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INFLAMMATION

Department of Pathology Anatomy Faculty of Medicine GMU

Overview of inflammation

Survival all organisms requires eliminate foreign invaders e.g. infectious pathogens and damage tissue These functions are mediated by a complex host response called : INFLAMMATION

Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult Inflammation accomplishes its protective mission by diluting, destroying, or neutralizing harmful agents (microbes and toxins)

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: - tumor swelling - rubor redness - calor warmth - dolor pain + functiolaesaimpair of function

Locomotor impaired function due to :


Pain Swelling Fibrosis

Causes
Burns

Chemical irritants Frostbite Toxins Infection by pathogens Physical injury, blunt or penetrating Immune reactions due to hypersensitivity Ionizing radiation Foreign bodies, including splinters, dirt and debris

Cardinal sign
English Redness Swelling Heat Pain
Loss of function

Celsus -- Aulus (Aurelius) Cornelius, a Roman physician and medical writer, who lived from about 30 B.C. to 45 A.D.
The classic signs and symptoms of acute inflammation: Latin Rubor* Tumor/Turgor* Calor* Dolor* Functio laesa** ow
Virch

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; pain is due to release of chemicals that stimulate nerve endings. 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 full set. 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.

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.**

CLINICAL FEATURES OF ACUTE INFLAMMATION

Clinical features of chronic inflammation

ABSCES

INCOMPLETE REPAIR/FIBROSIS

Microscopic features of acute (left) and chronic (right) inflammation

Tissue and cell involvement in inflammatory event

Mechanisms of increased vascular permeability in inflammation

Increased Vascular Permeability

Vascular Leakage

(20-60 m)

15-30 minutes immediate transient response Cytokines (IL-2, TNF, IFN-) also increase vascular permeabilityby inducing a structural reorganization of cytoskeleton endothelium retract from one another

Increased Vascular Permeability

Vascular Leakage

Resulting in endothelial cells necrosis and detachment

Immediate sustained response

All levels of of the microcirculation are affected, including venules, capillaries, and arterioles
DELAYED Sunburn

Increased Vascular Permeability

Vascular Leakage

Leukocyte-mediated endothelial injury

Vascular Leakage

Increased Vascular Permeability

Vesiculovacuolar organelle

Vascular Leakage

Increased Vascular Permeability

Acute Inflammation

is the immediate and early response to an injurious agent. Vascular phenomena play a major role : Alterations in vascular caliber that lead to
an increase blood flow

Structural changes in the microvasculature that permit the plasma


proteins and leucocytes to leave the circulation Emigration of the leukocytes from the microcirculation and their accumulation in the focus of injury

The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (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.

the Sequence of Events


1.In the lumen: margination rolling adhesion to 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.Migration in interstitial tissue toward a chemotactic stimulus

Extravasation of leukocyte

Sequence of leucocytic events in inflammation

Scanning electron micrograph of moving leucocyte

The Adhesion Receptors Involved in Leukocyte Adhesion & Transmigration


1. 2.

3.
4.

SELECTIN THE IMMUNOGLOBULIN FAMILY MOLECULES INTEGRIN MUCIN-LIKE GLYCOPROTEN

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 Lymphocyte homing CD34 to high end.venules

Cells of the inflammatory process

Neutrophils phagocytize a foreign material e.g.bacteria, and then attempt to oxidize and digest it through oxidase and protease. To be seen particularly in acute phase Eosinophils also phagocytic and posess many enzymes of the neutrophil, also can dispense antihistamine in an area of histamine release, and these cells is associated with allergic responses. It is seen in both acute and chronic inflammation

Biochemical events in leucocyte activation

Cells of the inflammatory process

Simple-appearing cells with varied and complex functions Briefly, some lymphocytes are in the T-cell system and produce various types of lymphokine, which have local effect Immunoglobulins or antibodies can also be produced by this cells as a B cells Characterizes chronic inflammation, antibody production is the function of the plasma cells, a specialized B cell. It is particularly prominent in chronic inflammation involving mucosal surfaces

Cells in the inflammatory process . .cont Macrophag phagocytosis 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

Mechanism of phagocytosis

Cells of inflammation
CELL
NEUTROPHIL EOSINOPHIL MACROPHAG

ACTIVITY
PROTEASES, OXIDASES ANTIHISTAMINE ANTIGEN PROCESSING, DIGESTION

PHAGOCYTOSIS INFLAMMATION
+ + + ACUTE ACUTE, CHRONIC LATE ACUTE, CHRONIC

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

LYMPHOCYTE LYMPHOKINES

CHRONIC

PLASMA CELL ANTIBODY PRODUCTION

CHRONIC

ACUTE immediate; short duration; exudative; - Systemically may be accompanied by fever, leucocytosis especially neutrophil.

