Pathophysiology of

Inflammation
Outlines
• Definition
• Types
Definition

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
It serves to rid the host of both the initial cause of cell injury (e.g.,
microbes, toxins)

and the consequences of such injury (e.g., necrotic cells and tissues).

The mediators of defense include : phagocytic

leukocytes, antibodies, and complement proteins

Without inflammation,
infections would go unchecked, wounds would never

heal, and injured tissues might remain permanent festering sores.

Series of typical inflammation
• The offending agent, which is located in extravascular tissues, is recognized by
host cells and molecules.

• Leukocytes and plasma proteins are recruited from the circulation to the site
where the offending agent is located.

• The leukocytes and proteins are activated and work together to destroy and
eliminate the offending substance.

• The reaction is controlled and terminated.

• The damaged tissue is repaired.
Macrophages
. macrophages are specialized cells involved in the detection, phagocytosis and
destruction of bacteria and other harmful organisms. In addition, they can also
present antigens to T cells and initiate inflammation by releasing molecules (known
as cytokines) that activate other cells.
d
Leukocytes
• A white blood cell, also known as a leukocyte or white corpuscle, is a cellular
component of the blood that lacks hemoglobin, has a nucleus, is capable of
motility, and defends the body against infection and disease
Neutrophils
• Neutrophils are the most abundant type of granulocytes and make up
40% to 70% of all white blood cells in humans. They form an essential
part of the innate immune system, with their functions varying in
different animals
Acute inflammation
Its main characteristics
are the exudation of fluid and plasma proteins resulting in
(edema) and the emigration of leukocytes, predominantly
neutrophils (also called polymorphonuclear leukocytes).
When acute inflammation achieves its desired goal of eliminating
the offenders, the reaction subsides and residual
injury is repaired.
if the initial response fails to clear the stimulus, the reaction progresses to a
protracted type of inflammation that is called chronic inflammation. As discussed

later, chronic inflammation may

follow acute inflammation or arise de novo. It is of longer

duration and is associated with more tissue destruction,

the presence of lymphocytes and macrophages, the proliferation

of blood vessels, and fibrosis

Inflammation is induced by chemical mediators that
are produced by host cells in response to injurious
stimuli. When a microbe enters a tissue or the tissue is
injured, the presence of the infection or damage is sensed
by resident cells, including macrophages, dendritic cells,
mast cells, and other cell types. These cells secrete molecules
(cytokines and other mediators) that induce and
regulate the subsequent inflammatory response. Inflammatory
mediators are also produced from plasma proteins
that react to the microbes or to products of necrotic cells.
Some of these mediators promote the efflux of plasma
and the recruitment of circulating leukocytes to the site
where the offending agent is located. Mediators also activate
the recruited leukocytes, enhancing their ability to
destroy and remove the offending agent
The external manifestations of
inflammation
Often called its cardinal signs,
are heat
redness
swelling
pain
loss of function
Inflammation is terminated when the offending agent
is eliminated.
The reaction resolves because mediators are
broken down and dissipated, and leukocytes have short
life spans in tissues. In addition, anti-inflammatory mechanisms
are activated, serving to control the response and
prevent it from causing excessive damage to the host. After
inflammation has achieved its goal of eliminating the
offending agents, it sets into motion the process of tissue
repair.
in some situations, the
inflammatory reaction becomes the cause of disease,
and the damage it produces is its dominant feature
Not only excessive inflammation but also defective inflammation is responsible for

serious illness. Too little inflammation, which is typically manifested by increased

susceptibility to infections, is most often caused by a reduced number of

leukocytes resulting from replacement of the bone marrow by cancers and

suppression of the marrow by therapies for cancer and graft rejection..

