Inflammation - Lecturio 19/12/22, 6:34 AM

Inflammation
Inflammation is a complex set of responses to infection and injury involving
leukocytes as the principal cellular mediators in the body’s defense against
pathogenic organisms. Inflammation is also seen as a response to tissue injury in
the process of wound healing. The 5 cardinal signs of inflammation are pain,
heat, redness, swelling, and loss of function. The major cellular response involves
neutrophils and macrophages to phagocytose and lyse the injurious organism or
repair necrosed tissue after injury. Inflammation can be pathologic if it is
prolonged or when normal processes create an excessive response (such as with
atherosclerosis). There are multiple mediators of inflammation that overlap with
innate immunity when they respond to injurious stimuli. Inflammation can become
chronic, resulting in the formation of granulomas, tissue damage, and the loss of
organ function.

Last updated: April 6, 2022

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CONTENTS

Introduction
and Classic
Signs
Mediators
of
Inflammation
Physiology
of Acute
Inflammation
Outcomes
of Acute
Inflammation
Chronic
Inflammation
Clinical
Relevance
References

Introduction and Classic Signs

Inflammation is a complex set of responses to infection and
injury, involving leukocytes as the principal cellular mediators in
the body’s defense against pathogenic organisms. Inflammation
is also seen as a response to tissue injury in the process of
wound healing.

Inflammatory responses
Types:
Physiologic (e.g., wound healing, localizing infection)
Pathologic (e.g., malignancy, chronic inflammation)
Triggers of acute inflammation:

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Infections/microbial toxins:
Bacterial (primarily)
Viral
Fungal
Parasitic
Physical or chemical injury: 
Thermal injury
Radiation
Environmental chemicals
Foreign bodies: 
Splinters
Dirt, glass, or rust in a wound
Surgical sutures
Necrotic tissue due to ischemia or trauma
Thrombus
Uric acid (from the breakdown of DNA in cells)
Mediators from mast cells, macrophages, and
fibroblasts
Characteristics of acute inflammation:
Immediate onset (minutes)
Short duration: Resolves within days
Classic signs and symptoms
Primary response by neutrophils:
Remove pathogens and necrotic cells/tissues
Bridge to innate immunity
Initiate tissue repair
Release proteases that may damage normal
tissues
Characteristics of chronic inflammation:
Slow onset (days)
Long duration: months or years
More specific signs or symptoms
Monocytes in the circulation become macrophages in
the tissues → degrade debris and orchestrate
healing versus scarring

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Innate inflammation:
Has proinflammatory and antiinflammatory checks
and balances
Has potential to cause harm

Acute

Predominantcell Macrophage
Neutrophil
type Tlymphocyte

Rapidonset, Slowonset,
Timecourse
short-lived long-lived

Contrasting acute and chronic inflammation

Image by Lecturio.
Natureofthe
Physiologic Pathologic
response
Classic signs (Latin terms)
Usuallymildand Oftensevere
TissueRubor
damage(redness): due to ↑ blood flow and
resolvesquickly andprogressi
accumulation at the point of injury or inflammation
Calor (heat): due to a combination of blood flow and
local reaction 
Tumor (swelling): due to inflammatory mediators →↑
fluid extravasation → edema
Dolor (pain): mediated by cytokines, bradykinin, and
prostaglandins
Functio laesa (loss of function): results from tissue
damage

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Heat Redness Swelling Pain

Acute inflammatory response
Image by Lecturio.

Duetostimulatio
Duetoincreased Dueto
sensoryneurons
bloodflowtosite accumulation
inflammatory
ofinflammation offluidandcells
mediators
Mediators of Inflammation
There are multiple mediators of inflammation that bring
inflammatory cells into the sites of injury and overlap with
innate immunity when they respond to injurious stimuli.

