blnpertama dan oleh perubahan struktural kolagen ketikasintesisnya berkurang di saat selanjutnya.

Kekuatan luka mencapai + 70-80% dari normal padabulan ke-3, tetapi biasanya tidak akan meningkatmelebihi angka tersebut


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Orderly Phases of Wound Healing

BONE HEALING


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BONE HEALING


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L l f t i fl h li


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Local factors influence healing

Infection

Mechanical factors

Foreign bodiesSize, location, and type of wound

f


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Pathologic Aspects of Wound Repair

Deficient scar formation

- wound dehiscence

- ulceration

Excessive formation of the repaircomponents

- hypertrophic scar

- exuberant granulation- desmoid (aggressive

fibromatosis)

Formation of contractures

deformities of the wound and

surrounding tissue

REFERENCES


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REFERENCES

Pathologic basis of disease, Robbins andCotran, 8thed. 2010

General and systemic Pathology,

Underwood, 5thed. 2009

Pathology, Rubbin, 2006

Pathology illustrated, Reids/Robert, 6thed.

2005


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Thank you

dr.edati-25 march 2013-inflammation and repair

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