Inflammation: A Protective Response to Tissue Injury

INFLAMMATION
Presented by- Dr. SHILPY JAIN

CONTENT
• INTRODUCTION
• DEFINITION
• ROLE OF INFLAMMATION
• SIGNS OF INFLAMMATION
• ETIOLOGY
• VASCULAR EVENTS
• CELLULAR EVENTS
• CHEMICAL MEDIATORS OF ACUTE INFLAMMATION
• SEQUELAE OF ACUTE INFLAMMATION
• MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION
• EFFECTS OF ACUTE INFLAMMATION
• ACUTE INFLAMMATORY LESIONS OF THE ORAL CAVITY
• CHRONIC INFLAMMATION
• GRANULOMATOUS INFLAMMATION
• REFERENCES

INTRODUCTION
• Derived from the latin word INFLAMMARE ( to
set on fire).
• Inflammation is a protective response to tissue
injury.
Kumar, Abbas, Aster (2013) Robbins Basic Pathology, 9th Edition

DEFINITION
• Inflammation is a protective response involving
host cells, blood vessels, proteins and other
mediators that is intended to eliminate the initial
cause of cell injury, as well as the necrotic cells and
tissues resulting from the injury, and to initiate the
process of repair.

ROLE OF INFLAMMATION
WHY IT IS A PROTECTIVE OR DEFENSIVE
PROCESS?
• It removes or destroys the causative agents.
• Repairs tissue damage
• Inactivate toxins
• Prepare tissue or organ for healing and repair

WHAT WOULD HAPPEN WITHOUT
INFLAMMATION?
• Infections would go unchecked
• Wounds would never heal
• Injured organs may remain
permanently damaged.

SIGNS OF INFLAMMATION:
• Heat (calor)
• Redness (rubor)
• Swelling (tumor)
• Pain (dolor)
• Loss of Function (functio laesa)
GIVEN BY
CELSUS
GIVEN BY
RUDOLF
VIRCHOW
Due to the movement of plasma fluids, proteins, and inflammatory
cells from the lumen of the vascular system out into the tissues.

TYPES OF INFLAMMATION
On the basis of severity, duration and onset,
categorized as
• ACUTE INFLAMMATION
• CHRONIC INFLAMMATION

FEATURE ACUTE CHRONIC
ONSET FAST: MINUTES OR HOURS SLOW: DAYS
CELLULAR INFILTRATE MAINLY NEUTROPHILS MONOCYTES/
MACROPHAGES AND
LYMPHOCYTES
TISSUE INJURY , FIBROSIS USUALLY MILD AND SELF-
LIMITED
OFTEN SEVERE AND
PROGRESSIVE
LOCAL AND SYSTEMIC SIGNS PROMINENT LESS PROMINENT; MAY BE
SUBTLE

COMPONENTS OF ACUTE AND CHRONIC INFLAMMATORY RESPONSES

FIVE STEPS OF INFLAMMATORY RESPONSE ARE
• Recognition of the injurious agent
• Recruitment of leukocytes
• Removal of the agent
• Regulation of the response
• Resolution (Repair)

Recognition of Microbes, Necrotic Cells, and Foreign Substances:

ACUTE INFLAMMATION
• The acute inflammatory response delivers leukocytes and
plasma proteins to sites of injury.
• Leukocytes clear the invaders and begin the process of
digesting and getting rid of necrotic tissues.
CELLS OF ACUTE
INFLAMMATION
NEUTROPHILS
(6-24HRS)
MONOCYTES
(24-48HRS)

ETIOLOGY
FOREIGN BODIES
• SPLINTERS
• DIRT
• SUTURES
CRYSTAL
DEPOSITS
TRAUMA
• BLUNT
• PENETRATING

TWO MAJOR COMPONENTS OF ACUTE INFLAMMATION
ARE:
VASCULAR
CHANGES
Changes in
vascular flow
and calibre
Vascular
leakage
CELLULAR
EVENTS
 Margination
 Rolling
 Adhesion
 Transmigration
 Chemotaxis
 Phagocytosis

VASCULAR
CHANGES:
• TRANSIENT
VASCONSTRICTION
• PERSISTENT PROGRESSIVE
VASODILATION
• STASIS
• LEUKOCYTE
MARGINATION

FEATURES OF HAEMODYNAMIC CHANGE
LEWIS EXPERIMENT
Injected intradermally histamine elicits
the triple response consisting of:
1.Red spot: due to capillary dilatation
2.Flare: redness in the surrounding area
due to arteriolar dilatation mediated
by axon reflex.
3.Wheal: due to exudation of fluid from
capillaries and venules
Triple response
Harsh Mohan. Textbook of Pathology, 4th Edition