Primary cellular response (WBCs)

Neutrophils
Macrophages and monocytes
Mast cells and basophils

Mediators of inflammation
Acute-phase proteins (e.g., CRP)
Cytokines: signaling proteins released by immune
cells
Interleukins:
Proinflammatory: IL-1β, IL-6, IL-8, interferon
(IFN)-γ
Antiinflammatory: IL-4, IL-10, IL-13
Tumor necrosis factor (TNF)
Reactive oxygen species (ROS)

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Platelet-activating factor:
Made from membrane phospholipids
Causes vasodilation, ↑ vascular permeability,
and platelet activation
Also is a cytokine
Arachidonic acid (AA) metabolites: 
Prostaglandins → vasodilation; increased
vascular permeability
Prostacyclin (prostaglandin I2 (PGI2)) →
vasodilation; inhibits platelet aggregation
Thromboxane A2 → vasoconstriction; promotes
platelet aggregation (opposite effect of
prostacyclin) 
Leukotrienes (proinflammatory) →
vasoconstriction, bronchospasm, ↑ vascular
permeability

Acute-phase reactants (APRs)

Under the influence of cytokines (IL-6), hepatocytes
produce APRs.
> 30 APRs are produced.
Used as laboratory markers of acute inflammation

Table: Selected acute-phase reactants (APRs)

Reactant Function

CRP Activates the complement cascade → promotes

phagocytosis
Sensitive, but nonspecific
↑ within 12 hours after onset
Half-life: 24 hours

ESR The rate at which red blood cells settle at the

bottom of a thin tube
Rate ↑ when inflammatory proteins are present
Nonspecific

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Haptoglobin Binds iron to ↓ availability to pathogens

Removes free heme from hemolysis (heme is an
oxidant → cell damage)

SAA Causes immune cell recruitment at the site of

inflammation

ESR: erythrocyte sedimentation rate

SAA: serum amyloid A

Physiology of Acute Inflammation

General process
Recognition of injury → vascular response phase →
cellular response phase (neutrophil recruitment,
phagocytosis and killing, mediator release) → tissue
swelling
Lines of defense:
1st: Resident macrophages begin phagocytosis.
2nd: Chemokine-induced neutrophil
extravasation
3rd: Monocyte extravasation → tissue
macrophages (phagocytosis)
4th: ↑ Cell production by the bone marrow

Recognition of tissue injury

Tissue damage → stimulates
pathogen-associated molecular patterns (PAMPs) 
Neutrophils migrate in response to infection, then
recognize these molecules:
PAMPs (from pathogens such as bacteria):
Double-stranded RNA (dsRNA)

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Unmethylated islands of DNA (found in

bacteria, not humans)
Lipopolysaccharides 
Mannose
Phosphorylcholine
Damage-associated molecular patterns
(DAMPs):
Found in dead tissue; neutrophils respond
to degrade it 
Part of the host defense system
Can also promote pathologic inflammatory
responses in chronic inflammatory
diseases (e.g., rheumatoid arthritis,
systemic lupus erythematosus,
atherosclerosis, Alzheimer disease, and
cancer)
Opsonins: proteins that induce phagocytosis
IgG
Complement fragments
Pattern-recognition receptors (PRRs): 
TLR: expressed on sentinel cells such as
macrophages
Pentraxins: proteins involved in
immunologic responses, including CRP
and serum amyloid
Immune receptors: Fc receptors, complement
receptors
PAMPs and DAMPs → activate
proinflammatory cytokines and chemokines →
Endothelial cells on blood vessels release
prostaglandins and nitric oxide.
Mast cells and basophils release histamine.
Platelets release prostaglandins and serotonin.

Vascular response phase

Vasodilation:

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Brings more blood flow to the tissue

Allows delivery of cells and mediators to the injured
tissue for response
Mediators of the vascular response:
Mast cell degranulation → histamine release →
relaxation of smooth muscle (vasodilation)→ ↑
blood flow
Nitric oxide (synthesized by endothelium and
macrophages) → vasodilation → ↑ blood flow
Eicosanoids (prostaglandins and leukotrienes):
also cause vasodilation
Increased permeability: 
Causes extracellular fluid shift
Slows blood flow and allows cell recruitment
Deposits circulating mediators to the site of injury
Early response (in minutes) → direct endothelial
injury and driven by:
Histamine
Bradykinin
Leukotrienes
Late response (hours later) is by leukocyte-mediated
damage through:
Cytokines:
IL-1
TNF
ROS
Prostaglandins
Edema is seen because of:
↑ Endothelial permeability
Endothelial damage
Vasodilation and stasis
Cellular release of chemicals causes:
Transient vasoconstriction due to endothelial cell
contraction
Followed by endothelial cell retraction →
vasodilation 

