Inflammation

By
Dr Muchindu N
BSc Biomed, BSc HB, MBChB
REGISTRAR ANATOMICAL PATHOLOGIST
 Introduction
• Inflammation is a response of vascularized tissues to
injury.

• It brings cells and molecules of host defense.

• Therefore ,without inflammation;

– Infections would go unchecked
– Wounds would never heal and
– Injured tissues might remain permanent festering
sores.
Inflammatory sequential steps:
• The offending agent, which is located in extravascular
tissues, is recognized by host cells and molecules.

• Leukocytes and plasma proteins are recruited from the

circulation to the site where the offending agent is located.

• The leukocytes and proteins are activated and work

together to destroy and eliminate the offending substance.

• The reaction is controlled and terminated.

• The damaged tissue is repaired.

 Historical Highlights
• Celsus, a first century A.D. Roman, listed four
cardinal signs of acute inflammation:
– Rubor (erythema [redness]): vasodilatation,
increased blood flow
– Tumor (swelling): extravascular
accumulation of fluid
– Calor (heat): vasodilatation, increased blood
flow
– Dolor (pain)
 Nomenclature
• Ends with TIS
• Example
– Hepatitis
– Meningitis
– Gastritis
• However, not absolute
– Pneumonia
 Types of Inflammation

• Acute inflammation • Chronic inflammation

– Short duration – Longer duration
– Edema – Lymphocytes &
– Mainly neutrophils macrophages
predominate
– Fibrosis
– New blood vessels
(angiogenesis)
 Acute Inflammation
• Three major components:

– Increase in blood flow (redness & warmth)

– Edema results from increased hydrostatic

pressure (vasodilation) and lowered
intravascular osmotic pressure (protein leakage)

– Leukocytes emigrate from microcirculation and

accumulate in the focus of injury
 Vascular Reactions
• Vasodilation is induced by inflammatory mediators such
as histamine

• Increased vascular permeability is induced by

histamine and kinins

• This allows plasma proteins and leukocytes

• Fluid leak from blood vessels (exudation) results in

edema.
• Lymphatic vessels and lymph nodes also are involved in
inflammation, and often show redness and swelling.
Edema in inflammation
 Leukocyte Extravasation
• Extravasation: delivery of leukocytes from the
vessel lumen to the interstitium
– In the lumen: margination, rolling, and
adhesion

– Migration across the endothelium (diapedesis)

– Migration in the interstitial tissue (chemotaxis)

• Leukocytes ingest offending agents

(phagocytosis), kill microbes, and degrade
necrotic tissue and foreign antigens
 Phagocytosis and Clearance of
the Offending Agent
• Leukocytes can eliminate microbes and dead
cells by phagocytosis, followed by their
destruction in phagolysosomes.

• Destruction is caused by free radicals (ROS,

NO) generated in activated leukocytes and by
granule enzymes.
Contact,Recognition, Internalisation.
Opsonins: e.g. Fc and C3b receptors
 Microbial killing
• Phagosomes fuse with lysosomes to produce secondary
lysosomes ( phagolysosomes)
Mechanisms:
• O2 dependent killing Mechanism
– NADPH oxidase activated; produces superoxide ion.
This converts to hydrogen peroxide.
– H2O2-Myeloperoxidase-halide system: produces HOCl.
(i.e. bleach!)

– Myeloperoxidase independent:
– Uses superoxide and hydroxyl radicals. Less efficient
O2 independent killing mechanisms
• Lysozyme & hydrolases
• Lactoferrin
• Bactericidal Permeability Increasing Protein
(BPI)
• Cationic proteins (‘Defensins’)
• Major Basic Protein (MBP; Eosinophils)
 Morphologic patterns of
inflammation
• Serous - excessive accumulation of fluid, few
proteins - skin blister.

• Mucous membranes - catarrhal -

accumulation of mucus

• Fibrinous - higher vascular permeability leads

to exsudation of fibrinogen which leads to
fibrosis -scar formation
• Suppurative (purulent) - accumulation of
neutrophillic leucocytes that lead to formation
of pus (pyogenic bacteria).

• Interstitial
– phlegmone – diffuse soft tissue
– abscess - localized collection

• Formation of suppurative fistule

• Accumulation of pus in preformed cavities -

empyema (gallbladder, thoracic)
complications of suppurative inflammation
• Bacteremia (no clinical symptoms) danger of
formation of secondary foci of inflamm.
(endocarditis, meningitis)

• Sepsis (= massive bacteremia) - septic fever,

activation of spleen, septic shock

• Thrombophlebitis - secondary inflammation of

wall of the vein with subsequent thrombosis

• lymphangiitis, lymphadenitis
• Pseudomembranous - fibrinous
pseudomembrane (diphtheria -
Corynebacterium, dysentery - Shigella) - fibrin,
necrotic mucosa.

