inflammation lecture 1

Lecture 1 Inflammation
Dr.Ahmed Raji
Definition: is the response of living tissue to injurious agent.
Etiology:
1- Physical Agents: Mechanical trauma, extremes of temperature, radiation.
2- Chemical Agents and Drugs: Industrial and occupational hazards, such as asbestos.
3- Infectious Agents.
4- Tissue necrosis.
5- Immune reaction.
6- Foreign body.
Classification of inflammation:
1- Acute
2- Chronic
Acute inflammation:
Is a rapid host response that serves to deliver leukocytes and plasma proteins, such as
antibodies, to sites of infection or tissue injury.
Etiology of Acute Inflammation:
Acute inflammatory reactions may be triggered by a variety of stimuli:
• Infections (bacterial, viral, fungal, parasitic) and microbial toxins.
• Tissue necrosis from any cause, including ischemia (as in a myocardial
infarct), trauma, and physical and chemical injury.
• Foreign bodies (splinters, dirt, sutures) typically elicit inflammation because
they cause traumatic tissue injury or carry microbes.
• Immune reactions (also called hypersensitivity reactions).
Macroscopical features of acute inflammation:
Swelling, Redness, Hotness, Pain, Loss of function.
Changes of acute inflammation:
A- Vascular changes: which includes
(1) Changes in vascular caliber and blood flow:
First: there is a transient constriction of arterioles, lasting a few seconds.
Second: vasodilation which involves the arterioles and then leads to opening of new
capillary beds, the result is increased blood flow, which is the cause of heat and redness
(erythema) at the site of inflammation, vasodilation is induced by the action of several
mediators, notably histamine and nitric oxide (NO).
Third: slowing of blood flow (stasis) as a result of the loss of fluid, increased vessel
diameter, concentration of red cells in small vessels, and increased viscosity of the
blood.
(2) Changes in the in vascular structure :(increased vascular permeability)
Increased vascular permeability leads to the escape of a protein-rich exudate into the
extravascular tissue, causing edema. Several mechanisms are responsible for the
increased vascular permeability:
• Contraction of endothelial cells: resulting in increased interendothelial spaces
is the most common mechanism of vascular leakage.
• Endothelial injury: resulting in endothelial cell necrosis and detachment.
• Increased transport of fluids and proteins through the endothelial cell (called
transcytosis).
B- Cellular changes: which includes
(1) Emigration of the leukocytes from the microcirculation:
Leukocyte Adhesion to Endothelium.
Leukocyte Migration through Endothelium.
(2) Accumulation of the leukocytes in the focus of injury:
Chemotaxis of Leukocytes.
(3) Activation of the leukocytes to eliminate the offending agent:
Recognition of Microbes and Dead Tissues
Removal of the Microbes and Dead Tissues
(1) Emigration of the leukocytes from the microcirculation.
Leukocyte Adhesion to Endothelium.
Margination: is the process of leukocyte redistribution, because blood flow slows
early in inflammation (stasis), more white cells assume a peripheral position along the
endothelial surface.
Rolling: is the process of leukocytes adhesion transiently to the endothelium, detach
and bind again, thus rolling on the vessel wall.
Rolling is mediated by a family of proteins called selectins (adhesion molecules). There
are three types of selectins: one expressed on leukocytes (L-selectin), one on
endothelium (E-selectin), and one on platelets and on endothelium (P-selectin).
Adhesion: is the process of leukocytes adhesion firmly to the endothelium,firm
adhesion is mediated by a family of proteins called integrins (VLA-4, LFA-1 and Mac-
1).
Leukocyte Migration through Endothelium.
The next step is migration of the leukocytes through the endothelium, called
transmigration or diapedesis. Transmigration of leukocytes occurs mainly in postcapillary
venules. Chemokines act on the adherent leukocytes and stimulate the cells
to migrate through interendothelial spaces toward the chemical concentration gradient,
(toward the site of injury or infection where the chemokines are being produced), after
traversing the endothelium, leukocytes penetrate the basement membrane, by secreting
collagenases, and enter the extravascular tissue.
(2) Accumulation of the leukocytes in the focus of injury.
Chemotaxis of Leukocytes.