DIFFERENT MECHANISM OF INCREASED VASCULAR
PERMEABILITY

CELLULAR EVENTS:
LEUKOCYTE RECRUITMENT ACTIVATION
• MARGINATION
• ROLLING
• ADHESION
• TRANSMIGRATION
• CHEMOTAXIS
• PHAGOCYTOSIS
• KILLING AND DEGRADATION
OF PHAGOCYTOSED
MICROBES
• SECRETION OF MICROBICIDAL
SUBSTANCES
• NEUTROPHIL EXRACELLULAR
TRAPs

LEUKOCYTE RECRUITMENT

CELLULAR CHANGES

LEUKOCYTE RECEPTORS AND RESPONSES

CHEMOTAXIS
• Leukocytes move towards the site of infection
or injury along a chemical gradient by a
process called Chemotaxis
• Both Exogenous and endogenous stimuli can
act as chemoattractants
• Exogenous : Bacterial product ( E.g. N-formyl-
methionyl peptides)
• Endogenous: Anaphylatoxins (C5a),
Leukotrienes (LTB4), chemokines (IL-8)

Most Chemotactic agents signal via
G-protein coupled 7 transmembrane
receptors
Activation of phospholipase C
Intracellular Calcium release &
activation of small GTPases (Rac,
Rho, cdc42)
Actin/myosin polymerization and
morphological response with
directional filopodia formation
Hall, A. (1998). Rho GTPases and the Actin Cytoskeleton. Science, 279, 509–514
Hydrolysis of
Phosphatidylionositol

• Signaling of chemo attractants induces a morphological response
(locomotion of neutrophils)
• Pattern recognition receptors induce neutrophil and macrophage
effector functions
Pattern recognition receptors Recognize
CD14 LPS
Toll like receptor Endotoxin, dsRNA, bacterial
proteoglycans
Mannose receptor Bacterial carbohydrates
Scavenger receptors Lipids
CR1 (Opsonin receptor) Complement product C3b
Fcγ receptor (Opsonin receptor) IgG coated pathogens

PHAGOCYTOSIS

Most important microbicidal substances are:
• Reactive Oxygen Species (ROS) (OXYGEN
DEPENDENT MECHANISM)
• Most important Lysosomal enzyme involved in
bacterial killing is ELASTASE)
Other constituents of leukocyte
granules: (OXYGEN
INDEPENDENT MECHANISM)
Degradation
Bactericidal permeability increasing
protein
membrane phospholipid
Lysozyme bacterial coat oligosaccharides
Major basic protein (eosinophil
granule )
cytotoxic for parasites
Defensins microbes by creating holes in their
membranes

Chemical mediators of acute inflammation

• Perform biological activity by binding to specific
receptors on target cells
• Some have direct enzymatic activity that do not require
binding to specific receptors ( e.g. ROS, lysosomal
proteases)
• Once activated and released from the cell, most of these
are short lived, quickly decay, inactivated or inhibited.

Preformed Cell Derived
Chemical Mediators
Newly Synthesized Cell
derived Chemical
mediators
Plasma derived Chemical
mediators
Histamine
Serotonin
Arachidonic acid
metabolites
• Prostaglandins
• Leukotrienes
• Lipoxins
The kinin system
Platelet Activating factor The clotting system
Cytokines The fibrinolytic system
Nitric oxide The complement system
Lysosomal enzymes of
leukocytes

Preformed Chemical Mediators:
a)Histamine
• Mast cell -Richest source
• Together with PAF is
contained in granules of mast
cells
• Induces vasodilation and
increased vascular
permeability

b)Serotonin
• Richest source -Platelets
• Release of PAF
• Induces vasoconstriction during
clotting
• Produced mainly in neurons,
enterochromaffin cells and
regulate intestinal motility

Newly Synthesized Cell
Derived Chemical
Mediators

1) Arachidonic Acid Metabolites:

2) Platelet Activating Factor:
• PAF is phospholipid derived mediator
• Generated from the membranes of
neutrophils, monocytes, basophils,
endothelial cells and platelets by action
of phospholipase A2
• Act directly on target cells – specific G
protein coupled receptor
FUNCTIONS
• Stimulating platelets
• Bronchoconstriction
• Vasodilation (1000times more
potent than histamine)
• Increased vascular
permeability
• Synthesis of other mediators ,
eicosanoids and cytokines
• Elicit reactions of
inflammation

3) Cytokines
• Functions as mediators of inflammation and immune responses
• Molecularly characterized cytokines are called Interleukins
Major cytokines in acute inflammation Actions
Tumor Necrosis Factor (TNF) Increased leucocyte adhesion, Increases
thrombogenicity of endothelium
Interleukin-1, Interleukin-6 Increased production of ECM
Chemokines Recruit leukocytes to site of inflammation,
control normal anatomic organization of
cells

