Inflammation

Yodit Getahun, MD
Inflammation
•Is the body’s mechanism for coping with agents that could damage it

•Is a protective response to rid the body of the cause of cell injury and the
resultant necrotic cells that cell injury produces

•Leakage of fluid, inflammatory substance and plasma proteins from the vessels
to the interstitial space
•Brings cells and molecules of host defense to the sites where they are needed
•Response to injury
•The suffix: “itis” is added e.g. appendicitis, lymphadenitis
Cont’d
• vasodilation and increased vascular permeability in the area of inflammation

• Accumulation of white blood cells (leukocytes)

• White blood cells leave the blood vessel

• white blood cells must then leave the blood vessel, cross the basement
membrane, and be drawn to the area where they are needed= Chemotaxis
Acute Inflammation
• Has a rapid onset, lasts for minutes to days

• Characterized by exudation of fluid and protein from vessels and

emigration of neutrophils

• Protective process that is designed to rid the body of the inciting

agent and set up the process of repair
Cont’d
Cardinal signs of acute inflammation
• Rubor (red discoloration)
• Calor (heat)
• Dolor (pain)
• Tumor (mass effect)
• Loss of function
Cont’d
Causes of acute inflammation
• Infection
• Trauma
• Physical and chemical agents
• Necrosis
• Foreign bodies
• Immune reactions.
Stages of acute inflammation
1. Vasodilation (after a transient vasoconstriction)
• How: Vasodilation occurs through release of mediators from cells.
These mediators include histamine, prostacyclin (PGI2), and nitric oxide
(NO).

• Why: Vasodilation increases the hydrostatic pressure by causing

slowing (sludging) of blood flow. Sludging of blood also causes
margination of leukocytes along the wall of the blood vessel
Cont’d
2. Increased vascular permeability (increased leakiness of vessels)
• How: Increased vascular permeability occurs through release of
mediators from cells. These mediators include histamine and
leukotrienes C4, D4, and E4.
• Why: Increased vascular permeability allows fluid to cross into the
interstitial tissue, which increases protein levels in the interstitial tissue,
thereby decreasing osmotic pressure in the blood and increasing
osmotic pressure in the interstitial tissue. These changes cause fluid to
flow out of the vessel, leading to edema of the interstitial tissue.
Cont’d
Mechanisms of increased vascular permeability:
 Endothelial contraction (referred to as immediate-transient
response)
• Mediators: Histamine, bradykinin, and leukotrienes.
• Vessels affected: Post capillary venules.
• Time course: Immediate; short lived (up to 30 minutes
Cont’d
 Endothelial cell retraction
• Mediators: Tumor necrosis factor (TNF) and interleukins(e.g. IL-1)
• How: Structural rearrangement of cytoskeleton
• Time course: 4–6 hours (referred to as delayed response); long lived
 Direct endothelial injury
• Mediators: Bacterial enzymes
• Vessels affected: All
• How: Endothelial cell necrosis
• Time course: Immediate (referred to as immediate sustained response)
Cont’d
 Delayed prolonged response
• Due to ultraviolet light, x-ray, and mild thermal injury
• Uncertain mechanism

 Leukocyte-mediated damage
Cont’d

3. Movement of white blood cells from blood vessels into soft

tissue at the site of inflammation:
• The steps required are rolling, pavementing (adhesion), and
transmigration
 Rolling
• Loose, intermittent contact of white blood cells with endothelium, partially due
to margination of white blood cells from stasis of blood
• Mediated by Sialyl-Lewis X molecules on white blood cells bind with E-selectins
on endothelial cells
• Selectins: weak binding, initiate rolling
• P-selectin: activated by histamine
• E-selectin: activated by IL-1 and TNF
• L- selectin
Cont’d
 Pavementing (Adhesion)
• Tight, constant contact of white blood cells with endothelium
• Mediated by Integrins: stable binding and adhesion
• ICAM-1
• VCAM-1
• LFA-1
• MAC-1
Cont’d
 Transmigration
• White blood cells crossing through the endothelial layer
• Mediated by : CD31 or platelet endothelial cell adhesion molecule(PECAM) on
both white blood cells and endothelial cells
Chemotaxis
• Process by which white blood cells are drawn to the site of
inflammation
Mediators
■ Exogenous mediators: Bacterial polysaccharides
■ Endogenous mediators:
* C5a
* AA metabolites e.g. leukotriene B4 (LTB4)
* cytokines (IL-8)
Cont’d
The role of leukocytes
• White blood cells recognize foreign particles through mannose and
scavenger receptors.
• Opsonins are particles that bind to foreign material and signal
leukocytes to remove it.
Types of opsonins include:
1. IgG (recognized by Fc receptor on white blood cells).
2. C3b (recognized by CR 1, 2, and 3 on leukocytes).
3. Collectins (recognized by C1q on leukocytes).
Cont’d
■ Killing and/or degradation of foreign substances occurs by:
• Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (has membrane and
cytoplasmic component)
• It uses two oxygen molecules to produce a superoxide radical (O2) and the superoxide radical converts to
hydrogen peroxide.

