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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)8/12/2019 Dr.edati-25 March 2013-Inflammation and Repair
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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/Rubor8/12/2019 Dr.edati-25 March 2013-Inflammation and Repair
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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