4) Nitric Oxide
• NO is short lived, soluble, free radical gas
• In the CNS , it regulates neurotransmitter release and blood flow
• FUNCTIONS
• Microbicidal agent in activated macrophages
• Vasodilation
• Reduced platelet adhesion, aggregation,
degranulation
• Reduced leukocyte recruitment at inflammatory
sites

5) Lysosomal enzymes of leukocytes
• Granules of neutrophils and monocytes contain enzymes that destroy
phagocytosed substance
• Tissue damage
Granules of neutrophils Granules of monocytes
Azurophil or primary granules
• Myeloperoxidase
• acid hydrolases
• neutral proteases – elastase
collagenase
proteinase
Acid proteases
Collagenases
Elastase
Plasminogen activator
Specific or secondary granules
• Lactoferrin
• Lysozyme
• Alkaline phosphatase
• Collagenase
Active in chronic inflammation

6) Neuropeptides:
• Small proteins such as substance P
• Transmit pain signals, regulate vessel tone and
modulate vascular permeability
• Nerve fibers that secrete neuropeptides are
prominent in the lung and gastrointestinal tract

PLASMA PROTEIN DERIVED MEDIATORS:
• The complement system
• The kinin system
• The clotting system
• The fibrinolytic system

The Complement system:

Kinin- Bradykinin system:
• Bradykinin increases vascular permeability, contraction of smooth
muscles, vasodilation and pain
• Kallikrein is a potent activator of factor XII , chemotactic and
directly converts C5 to C5a

Actions of the Principal Mediators of inflammation:
Fever
IL-1,TNF
Prostaglan
dins

OUTCOMES OF ACUTE INFLAMMATION

MORPHOLOGIC
PATTERNS OF
ACUTE
INFLAMMATION
• Serous inflammation
• Catarrhal inflammation
• Fibrinous inflammation
• Hemorrhagic inflammation
• Suppurative inflammation
J C E Underwood, General and Systemic Pathology,4th Edition

MORPHOLOGIC
PATTERNS OF
ACUTE
INFLAMMATION
• Necrotizing inflammation
• Membranous inflammation
• Pseudomembranous
inflammation
• Ulcerative inflammation

HISTOPATHOLOGY OF THE MORPHOLOGIC
PATTERNS OF ACUTE INFLAMMATION

MEMBRANOUS
INFLAMMATION
PSEUDOMEMBRANOUS
INFLAMMATION

NECROTISING INFLAMMATION
100x 400x

EFFECTS OF ACUTE INFLAMMATION:
BENEFICIAL EFFECTS HARMFUL EFFECTS
Dilution of toxins Digestion of normal tissues
Entry of antibodies Swelling
Transport of drugs Inappropriate inflammatory
response
Fibrin formation
Delivery of nutrients and
oxygen
Stimulation of immune
response

SYSTEMIC EFFECTS OF INFLAMMATION
1)Fever (temperature >37.8°C or 100F)
• Increased pulse, blood pressure
• Chills
• Anorexia
2)Leukocytosis
• Neutrophilia and left shift of neutrophil points to bacterial infection
• Lymphocytosis points to viral infection
• Eosinophilia points to allergy or parasitic infection
3)Acute phase protein production in liver
• Increased ESR
4)Reactive hyperplasia of reticulo-endothelial system

Acute inflammatory lesions of the Oral
cavity
• Acute pulpitis*
• Acute apical periodontitis*
• Acute periodontal cyst*
• Acute periapical abscess*
• Acute suppurative osteomyelitis*
• Cellulitis
• Acute necrotizing ulcerative gingivitis*

ACUTE PULPITISACUTE APICAL PERIDONTITIS

VITAL NECROTIC BONE
Lacunae with osteocytes Empty lacunae
Osteoblasts are seen Ragged margins with osteoclasts on one side
and osteoblasts on other
Necrosis

CHRONIC INFLAMMATION
DEFINITION:
Chronic inflammation is defined as a prolonged
process in which destruction and inflammation are
proceeding at the same time as attempts at healing.
J.B Walter And Israel, General Pathology-7th Edition

MORPHOLOGIC FEATURES
• Infiltration with mononuclear cells.
• Tissue destruction.
• Attempts at healing (angiogenesis and
fibrosis)
Replacement of damaged tissue with connective
tissue.