TYPES OF INFLAMMATION

- Locally, it is vascular response to injury arteriolar vasocontriction, followed by vasodilatation and > vascular permeabilities

CHRONIC long duration, proliferative of cells

Histopathology of acute inflammation

Characteristics of transudate, exudate and pus


FLUID TYPE SPECIFIC GRAVITY --------------------------------------------------------------------------------------------------------------------TRANSUDATE
INCREASED HYDROSTATIC PRESSURE LOW PROTEIN < 1.020

CONDITION

CONTENT

EXUDATE

ACUTE INFLAMMATION

HIGH PROTEIN

> 1.O20

PUS

ACUTE INFLAMMATION

HIGH PROTEIN + NEUTROPHILS

> 1.020

Chemical Mediators

Chemical Mediators

Mediators originate either from plasma and from cells Mediators perform their biologic activity by binding to specific receptors on target cells. But some have direct enzymatic activity or mediate oxidative damage A chemical mediator can stimulate the release of mediators by target cells themselves Mediators can act on one or few target cell types Once activated and released from the cell, most of these mediators are short-lived Most mediators have the potential to cause harmful effects

Chemical Mediator

MEDIATOR OF ACUTE INFLAMMATION


MEDIATOR 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 _ _ ++ _ _ _ --------------------------------------------------------------------------------------------------------------------------------------------------------------

MEDIATORS OF CHRONIC INFLAMMATION


AGENT ACTION SOURCE

----------------------------------------------------------------------------------------------Migration inhibition Aggregation of Activated T Factor (MIF) macrophages at lymphocytes site of injury Macrophage Increased Activated T Activation factor phagocytosis by lymphocytes (MAF) macrophages Complement 5a Chemotactic for Complement macrophages system Eosinophil chemo- Chemotactic for Mast cells and Tactic factor of eosinophils in basophils Anaphylaxis(ECF-A) metazoan infections

Events in the resolution of inflammation

Summary of the acute inflammatory response

Vascular phenomena Dilatation of arteriolar and capillary beds - increased bloodflow to the injured area Increased vascular permeability Exudate

Leukocyte activity adhesion molecule, transmigrate, migrate to the site of injury; phagocytosis of the offending agents During chemotaxis and phagocytosis activated leukocyte may released toxic metabolites and proteases extracellulary, potentially causing tissue damage.

2 3 Outcomes of acute inflammation

Chronic inflammation

Collection of inflammatory cells (monocyte) lymphocytes , plasma cells Tissue destruction Replacement by connective tissue accomplished by angiogenesis & fibrosis

Three characteristics histologic pictures in chronic inflammation

Macrophage-lymphocyte interaction in chronic inflammation

Activated lymphocytes and macrophages influence each other and also release inflammatory mediators that affect other cells

Granulomatous Inflammation
is a distinctive pattern of chronic inflammation characterized by aggregates of activated macrophages 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 ex. TBC - TUBERCEL

Central necrosis Epitheloid cells Langhans type giant cells Lymphocytes

SUMMARY
Features 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 lymphocytes tend to amplify and prolong inflammatory reaction

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.

Morphologic Patterns in acute and chronic inflammation


Serous Fibrinous Suppurative or Purulent Cattarhalis Pseudomembrane Sanguinis / haemorrhagic Ulcers

Serous inflammation

Low power view of a cross section of a skin- blister showing the epidermis separated from the dermis by a focal collection of serous effusion

Fibrinous Pericarditis

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

Suppurative Inflammation

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

The morphology of an ulcer

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

Systemic effects of Inflammation

Fever acute phase reaction ( Endocrine and metabolic, Autonomic, Behavioral )


Leukocytosis
esp. bacterial infection - neutrophilia. Leukocyte Increase ( N : 3.600 11.000 ) - 15.000 20.0000 cells/uL, extraordinary 40.000 100.000 leukemoid reactions TNF & IL-1. Viral infection : lymphocytosis, Asthma, hay fever, parasite inf. - eosinophillia, Typhoid, certain viral viruses, rickettsiae, certain protozoa leukopenia.