After exiting the circulation, leukocytes emigrate in tissues toward the site of injury by
a process called chemotaxis, which is defined as locomotion oriented along a chemical
gradient.
Both exogenous and endogenous substances can act as chemoattractants.
The most common exogenous agents are bacterial products.
Endogenous chemoattractants include several chemical mediators:
(1) Cytokines (e.g., IL-8).
(2) Components of the complement system, particularly C5a.
(3) Arachidonic acid (AA) metabolites, mainly leukotriene B4 (LTB4).
All these chemotactic agents bind to specific receptors on the surface of leukocytes
result in increased cytosolic calcium, with actin and myosin changes at the leading edge
of the cell. The leukocyte moves by extending filopodia that pull the back of the cell in
the direction of extension, the net result is that leukocytes migrate toward the
inflammatory stimulus in the direction of the gradient of locally produced
chemoattractants.
The nature of the leukocyte infiltrate varies with the:
1- Age of the inflammatory response.
In most forms of acute inflammation neutrophils predominate in the
inflammatory infiltrate during the first 6 to 24 hours and are replaced by
monocytes in 24 to 48 hours. After entering tissues, neutrophils are short-lived;
they undergo apoptosis and disappear after 24 to 48 hours.
Monocytes survive longer and proliferate in the tissues, and thus become the
dominant population in chronic inflammatory reactions.
2- Type of stimulus.
In certain infections—for example, those produced by Pseudomonas bacteria—
the cellular infiltrate is dominated by continuously recruited neutrophils for
several days.
In viral infections, lymphocytes may be the first cells to arrive.
In some hypersensitivity reactions, eosinophils may be the main cell type.
(3) Activation of the leukocytes to eliminate the offending agent.
Recognition of Microbes and Dead Tissues
Leukocytes express several receptors that recognize external stimuli:
• Receptors for microbial products.
• G protein–coupled receptors.
• Receptors for opsonins: Leukocytes express receptors for proteins that coat
microbes. The process of coating a microbe, to target it for ingestion
(phagocytosis) is called opsonization, and substances that do this are opsonins.
These substances include antibodies, complement proteins.
Removal of the Microbes and Dead Tissues
Recognition of microbes or dead cells by the receptors induces leukocytes for
destruction of microbes by phagocytosis and intracellular killing.
Phagocytosis and intracellular killing, involves three sequential steps:
(1) Attachment of the particle to be ingested by the leukocyte
(2) Engulfment, with subsequent formation of a phagocytic vacuole; by extensions of
the cytoplasm (pseudopods) around the microbe, and the formation of a vesicle
(phagosome) that encloses the particle. The phagosome then fuses with a lysosomal
granule, resulting in discharge of the granule s contents into the phagolysosome
(3) Killing or degradation of the ingested material within neutrophils and
macrophages, microbial killing is accomplished largely by reactive oxygen species
(ROS, also called reactive oxygen intermediates) and reactive nitrogen species and
action of other substances in leukocyte granules such as enzymes ( elastase) , lysozyme,
which hydrolyzes the bond found in the coat of all bacteria.
Termination (Control) of the Acute Inflammatory Response
Acute inflammation, needs tight controls to minimize the damage.
1- Inflammation declines simply because the mediators of inflammation have
short half-lives, and are degraded after their release.
2- Neutrophils also have short half-lives in tissues and die by apoptosis within a
few hours after leaving the blood.
3- There are a variety of stop signals that serve to terminate the inflammation,
including transforming growth factor-? (TGF-?) and IL-10.
Sequelae of Acute Inflammation
There are four main possible sequelae of acute inflammation:
? Resolution: complete resolution occurs following short-lived tissue injury in which
there has been little tissue damage. The bacterium may be neutralized, killed and
cleared by the acute inflammatory response and the affected tissues return entirely to
normal. This occurs in some acute bacterial infections and is the ideal outcome.
? Abscess formation: This is characteristically seen with certain pyogenic organisms
such as staphylococci. An abscess may discharge spontaneously or require drainage by
surgical intervention.
? Healing by fibrosis and scar formation: Healing by fibrosis and scar formation
occurs when substantial tissue destruction is seen during the acute inflammation. The
damaged tissues are unable to regenerate and are replaced by fibrous tissue.
? Progression to chronic inflammation.