CAUSES:
PERSISTENT INFECTIONS BY
MICROBES
• Mycobacterium tuberculosis
• Treponema pallidum
• Viruses and fungi
IMMUNE MEDIATED
INFLAMMATORY DISEASES
• Rheumatoid arthritis
• Inflammatory bowel disease
• Psoriasis
PROLONGED EXPOSURE TO
POTENTIALLY TOXIC AGENTS
• Inhaled particulate silica
• Cholesterol crystals
OTHER DISORDERS • Alzheimer disease
• Atherosclerosis
• Metabolic syndrome
• Type II diabetes
• Some forms of cancer

1) MACROPHAGES
• Predominant cells of chronic inflammation.
• Derived from circulating blood monocytes.
• Diffusely scattered in most connective tissues
• Constitute Mononuclear phagocyte system/Reticuloendothelial
system
Organs Macrophages
Liver Kupffer cells
Spleen and lymph node Sinus histiocytes
CNS Microglial cells
Lungs Alveolar macrophages

ORIGIN

MACROPHAGES:

Functions Of Macrophages:
1)Ingest and eliminate microbes and dead tissues
2)Initiate the process of repair
3)Secrete mediators of inflammation
4)Display antigens to T lymphocytes and respond to signals
from T cells

• IFN-γ can also induce macrophages to fuse into
large multinucleated giant cells.
FOREIGN BODY GIANT CELLS TOUTON GIANT CELLSLANGHANS’ GIANT CELLS

2) LYMPHOCYTES
• Lymphocytes are white blood cells that are also
one of the body's main types of immune cells.
• They are made in the bone marrow and found in
the blood and lymph tissue.

B and T lymphocytes migrate to the inflammatory sites.
B lymphocytes + antigens
plasma cells
antibodies
T lymphocytes + antigens
cytokines

SUBSETS OF CD4+ HELPER T cells
TH 1 – Cytokines IFN-γ
TH 2 – IL-4,IL-5 and IL-13.
TH-17 – secrete IL-17

MACROPHAGE-LYMPHOCYTE INTERACTION IN
CHRONIC INFLAMMATION

3) EOSINOPHILS
• 1 to 6 % of total leucocytes.
• Characteristically found in inflammatory sites around
parasitic infections.
• Recruitment is driven by adhesion molecules ,
leukocytes and epithelial cells
• Granules contain major basic protein, that is toxic to
parasites.

4)MAST CELLS
• Sentinel cells
• Widely distributed in connective tissue
throughout the body
• Participate in both acute and chronic
inflammation.

ACUTE ON CHRONIC INFLAMMATION
Inflamed connective tissue filling inter trabecular areas of bone

GRANULOMATOUS INFLAMMATION
Granulomatous inflammation is a distinctive pattern
of chronic inflammation characterized by aggregates
of activated macrophages with scattered
lymphocytes.

Granulomas causes:
CAUSE EXAMPLE
Specific
infections
Mycobacteria e.g. tuberculosis , leprosy, atypical mycobacteria
Many types of fungi
Parasites , larvae, eggs and worms
Syphilis
Foreign bodies Endogenous e.g. Keratin, necrotic bone, cholesterol crystals, sodium urate
Exogenous e.g. talc, silica, suture materials, oils, silicone
Specific
chemicals
Beryllium
Drugs Hepatic granulomas due to allopurinol, phenylbutazone, sulphonamides
Unknown Crohn’s disease
Sarcoidosis
Wegener’s granulomatosis

• A granuloma is a focal area of granulomatous
inflammation .
• It consists of a microscopic aggregation of
macrophages that are transformed into epithelium-like
cells surrounded by a collar of mononuclear
leukocytes, principally lymphocytes and occasionally
plasma cells.
• There are two types of granulomas:
Foreign body granuloma
Immune granulomas
Robbins and Cortan Pathologic Basis Of Diseases, 6th edition; 2005.p 50-87

Lymphocytes
Giant cells
Necrosis
MYCOBACTERIUM TUBERCULOSIS

REFERENCES:
• Kumar, Abbas, Aster (2013) Robbins Basic Pathology, 9th Edition
• Hall, A. (1998). Rho GTPases and the Actin Cytoskeleton. Sci-
ence, 279, 509–514
• J.B Walter And Israel, General Pathology-7th Edition
• Harsh Mohan. Textbook of Pathology, 4th Edition
• Inflammation: Robbins and Cortan Pathologic Basis Of Diseases,
6th edition; 2005.p 50-87.
• J C E Underwood, General and Systemic Pathology,4th Edition
• Bharadwaj, Dr. Prabal Deb, Boyd’s textbook of
Pathology. Vol 1.10th edn;2013,Walter Kluwer Pvt Ltd.

Inflammation: A Protective Response to Tissue Injury

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