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Inflammation and Repair

LM202
Dr. Hassan Kofahi
Inflammation
• Inflammation is a tissue response to infection or damage.
• The purpose of inflammation is to bring the mediators of host defenses to
the site of infection or tissue damage.
• Most of these mediators normally circulate in the blood.
• Inflammation brings them to the site of infection/tissue damage where they function
to eliminate the microbes and/or the damaging agents.
• These mediators include:
• Phagocytic leukocytes (monocytes/macrophages and neutrophils)
• Antibodies
• Antimicrobial proteins (such as complement proteins)
• Inflammation is also important for initiating the repair process of damaged
tissues.
• Inflammation is clinically denoted by the suffix “-itis”
• e.g., dermatitis inflammation of the skin
• e.g., pharyngitis inflammation of the pharynx
Causes of inflammation
1. Infections: (bacterial, viral, parasitic and fungal)
• The most common cause of inflammation.
• Different pathogen triggers distinct inflammatory responses that varies from mild to severe
and even fatal inflammations.
2. Tissue damage
• Inflammation can be triggered by some of the molecules that leak from dead cells (by
necrosis, necroptosis or pyroptosis).
3. Foreign bodies (splinters, dirt, sutures)
• May cause inflammation directly by causing tissue damage or indirectly by carrying microbes.
4. Some endogenous substances
• E.g., urate crystals cause gout disease, cholesterol crystals cause atherosclerosis.
5. Immune reactions
• Hypersensitivity and autoimmune reactions cause inflammation.
Types of inflammation
• Acute inflammation
• The initial response to infection/tissue damage.
• Rapid onset (minutes to few hours) after the infection/damage.
• Short duration (lasts for hours to few days).
• Chronic inflammation
• Develops if the acute inflammation fails to clear the infection or, in some
cases, could arises de novo.
• Slow onset (days) after the infection/damage.
• Long duration (weeks to years)
Acute inflammation
Steps of acute inflammation
1. Recognition of microbes or damaged
cells by sentinel cells in the tissue.
2. Production of inflammatory mediators.
3. Changes in the nearby blood vessels.
4. Migration of leukocytes from the
blood vessels to the site of
infection/damage.
5. Elimination of the microbe and/or
damaged cells.
6. Initiation of tissue repair.
1. Recognition of microbes or damaged cells
• The first step in any inflammatory reaction is the recognition of the
microbes or damaged cells by sentinel cells
• Sentinel cells include macrophages, mast cells and dendritic cells
• Recognition of the microbes
• Tissue-resident sentinel cells express surface and cytoplasmic receptors that can
recognize the microbes [e.g., Toll-like receptors (TLRs)].
• These receptors recognizes a group of microbial structures known as pathogen-
associated molecular patterns (PAMPs).
• PAMPs are structures/molecules found in microbes but not in human cells
• Furthermore, some plasma proteins (such as the complement proteins) can help in
the recognition of the microbes.
• Recognition of the damaged cells
• Damaged cell releases its cellular contents to the surroundings including a group of
molecules known as damage-associated molecular patterns (DAMPs).
• Tissue-resident sentinel cells recognize DAMPs by specific cytoplasmic receptors.
2. Production of inflammatory mediators
• Recognizing a microbe or damaged cells by the sentinel cells stimulates
them to produce soluble inflammatory mediators at the site of
infection/damage.
• These inflammatory mediators affect nearby blood vessels and cells and
may have systemic effects.
• The inflammatory mediators include
• Histamine: causes vasodilation and increase vascular permeability.
• Prostaglandins: cause vasodilation, pain and fever.
• Cytokines: local effects activate the endothelial cells to express adhesion
molecules.
Systemic effects fever, hypotension and shock.
• Chemokines: attract the leukocytes to the site of infection.
3. Changes in the nearby blood vessels
The inflammatory mediators affect nearby blood vessels and cause the
following vascular changes:
• Vasodilation (increased diameter of the blood vessel):
• Increases the blood inflow into the tissue.
