INFLAMMATION Mrs.

Bayan Subb Laban

( ACUTE AND CHRONIC)
INTRODUCTION
•Inflammation is a response of vascularized tissues to infections and tissue
damage that brings cells and molecules of host defense from the circulation
to the sites where they are needed, to eliminate the offending agents.

•In common medical and lay parlance inflammation suggest a harmful

reaction, BUT it is actually a protective response essential for survival.

•Inflammation serves to rid the host of both:

1) The initial cause of cell injury ( microbes, toxins,..)
2) The consequences of injury (necrotic, toxins,)
INTRODUCTION
• Inflammation occurs in the vascularized connective tissues.
• Without inflammation:
oInfections would go unchecked
oWounds would never heal
oInjured tissues might remain permanent festering sores…

• Inflammation has considerable potential to cause harm.

oe.g. life-threatening anaphylactic reactions to insect bites or drugs.

• Inflammation is followed by repair process:

oRegeneration
oScar formation
INFLAMMATION CAUSES: INJURY
1) Infections – bacterial, viral, fungal, parasitic
2) Tissue necrosis – ischemia, physical and chemical injury..
3) Foreign bodies – dirt, sutures, crystal deposits..
4) Immune reaction (hypersensitivity) – Normally protective immune system
damages the individual’s own tissues

­ May be directed against self antigens, causing autoimmune diseases

­ May be inappropriate reactions against environmental substances as in allergies.
CARDINAL SIGNS OF INFLAMMATION
External manifistation of inflammation

• Heat (calor) ……Increase in temperature (hyperaemia)

• Redness (rubor)……dilatation of blood vessels
• Swelling (tumor) …….increased extravascular fluid
• Pain (dolor) ……activation of afferents by mediators
• Loss of function …..Movement is inhibited by pain
CARDINAL SIGNS OF INFLAMMATION

• Redness ( Rubur):

oCaused by blood vessel dilatation ( arterioles)

oChemical mediators promote the vessel dilatation (contained in the
capillary walls or endothelium resulting in immediate response)

• Histamine
• Serotonin
• Bradykinins
• Prostaglandins
CARDINAL SIGNS OF INFLAMMATION

• swelling ( tumor)

oEdema fluid varies with the stage of inflammation

• Initially vessel permeability is only slight altered and no cells or

protein escapes and the fluid is mainly water and dissolved
electrolytes (transudate): like synovial fluid
• As capillary permeability increases and plasma proteins escape
the extravascular fluid becomes cloudy and more viscus. This is
called exudate (contains a large amount of leukocytes, called
bus)
CARDINAL SIGNS OF INFLAMMATION

•Pain ( dalor ):
o Results from irritation of nerve ending by chemical or physical factors.
o Physical trauma may initiate pain receptors
o Chemical mediators release when cell damage occurs sensitize pain
receptors.
•Heat ( calor)
o The result of chemical activity and increased blood flow in the injured
areas.
• loss of function
o May occur due to pain causing reflex guarding or muscle spasm
 9

PATTERNS OF INFLAMMATION:
Ø Acute inflammation:
• Initial and rapid response to injury.
• Develop within minutes to hours.
• Short duration lasting for several hours to few days.
• Characterized by fluid and plasma protein exudation (edema) and emigration of
leukocytes, predominantly neutrophils.

Ø Chronic inflammation:
• A response of prolonged duration, weeks or months.
• May follow acute inflammation or may arise de novo.
• Characterized by influx of macrophages and lymphocytes with associated vascular
proliferation and scarring.
• Associated with more tissue destruction.
SEQUENCE OF EVENTS
IN AN INFLAMMATORY
REACTION
1) Recognetion of the injurious agent
2) Recruitment of leukocytes
3) Removal of the agents
4) Regulation of the response
5) Resolution (repair)
COMPONENTS FOR INFLAMMATION:

Ø The vascular wall cells include the endothelial cells in direct contact with
the blood, and the underlying smooth muscle cells that control the vessels
tone.

Ø The circulating cells include bone marrow-derived leukocytes: neutrophils,

eosinophils, basophils, lymphocytes and monocytes.

Ø The circulating proteins include clotting factors, complement system.

COMPONENTS FOR INFLAMMATION

Ø The connective tissue cells include mast cells & macrophages, in addition
to the fibroblasts that synthesize the extracellular matrix and can proliferate
to fill in a wound.