• Necrotizing - inflammatory necrosis of the

surface - ulcer (skin, gastric)
Chemical Mediators of Inflammation
• General principles of chemical mediators
– May be derived from plasma or cells
– Most bind to specific receptors on target cells
– Can stimulate release of mediators by target cells, which may amplify or ameliorate the
inflammatory response
– May act on one or a few target cells, have widespread targets, and may have differing effects
depending on cell and tissue types
– Usually short-lived
– Most have the potential to cause harmful effects
 Chemical Mediators of Inflammation
• Vasoactive mediators • Chemotactic factors
– Histamine – Complement (C5a)
– Bradykinin – Leukotriene (B4)
– Complement (C3a, C5a) – Platelet activating
– Prostaglandins/ factor
leukotrienes – Cytokines (IL-1, TNF)
– Platelet activating factor – Chemokines
– Nitric oxide – Nitric oxide
 Histamine
• Mast cells (also basophils and platelets)
• Release mechanisms
– Binding of antigen (allergen) to IgE on
mast cells releases histamine-
containing granules
– Release by nonimmune mechanisms
such as cold, trauma, or other
chemical mediators
– Release by other mediators
• Dilates arterioles and increases
permeability of venules (wheal and flare
reaction)
 Complement
• Proteins found in greatest concentration in
the plasma
• Require activation
• Increase vascular permeability and cause
vasodilation
– Mainly by releasing histamine from mast cells
• Increase leukocyte adhesion, chemotaxis, and
activation
• C3b attaches to bacterial wall and enhances
phagocytosis by neutrophils & macrophages
 Bradykinin

• Small peptide released from plasma

precursors
• Increases vascular permeability
• Dilates blood vessels
• Causes pain
• Rapid inactivation
 Arachidonic Acid Metabolites
• Prostaglandins
– Vasodilators: prostacyclin (PGI2), PGE1, PGE2, PGD2
– Vasoconstrictors: thromboxane A2
– Pain (PGE2 makes tissue hypersensitive to bradykinin)
– Fever (PGE2)
– Production blocked by steroids and nonsteroidal anti-
inflammatory agents (NSAIDs)
• Leukotrienes
– Increase vascular permeability: leukotrienes C4, D4, E4
– Vasoconstriction: leukotrienes C4, D4, E4
– Leukocyte adhesion & chemotaxis: leukotriene B4,
HETE, lipoxins
– Production blocked by steroids but not conventional
NSAIDs
 Platelet Activating Factor
• Subclass of phospholipids
• Synthesized by stimulated platelets,
leukocytes, endothelium
• Inflammatory effects
– Stimulates platelet aggregation
– Vasoconstriction and bronchoconstriction
– Vasodilation and increased venular permeability
– Increased leukocyte adhesion to endothelium,
chemotaxis, degranulation, and oxidative burst
– Increases synthesis of arachidonic acid
metabolites by leukocytes and other cells
 Cytokines
• Proteins produced by many cell types
(principally activated lymphocytes &
macrophages)
• Modulate the function of other cell types
• Interleukin-1 (IL-1) and tumor necrosis factor
(TNF) are the major cytokines that mediate
inflammation
 Chemokines
• Small proteins that act primarily as
chemoattractants for specific types of
leukocytes (approximately 40 known)
• Stimulate leukocyte recruitment in
inflammation
• Control the normal migration of cells through
tissues (organogenesis and maintenance of
tissue organization)
• Examples: IL-8, eotaxin, lymphotactin
Nitric Oxide
 Other Mediators
• Neutrophil granules:
– Cationic proteins increase vascular permeability,
immobilize neutrophils, chemotactic for
mononuclear phagocytes
– Neutral proteases generate other mediators and
degrade tissue
• Oxygen-Derived Free Radicals:
– Produced during phagocytosis by neutrophils
(“respiratory burst”)
– Tissue damage including endothelium
Summary of Inflammatory Mediators

• Vasodilation • Increased vascular

– Prostaglandins permeability
– Nitric oxide – Histamine, serotonin
– Histamine
– Complement (C3a, C5a)
– Bradykinin
– Leukotrienes (C4, D4, E4)
– Platelet Activating
Factor
– Substance P
Summary of Inflammatory Mediators

• Chemotaxis, • Fever
leukocyte activation – Interleukin-1
– Complement (C5a) – Tumor necrosis factor
– Leukotriene B4 – Prostaglandins
– Chemokines
– IL-1, TNF
– Bacterial products
 Summary of Inflammatory Mediators

• Pain • Tissue Damage

– Prostaglandins – Neutrophil and
– Bradykinin macrophage lysosomal
enzymes
– Oxygen metabolites
– Nitric oxide
 Outcomes of Acute Inflammation
• Complete resolution
• Abscess formation
• Fibrosis
– After substantial tissue destruction
– In tissues that do not regenerate
– After abundant fibrin exudation, especially in
serous cavities (pleura, peritoneum)
• Progression to chronic inflammation
Chronic inflammation
• Chronic inflammation is a response of prolonged
duration (weeks or months) in which inflammation,
tissue injury and attempts at repair coexist, in varying
combinations

• Causes:
– Persistent injurious agent/infection
• Inability of the host to overcome the
injurious agent
– Hypersensitivity diseases
– Prolonged exposure to potentially toxic agents, either exogenous
or endogenous
 Characteristics:

–Chronic inflammatory cell infiltrate

• Lymphocytes
• Plasma cells
• Macrophages
–Tissue destruction
–Repair
• Neovascularization
• Fibrosis
 Under what circumstances, does it develop?