• Causes heat and redness of the inflamed tissue.
• Increased permeability of the blood vessels
• Enables plasma proteins and leukocytes to leave the circulation.
• Results in the outpouring of a protein-rich fluid, called exudate, into the
extravascular tissues.
The loss of fluid increases the concentration of red blood cells in the
blood vessel which increases the viscosity of the blood. High blood
viscosity, as well as vasodilation, together lead to a slower blood flow.
Exudate vs transudate
• Fluids can escape from blood vessels into the tissues to form an exudate or
a transudate.
• Exudate: an extravascular fluid that has a high protein concentration and
contains cellular debris.
• Usually results from an increase in the vascular permeability.
• Present in acute inflammation.
• Pus (purulent exudate), is an inflammatory exudate rich in leukocytes (mostly
neutrophils), the debris of dead cells (liquefactive necrosis) and ,sometimes,
microbes.
• Transudate: is a fluid with low protein content and little or no cellular
material
• Edema: an excess of fluid in tissues or body cavities; it can be either an
exudate or a transudate.
4. Migration of leukocytes from the blood
vessels to the site of infection/damage.
• Cytokines and other inflammatory mediators activate the endothelial
cells to express adhesion molecules.
• Adhesion molecules are responsible for the attachment of leukocytes to
endothelial cells in the blood vessel wall.
• Two types of adhesion molecules are important for leukocyte migration; selectins
and integrins.
• Steps of leukocyte migration:
1. Selectins cause weak attachment between leukocytes and endothelial cells and
cause the rolling of leukocytes along the vascular endothelial surface.
2. Chemokines activate the integrins.
3. Activated integrins cause stable adhesion of leukocytes to vessel wall.
4. Leukocytes then migrate through the vessel wall.
5. Chemokines activate the movement of leukocyte in the extravascular tissues
toward the site of infection/damage.
5. Elimination of the microbe and/or
damaged cells.
• At the site of infection or tissue injury, leukocytes recognize the
microbes and/or damaged tissues by surface or cytoplasmic receptors
and as a result, they become activated.
• Activated leukocytes kill or clear the offending agent by:
• Phagocytosis
• Degranulation
• Neutrophil extracellular traps (NETs)
Phagocytosis
• Phagocytosis involves three main steps
Degranulation
• Neutrophils contain granules filled with
enzymes and anti-microbial proteins.
• Activation of neutrophils at the site of
inflammation results in their
degranulation (i.e., the extracellular
release of granule contents).
• Granule contents kill microbes and
degrade dead cells. However, they may
cause damage in the surrounding
normal tissues.
 Neutrophil extracellular traps (NETs)
• In response to the microbe and
inflammatory mediators, neutrophils
die, and during this process they eject
their DNA to form a meshwork called
Neutrophil extracellular traps (NETs).
• NETs are impregnated with
antimicrobial substances.
• NETs trap and kill bacteria and fungi at
the site of infection.
NETs act like a spider’s
web
Leukocyte-mediated tissue injury
• Activated leukocytes release their toxic granule contents into the
extracellular milieu (by degranulation and NETs).
• As a result, normal cells and tissues at or near the site of infection
suffer collateral damage.
• In certain diseases, tissue injury occurs as a result of leukocyte
activation. Examples:
• In hepatitis and tuberculosis, leukocytes cause more pathology than the
infection itself.
• Autoimmune diseases.
• Allergy.
Signs of acute inflammation

• Heat
• Redness
• Swelling
• Pain
• Loss of function
Morphologic patterns of acute inflammation
Besides the 5 major signs of inflammation, other gross morphologic
patterns are often seen depending on the cause of inflammation,
location of the inflammation and the severity of the reaction.
These morphologic patterns include:
• Serous inflammation
• Fibrinous inflammation
• Purulent Inflammation, Abscess
• Ulcers
Serous inflammation
• Serous inflammation is marked by the exudation of thin fluid into
spaces created in the surface epithelia as a result of injury or into
body cavities (peritoneal, pleural or pericardial).