Other manifestation : increased heart rate & blood pressure,


decreased sweating, shivering, chills, anorexia, somnolense, malaise probably cytokin in brain. reactive, degenerative,septicaemia, pyaemia, bacteriamia

TISSUE REPAIR

TISSUE REPAIR

Restoration of normal structure - occurs when the connective tissue infrastructure remains relatively intact - requires that the surviving affected parenchymal cells have the capacity to regenerate

REPAIR
Two distinct processes: Regeneration Replacement of injured cells by cells of the same type Fibroplasia / fibrosis Replacement of injured cells by connective tissue
cell migration cell proliferation & differentiation cell-matrix interaction

repair

Mechanism regulating cell populations

Cell Cycle and Proliferative Potential


1. Labile cells

2. Stable cells 3. Permanent cells

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

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 - IP3 pathway - cAMP pathway - JAK/STAT pathway

Cell surface receptors and principal signal transduction pathways

General Patterns of Intracellular Signaling

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, laminin 3. gel of proteoglycans and hyaluronan

MINI TEST
1. Histamin akan memberi tipe endothelial leaking apa ? 2. Seorang laki2 44 th dengan gingivitis Tuberkulosa, bila di biopsi, bagaimana gambaran mikroskopiknya ? 3. Periodontitis supurativa, eksudatny apa dan bagaimana gambaran mikroskopiknya ? 4. Beda eksudat dan transudat ? 5. Apa saja tanda kardinal radang, berikan gambaran klinik nya dan mekanisme nya.

ECM & GF cell growth, motility, differentiation, protein synthesis

Repair by Connective Tissue


1. 2. 3. 4.

Formation of new blood vessels (angiogenesis) Migration and proliferation of fibroblast Deposition of ECM Maturation and organization of the fibrous tissue remodeling

Angiogenesis

Granulation tissue

Regulation of vascular morphogenesis by receptor tyrosine kinases and their ligands

WOUND HEALING

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 and connective tissue cells Synthesis of ECM proteins Remodeling of connective tissue and parenchymal components Collagenization and acquisition of wound strength

Wound Healing

Penyembuhan primer
Contoh : Insisi bedah yang bersih dan tidak terinfeksi di sekitar jahitan bedah 24 jam neutrofil pd tepi insisi, migrasi menuju bekuan fibrin, sel basal pada tepi irisan epidermis mulai mitosis 24 48 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 3 neutrofil digantikan makrofag , jar. Granulasi terbentuk kolagen muncul vertikal, proliferasi epitel berlanjut Hari ke 5 Neovaskularisasi, jar. Granulasi mengisi ruang insisi Serabut kolagen berlimpah menjembatani ruang insisi Epidermis mengembalikan ketebalan normal dg deferensiasi Minggu ke 2 penumpukan kolagen dan proliferasi fibroblas berlanjut infiltrasi lekosit dan vaskularisasi telah amat berkurang. deposisi kolagen dan regresi pembuluh darah Akhir bulan pertama Jaringa parut td. Jaringan ikat tanpa sel radang ditutupi epidermis normal

Penyembuhan Sekunder

o o

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 penyembuhan sekunder. Secara intrinsik, kerusakan jaringan luas membuat debris nekrotik, eksudat, dan fibrin yang lebih banyak yang harus disingkirkan Jaringan granulasi akan terbentuk lebih luas, lebih besar Penyembuhan sekunder menimbulkan fenomena kontraksi luka dlm 6 mgg kerusakan kulit luas dapat berkurang 5-10% ukuran semula, terutama melalui kontraksi oleh karena adanya miofibroblas

Kekuatan Luka

Luka yang dijahit cermat 70% kekuatan semula Jika jahitan dilepas (1 mgg ) kekuatan luka menjadi 10% dari kekuatan kulit yang tidak terluka, tetapi kekuatan ini meningkat cepat dalam waktu 4 mgg berikutnya Pemulihan kekuatan regangan diakibatkan sintesis kolagen yang melebihi degradasinya selama 2 bln pertama dan oleh perubahan struktural kolagen ketika sintesisnya berkurang di saat selanjutnya. Kekuatan luka mencapai + 70-80% dari normal pada bulan ke-3, tetapi biasanya tidak akan meningkat melebihi angka tersebut

Orderly Phases of Wound Healing

BONE HEALING

Systemic factors influence healing


Nutrition (deficiency vitamine C) Metabolic status (DM) Circulatory status Hormones (glucocorticoid inhibit collagen synthesis)

Local factors influence healing


Infection

factors Foreign bodies Size, location, and type of wound

Mechanical

Pathologic Aspects of Wound Repair

Deficient scar formation - wound dehiscence - ulceration Excessive formation of the repair components - hypertrophic scar - exuberant granulation - desmoid (aggressive fibromatosis) Formation of contractures deformities of the wound and surrounding tissue

REFERENCES
Pathologic basis of disease, Robbins and Cotran, 8th ed. 2010 General and systemic Pathology, Underwood, 5th ed. 2009 Pathology, Rubbin, 2006 Pathology illustrated, Reids/Robert, 6th ed. 2005

Thank you

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