Causes of inflammation
infections:(bacterial, viral, fungal, parasitic) and microbial
toxins are among the most common and medically
important causes of inflammation
Tissue necrosis elicits inflammation regardless of the
cause of cell death,
Foreign bodies (splinters, dirt, sutures) may elicit
inflammation by themselves or because they cause
traumatic tissue injury or carry microbes
Immune reactions (also called hypersensitivity) are reactions
in which the normally protective immune system
damages the individual’s own tissues
RECOGNITION OF MICROBES AND
DAMAGED CELLS
The first step in inflammatory responses
Cellular receptors for microbes. Phagocytes, dendritic cells
(cells in epithelia and all tissues whose function is to
capture microbes), and many other cells express receptors
that detect the presence of infectious pathogens.
The best defined of these receptors belong to the family
of Toll-like receptors (TLRs
TLRs are located in plasma
membranes and endosomes, so they are able to detect
extracellular and ingested microbes
TLRs recognize motifs common to many microbes, often called pathogen-

associated molecular patterns (PAMPs). Recognition of microbes by these

receptors stimulates the production and expression of a number of secreted and

membrane proteins. These proteins include cytokines that induce inflammation,

anti-viral cytokines (interferons), and cytokines and membrane proteins that

promote lymphocyte activation and even more potent immune responses

All cells have cytosolic receptors that recognize molecules that are liberated or
altered as a consequence of cell damage, and are hence appropriately called
damage-associated molecular patterns

(DAMPs). These molecules include uric acid (a product of DNA breakdown), ATP
(released from damaged mitochondria), reduced intracellular K+ concentrations

(reflecting loss of ions because of plasma membrane injury), DNA (when it is

released into the cytoplasm and not sequestered in nuclei, as it should be
normally), and many others
Circulating proteins. Several plasma proteins recognize

microbes and function to destroy blood-borne microbes

and to stimulate inflammation at tissue sites of infection.

The complement system reacts against microbes and produces

mediators of inflammation
Acute inflammation
Acute inflammation has three major components:
(1) dilation of small vessels, leading to an increase in blood flow,

(2) increased permeability of the microvasculature, enabling plasma proteins and

leukocytes to leave the Circulation

(3) emigration of the leukocytes from the microcirculation, their accumulation in

the focus ofinjury, and their activation to eliminate the offendingagent
When an injurious agent, such as an infectious microbe or dead cells, is

encountered, phagocytes that reside in all tissues try to eliminate these agents. At

the same time, phagocytes and other sentinel cells in the tissues recognize the

presence of the foreign or abnormal substance and react by liberating soluble

molecules that mediate inflammation

 Reactions of Blood Vessels in Acute
Inflammation
changes in the flow of blood and the permeability
of vessels

The escape of fluid, proteins, and blood cells from the vascular system into

interstitial tissues or body cavities is known as exudation

An exudate is an extravascular fluid that has a

high protein concentration and contains cellular debris

a transudate is a fluid with low protein content, little or no cellular material

1-changes in the flow of blood and the permeability
of vessels

Edema denotes an excess of fluid in the interstitial

tissue or serous cavities;

it can be either an exudate or a transudate

Plus, a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly

neutrophils), the debris of dead cells, and, in many cases, microbes
2-Changes in Vascular Flow and Caliber
Vasodilation is induced by the action of several mediators,notably histamine
increased permeability of the microvasculature, with the outpouring of protein-rich
fluid (an exudate) into the extravascular tissues.

The loss of fluid and increased vessel diameter lead to

slower blood flow, concentration of red cells in small vessels, and increased
viscosity of the blood

stasis develops, blood leukocytes, principally neutrophils,

accumulate along the vascular endothelium.
Increased Vascular Permeability (Vascular Leakage)
Responses of Lymphatic Vessels and Lymph Nodes

Lymphatics drain the small amount of extravascular fluid that seeps out of

capillaries under normal circumstances .lymph flow is increased to help drain

edema fluid leukocytes and cell debris, as well as microbes, may find their way into

lymph. Lymphatic vessels, like blood vessels, proliferate during inflammatory

reactions to handle the increased load

The lymphatics may become secondarily inflamed (lymphangitis

the draining lymph nodes (lymphadenitis). Inflamed lymph nodes are often

enlarged because of increased cellularity. This constellation of pathologic

changes is termed reactive, or inflammatory, lymphadenitis

Leukocyte Recruitment to Sites of Inflammation
the ones capable of phagocytosis, namely, neutrophils and

macrophage .Neutrophils are produced in the bone marrow and rapidly recruited

to sites of inflammation.