• Accumulation of fluid in these cavities is called an effusion.
• Example: Skin blisters as a result of burns
Serous inflammation. a skin blister showing the epidermis separated from the
dermis by a focal collection of serous effusion.
Fibrinous Inflammation
• Cause: Inflammation of the lining of body cavities such as meninges
and pericardium.
• These types of inflammation result in a large increase in vascular
permeability.
• The large increase in vascular permeability allows large molecules, such as
fibrinogen, to leave the blood vessels and deposit as fibrin in the extracellular
spaces (fibrinous exudate).
• Histologically, appears as an eosinophilic meshwork of fibrin.
• Fibrin deposits may be removed by fibrinolysis and macrophages or,
in some cases, may convert into scar tissue.
 A
Fibrinous pericarditis. (A) Deposits of fibrin on the pericardium. (B) A pink meshwork of fibrin exudate (F)
overlies the pericardial surface (P).
Purulent Inflammation, Abscess
• Purulent (also called suppurative) inflammation is caused mainly by
infections with pus-producing bacteria (pyogenic bacteria).
• Characterized by the production of pus
• Frequently, associated with the formation of abscesses.
• Abscesses are localized collections of pus within a tissue.
• They are caused by seeding of pyogenic bacteria into a tissue.
• Abscess morphology: central mass of dead neutrophils and necrotic
tissue surrounded by a zone of preserved neutrophils.
Ulcer
• Is a defect of the surface of an organ or a tissue that is produced by
the shedding of the inflamed necrotic tissue.
• Occur when the inflammation and necrosis are on or near the
surface.
• Most commonly occur in
• GI tract (ulcers in the mucosa of the mouth, peptic ulcers)
• Genitourinary tract
• Skin (especially the lower extremities of old diabetic patients).
• Acute and chronic inflammations often coexist in ulcers.
Outcomes of acute inflammation
• Depending on the nature of injury, site of injury and responsiveness of the
host, acute inflammations result in one of three outcomes:
• Complete resolution:
• The best possible outcome for the body.
• The offending agent is eliminated, and the tissue returns to normal.
• Occurs when the injury is limited and there is little tissue damage, and the damaged cell type
can regenerate.
• Healing by connective tissue replacement (scarring or fibrosis)
• The offending agent is eliminated, but the damaged tissue is replaced with fibrous tissue.
• Occurs when the damage is severe, when the damaged cell type can not regenerate or when
there is too much fibrin in the tissue to be cleared.
• Progression of the response to chronic inflammation
• Occurs when the acute inflammation fails in eliminating the offending agent.
Chronic inflammation
Chronic inflammation
• A response of prolonged duration (weeks-years).
• Three events coexist in chronic inflammation:
• Inflammation
• Tissue damage
• Attempts to repair
Causes of chronic inflammation
• Infection
• Chronic inflammation occurs when the pathogen is difficult to eradicate, such as
mycobacteria and some viruses.
• Autoimmune diseases
• Inflammatory response against self tissues.
• Examples: rheumatoid arthritis, multiple sclerosis.
• Hypersensitivity reactions:
• An immune response against harmless environmental substances.
• Example: bronchial asthma
• Prolonged exposure to exogenous or endogenous stimulating agents.
Examples:
• Silicosis: chronic inflammation in the lungs in response to prolonged inhalation of
particulate silica (exogenous agent).
• Atherosclerosis: chronic inflammation of the arterial walls in response to cholesterol
deposits (endogenous agent).
Morphologic features of chronic inflammation
• Infiltration with macrophages and T lymphocytes.
• Tissue destruction caused by the offending agent and the
inflammatory cells.
• Attempts to repair by forming new blood vessels (angiogenesis) and
fibrosis.
Granulomatous inflammation
• A form of chronic inflammation.