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↑ Vascular permeability → exudation of fluid and

cells into tissue → fluid shift

Cellular response phase

Neutrophil recruitment:
Chemotactic substances:
N-formyl methionine (on bacterial cell walls)
Leukotriene B4
Complement C5a
Platelet-activating factor
Chemokines:
Activate leukocyte integrins
Attract leukocytes to move out of the
bloodstream
Activate antimicrobial functions
Rolling and adhesion:
Endothelial cells express E-selectin and
P-selectin under the influence of TNF and IL-1 →
Bind to the sialyl-Lewis X glycoprotein on
neutrophils → 
Endothelial cells express ICAM-1 (intercellular
adhesion molecule 1, a glycoprotein also known
as CD54) and chemokines activate the integrins
on the neutrophil →
Activation and adhesion of the neutrophil 
Transmigration: 
Chemotaxis: chemokine-activated neutrophils
Diapedesis (also known as leukocyte
extravasation): neutrophils move to the site of
inflammation
Phagocytosis and killing: 
Neutrophils have transmigrated →
Phagocytosis: Neutrophils bind to PRRs →
membrane wraps around and engulfs microorganism
→
Leukocyte killing→ destruction of the engulfed

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microorganisms by:
Oxidative burst: ROS kill the pathogens.
Lysosomal proteases degrade the pathogens.
The complement pathway → cell death by formation
of a membrane attack complex (MAC)
Definition of complement:
A collection of circulating proteins from
the liver and macrophage-synthesized
proteins
A cascade of activation triggered by
antigen–antibody complexes, bacterial
polysaccharides, aggregated IgA
Activated complement fragments cause:
Vasodilation
↑ Permeability
Leukocyte adhesion
Chemotaxis
Neutrophil activation
Complement fragments are proinflammatory: 
C3a and C5a are potent chemotactic
agents (recruit and activate neutrophils).
C3b induces opsonization (recognizing
and targeting invading particles for
phagocytosis) → neutrophils and
macrophages bind and kill pathogens
C3b and cleavage of other complement
factors form a MAC → lysis of microbes
Mediator release:
Inflammatory stimuli on membrane phospholipids →
cascade of AA metabolites:
COX pathway is proinflammatory and
produces: 
Prostaglandins → vasodilation, ↑ vascular
permeability
PGI2 → vasodilation, inhibits platelet
aggregation

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Thromboxane A2 → vasoconstriction,
promotes platelet aggregation (opposite
effect of prostacyclin) 
Lipoxygenase pathway produces:
Leukotrienes (proinflammatory) →
vasoconstriction, bronchospasm, ↑
vascular permeability 
Lipoxins (antiinflammatory) → inhibit
neutrophil adhesion and chemotaxis 
ROS: involved in leukocyte killing
Platelet-activating factor: activated platelets set off
cascades of kinins and coagulation factors → pain
and clotting

Interplay of various chemokines:

Various ligands and receptors bind and promote neutrophil extravasation.
C3a and C5a: complement
ICAM-1: intercellular adhesion molecule 1
LPS: lipopolysaccharides
TNF-α: tumor necrosis factor alpha

Image by Lecturio.