Macrophages are slower responders s These leukocytes ingest and destroy bacteria

and other microbes, as well as necrotic tissue and foreign substances.

A price that is paid for the defensive potency of leukocytes is that, when strongly

activated, they may induce tissue damage and prolong inflammation, because the

leukocyte products that destroy microbes and help “clean up” necrotic tissues can

also produce “collateral damage” of normal host tissues. When there is systemic

activation of inflammation, as may occur when there is invasion of the bloodstream

by bacteria, the resulting systemic inflammatory response may

even be lethal
leukocytes from the vessel lumen to the tissue
Leukocytes normally flow rapidly in the blood, and in inflammation, they have to be
stopped and then brought to the offending agent or the site of tissue damage,
outside the vessels. This process can be divided into phases, consisting

first of adhesion of leukocytes to endothelium at the site of inflammation, then

transmigration of the leukocytes through the vessel wall, and movement of the
cells toward the offending agent. Different molecules play important roles in each
of these steps
Selectins mediate the initial weak interactions between
leukocytes and endothelium.
The three members of this family are E-selectin (also called CD62E), expressed on
endothelial cells; P-selectin (CD62P), present on platelets and endothelium; and L-
selectin (CD62L), found on the surface of most leukocytes
Firm adhesion of leukocytes to endothelium is mediated by a family of leukocyte
surface proteins calledintegrins
Various cytokines promote the expression of selectins and integrin ligands on
endothelium (TNF, IL-1), increase the avidity of integrins for their ligands
(chemokines), and promote directional migration of leukocytes (also chemokines).
Tissue macrophages and other cells responding to the pathogens or
damaged tissues produce many of these cytokines.
 Leukocyte Migration Through Endothelium

After being arrested on the endothelial surface, leukocytes migrate through the

vessel wall primarily by squeezing between cells at intercellular junctions. This

extravasation of leukocytes, called transmigration

Chemotaxis of Leukocytes
After exiting the circulation, leukocytes move in the tissues toward the site of injury by a
process called chemotaxis, which is defined as locomotion along a chemical gradient. Both
exogenous and endogenous substances can act as chemoattractants, including the
following:

• Bacterial products, particularly peptides with N formylmethionine

• Cytokines, especially those of the chemokine family

• Components of the complement system, particularly C5a

• Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly

leukotriene B4 (LTB4
The nature of the leukocyte infiltrate varies with the age of the inflammatory

response and the type of stimulus.

In most forms of acute inflammation, neutrophils predominate in the

inflammatory infiltrate during the first 6 to 24 hours and are gradually replaced by

monocyte-derived macrophages over 24 to 48 hours

Phagocytosis and Clearance of the Offending Agent
The functional responses that are most important for destruction
of microbes and other offenders are phagocytosis and intracellular killing.
Phagocytosis
Phagocytosis involves three sequential steps:

(1) Recognition and attachment of the particle to be ingested by the

leukocyte;

(2) engulfment, with subsequent formation of a phagocytic vacuole;

(3) killing or degradation of the ingested material

Phagocytosis
LEUKOCYTE ACTIVATION AND REMOVAL OF
OFFENDING AGENTS
Leukocytes can eliminate microbes and dead cells by phagocytosis, followed by
their destruction in phagolysosomes.
Destruction is caused by free radicals (ROS, NO) generated in activated leukocytes
and by granule enzymes
Neutrophils can extrude their nuclear contents to form extracellular
nets that trap and destroy microbes.
.
• Granule enzymes may be released into the extracellular environment.