• A cellular attempt to contain an offending agent that is difficult to
eliminate.
• Characterized by collections of activated macrophages with T lymphocytes,
and sometimes associated with central necrosis (caseous necrosis).
• Some activated macrophages may develop a shape that resembles
epithelial cells (called epithelioid cells), other macrophages may fuse to
form a multinucleated giant cells.
• T lymphocytes produce cytokines that induce the activation of
macrophages and other T lymphocytes.
Systemic effects of inflammation
• Besides the local tissue responses, inflammations (acute or chronic)
are usually associated with cytokine-induced systemic effects that
affects the whole body.
• These include:
1. Fever: an increase in the body temperature.
2. Acute phase proteins: plasma proteins produced by the liver and increase
several folds in response to inflammatory cytokines.
3. Leukocytosis: an increase in the number of circulating leukocytes.
4. Severe bacterial infections might cause septic shock.
Tissue repair
Mechanisms of tissue repair
1. Regeneration
• Occurs when the tissue is able to replace the damaged components and
returns back to normal.

2. Scar formation
• Occurs when the injured tissues are incapable of regeneration. In this case,
the damaged tissue is replaced with connective (fibrous) tissue (i.e., a scar)
Repair of epithelial tissues:
- Mild and superficial
injury, which damages the
epithelium but not the
underlying tissue, is
repaired by regeneration.
- Severe injury with
damage to the connective
tissue, is repaired by scar
formation.
Proliferative capacity of the tissues
• Repair depends largely on the proliferative capacity of the injured tissue.
• Tissues are divided into three types depending on their proliferative
capacity:
1. Labile tissues: continue to divide throughout life; replacing the cells that
are continually being lost (e.g., epithelial cells of skin, columnar epithelia
of gastrointestinal tract, bone marrow cells).
2. Stable tissues: normally not proliferating; undergo proliferation after
injury or loss of tissue mass, These tissues include the parenchyma of
most solid organs (e.g., liver, kidney and pancreas).
3. Permanent tissues: composed of non proliferative cells. once injured,
they are replaced with fibrous scar tissue (e.g., nerve, skeletal muscle,
and cardiac muscle cells)
Mechanism of regeneration
• Regeneration occurs when:
• The remaining cells that survive the injury can proliferate and replace the
damaged cells.
• The injury is mild.
• Mild injury to the epithelia of the skin and intestinal tract is repaired
by rapidly replacing the injured cells.
• The ability of parenchymal organs (except the liver) to regenerate is
limited.
• Human liver has a remarkable capacity to regenerate, and it can grow
back to its normal size after partial hepatectomy.
Repair by scaring
• Scaring occurs in the following conditions:
• When the tissue injury is severe or chronic and caused damage to both the
epithelial cells and the connective tissue framework.
• If the injury occurs in permanent tissues.
• Under these conditions, the tissue is repaired by replacing the
damaged tissue with a fibrous tissue to form a scar.
• Although the scar is not normal, it provides stability to the injured tissue to be
able to function.
Fibrosis: is a form of repair by scaring that results in the extensive
deposition of collagen fibers in the lungs, kidney or liver in response
to a chronic inflammation.
Steps in repair by scar formation
Healing of a large wound in the skin occurs by the following steps:
1. Formation of hemostatic plug (composed mainly of platelets) to stop the bleeding.
2. Inflammation: to eliminate the microbes and necrotic cells and to initiate the next
steps in tissue repair.
3. Cell proliferation
• Epithelial cells proliferate to cover the wound
• Endothelial and other vascular cells proliferate to form new blood vessels (a process called
angiogenesis).
• Fibroblasts proliferate and deposit collagen to form the scar.
 Granulation tissue is a type of tissue that is found in healing wounds and is composed of
proliferating fibroblasts, new blood vessels, scattered inflammatory cells and the loose connective
tissue.
4. Remodeling: the connective tissue deposited by the fibroblasts is reorganized to give a
more stable fibrous scar.