INFLAMMATION

Dep. Of Pathology Anatomy

Fac. 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
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
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:
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

English Latin
increased blood flow at body core
Redness Rubor* temperature to the inflamed site;
swelling is caused by accumulation of
Swelling Tumor/Turgor*
fluid; pain is due to release of
Heat Calor* chemicals that stimulate nerve
endings. Loss of function has multiple
Pain Dolor*
causes.
Virch
Loss of function Functio laesa** ow
These five signs appear when acute
inflammation occurs on the body's
surface, whereas acute inflammation of
All the above signs may be observed in specific instances, but
internal organs may not result in the full
no single sign must, as a matter of course, be present. These
set. Pain only happens where the
are the original, so called, "cardinal signs" of inflammation.*
appropriate sensory nerve endings exist in
the inflamed area e.g., acute
Functio laesa is a bit of an apocryphal notion, as it is not really inflammation of the lung (pneumonia)
unique to inflammation and is a characteristic of many disease does not cause pain unless the
states.** inflammation involves the parietal pleura,
which does have pain-sensitive nerve
endings.
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
 Vascular Leakage
Increased Vascular Permeability

(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
 Vascular Leakage
Increased Vascular Permeability

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
 Vascular Leakage
Increased Vascular Permeability
Leukocyte-mediated endothelial inury
 Vascular Leakage
Increased Vascular Permeability
Leukocyte-mediated endothelial inury
 Vascular Leakage

Increased Vascular Permeability

Vesiculovacuolar organelle
 Vascular Leakage

Increased Vascular Permeability

Intravascular blood flow
 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
 Extravasation of leukocyte

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
Sequence of leucocytic events in
inflammation
Scanning electron micrograph of
moving leucocyte
The Adhesion Receptors Involved in Leukocyte
Adhesion & Transmigration

1. SELECTIN
2. THE IMMUNOGLOBULIN
FAMILY MOLECULES
3. INTEGRIN
4. 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
 MINI TEST
INFLAMMASI : definisi
Tanda2 klasik radang dan mengapa terjadi
tanda2 tersebut
Perubahan vascular apa yang terjadi
pada radang akut
Rangkaian gerakan leukosit pada radang
 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
Mechanism of phagocytosis
 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
 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

 TYPES OF INFLAMMATION
ACUTE immediate; short duration;
exudative;
Systemically may be
accompanied by fever, leucocyt-
osis especially neutrophil.
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 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
 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.
 1

2
3
Outcomes of acute inflammation
 Chronic inflammation
Collection of inflammatory cells
(monocyte)
Tissue destruction
Replacement by connective tissue
accomplished by angiogenesis &
fibrosis
Three characteristics histologic
pictures in chronic inflammation
Maturation of mononuclear
phagocytes
 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
Morphologic Patterns in acute and
chronic inflammation

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. Increase - 15.000
20.0000 cells/uL, extraordinary 40.000 100.000 leukemoid
reactions TNF & IL-1.Viral infection : lymphocitosis, 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
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
Role of Cyclins
 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
ECM & GF cell growth, motility, differentiation,
protein synthesis
Adhesive Glycoproteins & Integrins
Integrin-mediated signaling complex
Proteoglycan
 Repair by Connective Tissue

1. Formation of new blood vessels

(angiogenesis)
2. Migration and proliferation of fibroblast
3. Deposition of ECM
4. Maturation and organization of the fibrous
tissue remodeling
Angiogenesis
Granulation tissue
Regulation of vascular morphogenesis by receptor tyrosine
kinases and their ligands
Tissue Remodeling: MMP regulation
 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
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
Mechanical factors
Foreign bodies
Size, location, and type of wound
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