Ø Connective tissue (extracellular matrix) consists of fibrous structural

proteins (e.g., collagen and elastin), gel-forming proteoglycans, and
adhesive glycoproteins (e.g., fibronectin) that are the cell-ECM and ECM-
ECM connectors
COMPONENTS FOR INFLAMMATION
INFLAMMATION - EXAMPLES

Dermatitis Appendicitis

Tonsillitis Meningitis
ACUTE INFLAMMATION

• Acute – up to days.
• Vascular changes : Hyperemia & exudation.
• Neutrophils, pus/suppuration.
• Immediate and early response to injury aiming at delivery of
leukocytes to the site of injury.
ACUTE INFLAMMATION
Acute inflammation has three major components:

1) Dilation of small vessels, leading to an increase in blood flow --

vascular
2) Increased permeability of the microvasculature, enabeling plasma
protein and leukocytes to leave the circulation -- vascular
3) Emigration of the leukocytes from the microcirculation, their
accumolation in the focus of injury, and their activation to eliminate
the offending agent. -- cellular
VASCULAR CHANGES
Changes in vascular flow
• Vasodilation is induced by the action of several mediators, notably
histamine, on vascular smooth muscle.
• Result in increase in blood flow, which is the cause of heat and redness at
the site of inflammation.
•Vasodilation is quickly followed by increased permeability, leading to
outpouring of proteins-rich fluid (an exudate) into the extravascular tissue, this
cause the swelling.
•Slowing of the circulation due to increased viscosity and stasis.
•As stasis develop, blood leukocytes, principally neutrophils, accumulate along
the vascular endothelium.
VASCULAR CHANGES
Increased vascular permeability
Related to three mechanism:
1) Retraction of endothelial cell
1) Immediate transient response.
2) The most common mechanism.
3) Mediated by histamine, bradykinine,leukotriene and other mediators.
2) Endothelial injury
1) Result in endothelial cell necrosis
2) Occurs in severe injury like burns, some microbes.
3) Sustained for several hours.
3) Increased transport of fluids and proteins called transcytosis, through the
endothelial cell.
VASCULAR CHANGES
Increased vascular permeability
Types of fluids that can be seen in interstitial fluid:
I. Exudate: is an extravascular fluid that has high protein concentrations and
contains cellular debris. Its presence implies that there is an increase in the
permeability of small blood vessels, typically during an inflammation.
II. Transudate: is a fluid with low protein content, little or no cellular material, and low
specific gravity. It is ultrafiltrate of blood plasma that is produced as a result
osmotic imbalance across vessels with normal vascular permeability.
III. Edema: an excess of fluid in the interstitial tissue or serous cavities; it cab be
either an exudate or a transudate.
IV. Pus or purulent exudates: inflammatory exudate rich in leukocytes ( mostly
neutrophils), dead cells debris and in many cases microbes.
RESPONSES TO LYMPHATIC
VESSELS
• In addition to blood vessels, lymphatic vessels also participate in
acute inflammation.
• In normal state, lymphatics drain the small amount of
extravascular fluids that out of the capillaries.
• In inflammation, lymph flow is increased to help drain edema fluid
that accumulates because of increased vascular permeability.
• In addition to fluid, leukocytes and cell debris, as well as
microbes, may find their way into the lymph.
CELLULAR EVENTS
• The inflammatory response involves many different WBC’s
(Leukocytes)
• They are recruited to sites of inflammation to perform the key function
of eliminating the offending agents.
• The most important leukocytes in acute inflammatory reactions are
the ones capable of phagocytosis, namely, neutrophils.
•In most forms of acute inflammation neutrophils predominate in the
inflammatory infiltrate during the first 6-24 hours and are replaced by
monocytes in 24-48 hours.
CELLULAR EVENTS
Neutrophils ( the main leukocyte in acute inflammation):
• Produced in bone marrow.
• Rapidly recruited to sites of inflammation.
• Short lifespan (hours in tissues).
Macrophages:
• Slower responder
• Long lifespan
These leukocytes ingest and destroy microbes, necrotic tissues and foreign
substances.
Leukocyte recruitment:
• Rolling – Adhesion - Transmigration - Chemotaxis (locomotion along a chemical gradient) –
Activation - Phagocytosis and degranulation
CHEMICAL MEDIATORS OF
INFLAMMATION
• Mediators are substances that initiate and regulate inflammatory