– Progression from acute inflammation

• Tonsillitis, osteomyelitis, etc.

– Repeated exposure to toxic agent

• Silicosis, asbestosis, hyperlipidemia, etc.

– Viral infections

– Persistent microbial infections

• Mycobacteria, Treponema, Fungi, etc.

– Autoimmune disorders
• Rhumatoid arthritis, SLE, systemic lupus, etc.
 Macrophages & the Mononuclear
Phagocytic System
• Macrophages:
–Derived from circulating monocytes

–Scattered in tissues:
• Kupffer cells (liver),
• Sinus histiocytes (spleen & LN),
• Alveolar macrophages (lung),
• Microglia (CNS)
• Activated mainly by IFN-g secreted from T
lymphocytes

–Increased cell size

–Increased lysosomal enzymes
–more active metabolism, i.e. greater ability
to kill ingested organisms
–Epithelioid appearance
 How do Macrophages Accumulate at Sites of Chronic Inflammation?

• Recruitment of monocytes from circulation by

chemotactic factors:

– Chemokines, C5a, PDGF, TGFa,

fibrinopeptides, fibronectin, collagen
breakdown fragments.

• Proliferation of macrophages at foci of inflammation

• Immobilization of macrophages at sites of inflammation

Macrophage-Lymphocyte Interactions
Other Cells in Chronic Inflammation

• Lymphocytes
– Produce inflammatory mediators
– Participate in cell-mediated immune reactions
– Plasma cells produce antibody
– Lymphocytes and macrophages interact in a
bi-directional fashion
Chronic Inflammatory Cells

Plasma cells Russell bodies

• Eosinophils
– Immune reactions mediated by IgE
– Parasitic infections
• Eosinophil granules contain a protein that is
toxic to parasites
• Mast cells
– Release mediators (histamine) and cytokines
Eosinophil Morphology
 Types of Chronic Inflammation
A. NONSPECIFIC CHRONIC INFLAMAMTION- DIFFUSE ACCUMULATION OF
MACROPHAGES AND LYMPHOCYTES AT INJURY SITE

MACROPHAGES FROM 3 SOURCES:

1) RECRUITMENT
2) LOCAL PROLIFERATION
3) PROLONGED SURVIVAL

B. GRANULOMATOUS-
GRANULOMA FORMATION – MASSING OF MACROPHAGES SURROUNDED BY
LYMPHOCYTES
 Granulomatous Inflammation
• A distinctive form of chronic inflammation
characterized by collections of activated (epithelioid)
macrophages

• Granuloma, in addition to epithelioid macrophages,

may have one or more of the following:

– A surrounding rim lymphocytes & plasma cells

– A surrounding rim of fibroblasts & fibrosis

– Giant cells

– Central necrosis e.g. caseating granulomas in TB

Histopathology of Granuloma
Histopathology of Granuloma
Caseating Granuloma
Examples of Granulomatous Inflammation
 Morphologic Appearance of Chronic
Inflammation
• Ulceration
–Ulcer: Local defect or loss of
continuity in surface epithelia
• Chronic abscess cavity
• Induration & fibrosis
• Thickening of the wall of a hollow viscus
• Caseous necrosis
Ulcer
 Systemic Manifestations
• Endocrine and metabolic
– Secretion of acute phase proteins by the liver
– Increased production of glucocorticoids
(stress response)
– Decreased secretion of vasopressin leads to
reduced volume of body fluid to be warmed
• Fever
– Improves efficiency of leukocyte killing
– Impairs replication of many offending organisms
 Systemic Manifestations
• Autonomic
– Redirection of blood flow from skin to deep
vascular beds minimizes heat loss
– Increased pulse and blood pressure
• Behavioral
– Shivering (rigors), chills (search for warmth),
anorexia (loss of appetite), somnolence, and
malaise
 Systemic Manifestations

• Leukocytosis: increased leukocyte count in the

blood
– Neutrophilia: bacterial infections
– Lymphocytosis: infectious mononucleosis, mumps,
measles
– Eosinophilia: Parasites, asthma, hay fever
• Leukopenia: reduced leukocyte count
– Typhoid fever, some viruses, rickettsiae, protozoa
Systemic Acute-phase Reactions
 Consequences of Defective
Inflammation
• Susceptibility to infections
–Defective innate immunity
• Delayed repair
–Delayed clearance of debris
and necrotic tissue
–Lack of stimuli for repair
 Consequences of Excessive
Inflammation
• Allergic reactions
• Autoimmune disorders
• Atherosclerosis-Ischemic heart disease