• The mechanisms that function to eliminate microbes and dead

cells (the physiologic role of inflammation) also are capable of damaging normal
tissues (the pathologic consequences of inflammation).

• Anti-inflammatory mediators terminate the acute inflammatory

reaction when it is no longer needed

Complement System
The complement system is a collection of soluble proteins and their membrane
receptors that function mainly in host defense against microbes and in pathologic

inflammatory reactions. There are more than 20 complement

proteins, some of which are numbered C1 through C9. They function in both innate
and adaptive immunity for defense against microbial pathogens. In the process of

complement activation, several cleavage products of complement proteins are

elaborated that cause increased vascular permeability, chemotaxis, and
opsonization.
Kinins

Kinins are vasoactive peptides derived from plasma proteins,called kininogens, by

the action of specific proteases called kallikreins. The enzyme kallikrein cleaves a

plasma glycoprotein precursor, high-molecular-weight kininogen,

to produce bradykinin.

Bradykinin increases vascular permeability and causes contraction of smooth

muscle, dilation of blood vessels, and pain when injected into the skin.
Repairs
Complete resolution.

with restoration of the site of acute inflammation to normal.

Resolution involves removal of cellular debris and microbes by macrophages, and

resorption of edema fluid by lymphatics

Healing by connective tissue replacement (scarring, or
fibrosis).

inflammatory injury involves tissues that are incapable of regeneration, or when

there is abundant fibrin exudation in tissue or in serous cavities (pleura,

peritoneum) that cannot be adequately cleared connective tissue grows into the

area of damage or exudate, converting it into a mass of fibrous tissue.

chronic inflammation

Progression of the response to chronic inflammation . Acute to chronic transition

occurs when the acute inflammatory response cannot be resolved, as a result of
either the persistence of the injurious agent or some interference with the normal
process of healing
CHRONIC INFLAMMATION
Chronic inflammation is a response of prolonged duration

(weeks or months) in which inflammation, tissue injury, and attempts at repair

coexist, in varying combinations
Causes of Chronic Inflammation

Persistent infections
mycobacteria and certain
viruses, fungi, and parasites. These organisms often
evoke an immune reaction called delayed-type hypersensitivity
Hypersensitivity diseases.
Prolonged exposure to potentially toxic agents, either
exogenous or endogenous
Morphologic Features
Infiltration with mononuclear cells, which include
macrophages, lymphocytes, and 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 angiogenesis (proliferation
of small blood vessels) and, in particular,
fibrosis
It is mediated by cytokines produced by macrophages and lymphocytes (notably T

lymphocytes); bidirectional interactions between these cells tend to amplify and

prolong the inflammatory reaction.

• Granulomatous inflammation is a morphologically specific pattern of chronic

inflammation induced by T cell and macrophage activation in response to an agent

that is resistant to eradication.

SYSTEMIC EFFECTS OF INFLAMMATION
Fever: Cytokines (TNF, IL-1) stimulate production of PGs in hypothalamus
Production of acute-phase proteins: C-reactive protein, others; synthesis
stimulated by cytokines (IL-6, others) acting on liver cells
Leukocytosis: Cytokines stimulate production of leukocytes
from precursors in the bone marrow
In some severe infections, septic shock: Fall in blood pressure,
disseminated intravascular coagulation, metabolic abnormalities;
induced by high levels of TNF and other cytokines
TISSUE REPAIR
Repair of damaged tissues occurs by two types of reactions: regeneration by
proliferation of residual (uninjured) cells and maturation of tissue stem cells, and
thedeposition of connective tissue to form a scar
Factors That Impair Tissue Repair
• Infection
• Diabetes
• Nutritional status
• Mechanical factors
• Poor perfusion,
• Foreign bodies
• location of the injury