Tissue swelling
Fluid in the interstitial space has ↑ amounts of protein
and fibrinogen:
Fibrinogen promotes clotting to contain the
pathogen
Migration of granulocytes and monocytes →

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extravasate into the tissue → swelling

Factor XIIa (Hageman factor):
 Activates the kinin cascade → bradykinin → 
Pain
↑ Vascular permeability → swelling
Activates the coagulation pathway → clotting
Indirectly activates the fibrinolytic system (
anticoagulation) at the same time as
coagulation → 
Breaks down fibrin to limit the amount of
clotting
Activates the complement cascade
involved in phagocytosis and killing
Factor IIa (thrombin):
Triggers acute inflammation
Cleaves fibrinogen to fibrin → fibrin-split
products

Outcomes of Acute Inflammation

Inflammation can resolve, form abscesses, or become chronic.
Resolution:
Mediated by IL-10 and
transforming growth factor beta (TGF-beta;
antiinflammatory cytokines)
Most inflammatory mediators will break down
on their own (e.g., eicosanoids).
Neutrophils: 
Die approximately 10 hours after
extravasation
Undergo apoptosis
Digested by macrophages
Tissue macrophages remove pathogens and
cellular debris → tissue repair → wound healing

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Lymphatic system → resolves edema

Scarring may occur owing to: 
Lack of stem cells 
Replacement with fibrotic tissue
Abscess formation may occur: 
Owing to pyogenic organisms
Mediated by IL-1 and TNF-alpha
Dead neutrophils, macrophages, and necrosed
tissue result in pus. 
Pus that is isolated by fibrosis into a fibrous
capsule → abscess
Systemic effects of acute inflammation:
Sepsis
Hypotension (due to cytokine-induced
vasodilation)
Thrombosis (due to mediators causing
activation of platelets and clotting factors)
Chronic inflammation:
Mediated by IL-6 and IL-12
Involves activation of T helper cells → infiltrate
tissue
Ongoing, unchecked inflammation → tissue
damage and necrosis

Chronic Inflammation
Acute inflammation with persistent reinjury can lead to chronic
inflammation. Chronic inflammation can also be seen with viral
infections and autoimmune disorders.

Overview of chronic inflammation

Lymphocytes and macrophages are key cells
involved.
Can be prolonged (weeks to years)

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A central component of various chronic conditions:

Autoimmune diseases, such as:
Rheumatoid arthritis
Systemic lupus erythematosus
Multiple sclerosis
Neurodegenerative diseases 
Granulomatous inflammation, such as with TB
Cancer
Chronic obstructive pulmonary disease (COPD)
Inflammatory bowel disease: 
Crohn disease
Ulcerative colitis

Etiology
Failure of complete removal of the pathogen (e.g., TB
)
Persistent stimuli (e.g., an inhaled foreign body such
as silica)
Inflammatory response producing continuous
oxidative damage stimulating chronic inflammation
(e.g., atherosclerosis)

Mediators of chronic inflammation

Macrophages:
Sources of cytokines and chemokines
Produce complement and coagulation factors
Also make: 
Proteases
ROS
Eicosanoids
T lymphocytes
B cells (plasma cells)
Eosinophils, mast cells
Cytokines:
IL-12
TNF

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Types of chronic inflammation

Nonspecific:
Proliferative 
Nonspecific granulation tissue → fibroblast
overgrowth
Granulomatous inflammation:
Granulomas are:
An aggregation of macrophages,
epithelioid cells, and giant cells
Surrounded by fibroblasts and
lymphocytes
Maintained by TNF-alpha secreted by
epithelioid cells
Caseating granuloma: necrotizing core due to
infectious material (e.g., TB)
Noncaseating granuloma: nonnecrotized core
owing to immune-mediated cellular damage
(e.g., sarcoidosis)

(A) Schematic representation and (B) histological appearance of an artificial

pulmonary granuloma induced in mouse 4 days after injection of purified
protein-derivative (PPD)-coated beads (H&E staining; magnification: ×800)
rbead: radius of the bead
rg: radius of the granuloma

Image (https://openi.nlm.nih.gov/detailedresult?
img=PMC2865521_pcbi.1000778.g001&query=granulomatous%20lesion&it=xg&lic=by&req=4&npos=40):
“PPD antigen-bead pulmonary granuloma model” by Fallahi-Sichani, M., et al. License: CC
BY 4.0 (https://creativecommons.org/licenses/by/4.0/)