• Mediators may be produced locally by cells at the site of inflammation

(Cell-derived mediators), or may be derived from circulating inactive
precursors that are activated at the site of inflammation (Plasma-
derived mediators)

• The major cell type that produce mediators of acute inflammation are
tissue macrophages, dendritic cells and mast cells.
CHEMICAL MEDIATORS OF
INFLAMMATION
• Cell-derived mediators
ü Maintained in intracellular granules
ü Quickly released or produced in response to tissue injury
ü Usually are short-lived but can stimulate the release of other
mediators, amplifying the inflammatory response

• Plasma protein systems

ü Sometimes referred to as cascades because each component is
activated sequentially (e.g., complement proteins)
Cell-Derived Mediators Description

Vasoactive amines •Histamine released in response to allergic reaction or injury;

vasodilates and increases vascular permeability
•Serotonin is a vasoconstrictor

Lipid mediators •Prostaglandins=vasodilation, pain, fever

(Eicosanoids) •Leukotrienes=increase vascular permeability, chemotaxis, and
leukocyte adhesion
•Lipoxins= suppress inflammation by inhibiting neutrophil
recruitment

Cytokines •Pro- or anti-inflammatory

•Many types ( TNF , IL-1 , IL-6)

Inflammasomes •Complex proteins that promote production of pro-inflammatory

cytokines

Chemokines •Small signaling proteins act in chemotaxis and leukocyte activation

Plasma Protein Description
Systems

Complement System •Produced in the liver

•Over 20 different complement proteins that are activated
with inflammation
•Cascade of events triggered by three different pathways:
classical, lectin, and alternative
Coagulation System
•Inflammatory mediators activate coagulation

Kallikrein–Kinin System •Produced in the liver

•Cascade of metabolic events that interacts with the clotting
system
•Plays important role in inflammation
•Kinins are potent vasodilators that regulate the inflammatory
process; involved in pain sensation and cell growth
 OUTCOMES OF ACUTE INFLAMMATION
Factor Description
Resolution • Healing of the tissue
• No permanent destruction
•Restoration of the site of acute inflammation to normal
•Resorption of edema fluid by lymphatics

• Example: recovery from the common cold

Fibrosis Formation • Scarring from significant tissue damage
• Epithelial cells are replaced by fibroblasts
•Inflammatory injury involves tissues that are incapable of regeneration

• Example: myocardial infarction

Abscess Formation • Usually caused by bacteria
• Cavity that contains pus

• Example: suppuration occurred after infection with the pus-producing

bacteria, such as Staphylococcus and Streptococcus.
Chronic Inflammation • Response cannot be resolved, as a result of either the persistence of the
injurious agent or some interference with the normal process of healing
OUTCOMES OF ACUTE INFLAMMATION
NOMENCLATURE AND ETIOLOGY OF COMMON TYPES OF INFLAMMATION
Tissue Acute inflammation Typical causes
Meninges Meningitis Bacterial and viral infections
Brain Encephalitis Viral infections
Lung Pneumonia Bacterial infections
Pleura Pleurisy Bacterial and viral infections
Pericardium Pericarditis Bacterial and viral infections, MI
Esophagus Esophagitis Gastric acid reflux, fungal infections
Stomach Gastritis Alcohol abuse, Helicobacter pylori infection
Colon Colitis Bacterial infections, ulcerative colitis
Rectum Proctitis Ulcerative colitis
Appendix Appendicitis Faecal obstruction
Liver Hepatitis Alcohol abuse, viral infections
Gallbladder Cholecystitis Bacterial infections, chemical irritation
Pancreas Pancreatitis Pancreatic enzyme release
Urinary bladder Cystitis Bacterial infections
Bone Osteomyelitis Bacterial infections
Subcutaneous tissues Cellulitis Bacterial infections
Skin Sunburn UV radiation
Joints Arthritis Bacterial & viral infections, immune complex deposition
Arteries Arteritis Immune complex deposition
CHRONIC INFLAMMATION
• Defined as inflammation that lasts more than two weeks, or months, or
years
• It may follow acute inflammation, or may begin insidiously without any signs
• Infiltration of macrophages and lymphocytes occurs in chronic
inflammation, versus neutrophils in acute inflammation
• Chronic inflammation is associated with tissue destruction and replacement
of damaged tissue with fibrous tissue
• Occurs via angiogenesis, blood vessel formation
• It is mediated by cytokines produced by macrophages and lymphocytes
CHRONIC INFLAMMATION
Causes of chronic inflammation:
1) Persistent infections by microorganisms that are difficult to eradicate
•Mycobacteria, certain viruses, fungi, and parasites
•Bacterial infection of the lung progresses to a chronic lung abscess.