• Myeloperoxidase
• Converts hydrogen peroxide and halogen (Cl) to HOCl., which causes halogenation or lipid or protein
peroxidation

• Bactericidal permeability increasing protein, lysozyme, and major basic protein

Diseases associated with impaired inflammatory response

• Chronic granulomatous disease

• Loss of NADPH oxidase
• Inheritance: The mutation for the autosomal recessive form of chronic
granulomatous disease results in a defective cytoplasmic component
• the mutation for the X-linked form of chronic granulomatous disease results
in a defective membrane component
• Effect of mutation: Inability to form hydrogen peroxide
Cont’d
• CHÉDIAK-HIGASHI SYNDROME
• Autosomal recessive
• A mutation occurs in a cytosolic protein, which plays a role in vesicle traffic
• Effects of mutation: Decreased cellular killing of bacteria because of reduced
transfer of lysosomal enzymes to phagocytic vesicles. Other effects of
mutation include albinism, nerve defects, and platelet disorders
Morphology of acute inflammation

• Serous inflammation
• Relatively clear, watery fluid
• Few cells; most of the inflammation is fluid (i.e. a transudate; a protein-poor
fluid with a specific gravity 1.012)
• Viral infections and burns
• Fibrinous inflammation
• Finely particulate, thick fluid
• Much more protein and cells than serous inflammation (i.e. an exudate; a
protein-rich fluid with a specific gravity 1.020)
• Uremic and postmyocardial infarct pericarditis
Serous Inflammation
Cont’d
• Purulent inflammation
• Pus (thick, white-yellow fluid)
• Neutrophils, protein, and necrotic cells (i.e.an exudate)
• Bacterial and fungal infections
Purulennt inflammation
Cont’d
Outcomes of Acute Inflammation
• Resolution
• The inciting agent is removed, and all damage done by the inciting agent and
inflammatory cells is repaired
• The organ affected must be capable of regeneration, and the body must be
capable of completely dealing with the inciting agent
• Abscess
• Collection of pus (neutrophils and necrotic debris)
• Any organ in the body can be affected
• Pain, fever, rupture, and swelling
Abscess
Cont’d
• Ulcer
• Loss of the mucosa and deeper tissues.
• If only the mucosa is lost, the correct term is an erosion
• Microscopically : The ulcer has four layers
• The layers, from superficial to deep, are fibrin, neutrophils, granulation tissue, and
fibrosis
• commonly seen in the gastrointestinal tract
• Complications of an ulcer:
• Pain, hemorrhage, peritonitis
Cont’d
• Fistula
• Anomalous patent connection between two organs; most commonly organs
with a lumen
• Inflammatory process involving full thickness of the wall of an organ, duct, or
blood vessel
• Chronic inflammation
• Scar formation
• Replacement of lost parenchyma with disorganized connective tissue (e.g.
collagen)
• Loss of function
Chronic Inflammation
• Prolonged inflammation consisting of active inflammation and tissue
destruction and repair, all occurring simultaneously
• It can also occur as a low-grade, asymptomatic, prolonged response
to an inciting agent
• Causes:
• Viral, persistent microbial infection, prolonged exposure to toxin, and
autoimmune dysfunction
• Macrophages and Lymphocytes
Morphology of chronic inflammation
• Infiltration with mononuclear cells which include macrophages,
lymphocytes, & plasma cells
• Tissue destruction , induced by the persistent offending agent or by
the inflammatory cells
• Attempts at healing by connective tissue replacement of damaged
tissue, accomplished by proliferation of blood vessels (angiogenesis)
& fibrosis
Cont’d
• Important type of chronic inflammation: Granulomatous
inflammation
• Granuloma: is a Collection of epithelioid histiocytes
• Morphology of granuloma: Collection of activated macrophages(i.e.,
epithelioid histiocytes); can have multinucleated giant cells
• Causes: Mycobacteria, fungi, foreign material, sarcoidosis, and silica