Outcome of chronic inflammation

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Scarring and fibrosis within the organ → damage and

loss of function 
Continuous inflammation → neoplasm
Amyloidosis

Clinical Relevance
Examples of inflammation becoming a pathologic response: 
Atherosclerosis: common form of arterial disease in
which lipid deposition forms a plaque in the blood
vessel walls. Atherosclerosis starts with endothelial
injury secondary to turbulent flow and is followed by
lipid retention through monocytic response, leading
to the formation of foam cells. This process ultimately
results in the formation of a fibrous plaque. The
plaque narrows the lumen and can cause ischemia,
resulting in MI, stroke, CKD, and other organ
compromise.
Multiple sclerosis (MS): chronic inflammatory
autoimmune disorder leading to demyelination of the
CNS. Inflammation occurs when the oligodendrocyte
recognizes self myelin as a foreign antigen and
results in the removal of the myelin sheath.
Symptoms arise owing to the swelling plus loss of
tissue function and include neurologic symptoms
affecting vision, motor functions, sensation, and
autonomic function.
Pulmonary fibrosis: type of interstitial lung disease.
Environmental exposure to minute inhalants such as
smoke, pollutants, and dust causes an inflammatory
process within the lung tissue, resulting in fibrosis on
injury repair. Individuals often present in a moderate-
to-advanced stage with progressive dyspnea and
nonproductive cough. The diagnosis is made on the

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basis of imaging findings and

pulmonary function testing. Lung transplantation is
the only curative intervention. 
Disorders due to deficiency in some mediators of the
inflammatory response: 
Defects in adhesion: Leukocyte adhesion deficiency
I (LAD I) is due to defective synthesis of integrin in the
cellular response phase and deficient binding to
immunoglobulins, which result in recurrent infections.
Leukocyte adhesion deficiency II (LAD II) is a rare
disorder in which neutrophils are deficient in the
expression of sialyl-Lewis X, which is needed for
rolling in the cellular response phase of inflammation.
Leukocyte adhesion deficiency II is characterized by
recurrent infections, persistent leukocytosis, and
severe deficits in development and growth.
Defect in phagolysosome formation: Chediak-
Higashi syndrome is an autosomal recessive disorder
caused by mutations affecting a
lysosomal trafficking regulator protein, whereby
phagocytosed bacteria are not destroyed by
lysosomal enzymes. Chemotaxis is also disrupted,
resulting in poor neutrophil recruitment and function.
Individuals exhibit recurrent pyogenic infections, easy
bleeding and bruising, and neurologic manifestations.
The diagnosis is based on analysis of the individual's
blood or bone marrow smear and genetic testing. 
Defect in microbicidal activity:
Chronic granulomatous disease (CGD), seen in
individuals with a genetic mutation for
NADPH oxidase, which is responsible for the
respiratory burst in phagocytic leukocytes. Infections
may be contained; however, lysis does not occur,
thus resulting in chronic granuloma formation.
Individuals with CGD are at increased risk of life-
threatening infections with fungi and catalase-

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positive bacteria.

References

1. Hall, J. E., Guyton, A. C. (2011). Resistance of the body to infection I.

Chapter 33 of Guyton and Hall Textbook of Medical Physiology, 12th
ed. Philadelphia: Saunders Elsevier, pp. 428–430.

2. Kumar, V., Abbas, A. K., Aster, J. C. (2017). Inflammation and repair.

Chapter 3 of Robbins Basic Pathology, 10th ed. Elsevier, pp. 57–70,
79–82.

3. Johnston, R. B. (2021). An overview of the innate immune system.

UpToDate. Retrieved September 14, 2021, from
https://www.uptodate.com/contents/an-overview-of-the-innate-
immune-system (https://www.uptodate.com/contents/an-overview-of-
the-innate-immune-system?source=history_widget)

4. Stone, W. L., Basit, H., Burns, B. (2020). Pathology, inflammation.

StatPearls. Retrieved September 14, 2021, from
https://www.ncbi.nlm.nih.gov/books/NBK534820/
(https://www.ncbi.nlm.nih.gov/books/NBK534820/)

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