1) Hypersensitivity diseases
•Autoimmune diseases (rheumatoid arthritis, multiple sclerosis)
•Allergic diseases (bronchial asthma)

1) Prolonged exposure to potentially toxic agents, either exogenous or endogenous

•Exogenous agent (silica, suture material, asbestos)
•Endogenous (fat causes Atherosclerosis, uric acid crystals in gout )
CHRINIC INFLAMMATION
Morphologic features:
1. Infiltration with mononuclear cells: macrophages, lymphocytes and
plasma cells.

2. Tissue distruction: induced by the persistent offending agent or by

the inflammation cells.

3. Attempts at healing: by connective tissue replacement of damaged

tissue, accomplished by angiogenesis ( proliferation of small blood
vessels) and fibosis.
 ACUTE VERSUS CHRONIC INFLAMMATION
Acute Chronic
Duration Short (days) Long (weeks to months)
Onset Fast: minutes or hours Slow: days
Lymphocytes, plasma
Inflammatory
Neutrophils, macrophages cells, macrophages,
cells
fibroblasts
Active vasodilatation, New vessel formation
Vascular changes
increased permeability (angiogenesis)
Tissue injury, May be severe and
Usually mild and self-limited
fibrosis progressive
Cardinal signs + –
SYSTEMIC EFFECTS OF INFLAMMATION

• Inflammation, even if it is localized, is associated with cytokine-induced

systemic reactions that are collectively called the acute-phase response.
• Anyone who has suffered through a severe bout of a bacterial or viral illness
(e.g., pneumonia or influanza) has experienced the systemic manifistation of
acute inflammation.
• These changes are reactions to cytokines whose production is stimulated by
bacterial products such as LPS, viral double stranded RNA and by other
inflammatory stimuli.
• The cytokines TNF, IL-1 and IL-6 are important mediators of the acute-phase
reaction
• Other cytokines, notably type 1 interferons, also contribute to the reaction.
SYSTEMIC EFFECTS OF INFLAMMATION
Clinical and pathological changes related to acute-phase
reaction:
1) Fever
2) Acute-phase proteins
3) Leukocytosis

oOther manifestations of acute-phase response include increased heart rate

and blood pressure, decreased sweating, rigors, chills, anorexia and malaise.
SYSTEMIC EFFECTS OF INFLAMMATION

Fever
• Is one of the most prominent manifestation of the acute-phase reaction,
especially when inflammation is assocuated with infections.
• Substances that induce fever are called pyrogens.
• Bacterial products, such as LPS ( called exogenous pyrogens), stimulate
leukocytes to release cytokines such as IL-1 and TNF (called endogenous
pyrogens).
• This cytokines increase the enzymes (cyclooxygenases) that convert
arachadonic acid into prostaglandins.
• In the hypothalamus, prostaglandins, especially PGE2, stimulate the production
of neurotransmitters that reset the temperature set point at a higher level.
o NSAID, including aspirin, reduce fever by inhibiting prostaglandin synthesis.
SYSTEMIC EFFECTS OF INFLAMMATION

Serum proteins increase

• Are plasma proteins, mostly synthesized in the liver through
stimulation of cytokines.
• Three of the best-known of these proteins are C-reactive protein
(CRP), fibrinogen, and serum amyloid A (SAA) proteins.
• Many acute-phase proteins, such as CRP and SAA, binds to
microbial cell walls to facilitate phagocytosis.
SYSTEMIC EFFECTS OF INFLAMMATION

Leukocytosis
• Elevated WBC count of 15,000 - 20,000 cells/μL (normal =
4,000 - 10,000 cells/μL)

•Increased neutrophils = acute inflammation and bacterial infections.

•Increased macrophages = chronic inflammation.
•Increased lymphocytes = viral infections.
•Increased eosinophils = allergic reaction.