Inflammation and inflammatory

mediators

Dr. Feyan M. Abdullah

Hawler Medical University
College of Medicine
Microbiology, Physiology and Genetic Dep.
Medical Microbiology Unit
Overview
o 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.

o 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).

o The mediators (cells and molecules) of defense include phagocytic

leukocytes, antibodies, complement proteins….etc.

Most of these are normally circulate in the blood,

where they are sequestered so they cannot damage
normal tissues but can be rapidly recruited to any site
in the body.
o Some of the cells involved in inflammatory responses also reside in
tissues, where they function as sentinels on the lookout for threats.

o 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. Likewise ,
anti-inflammatory mechanisms are activated, serving to control the
response and prevent it from causing excessive damage to the host.

Without inflammation, infections would go

unchecked, wounds would never heal, and
injured tissues might remain permanent
festering sores.

o Inflammation may be of two types:- acute and chronic.

o Inflammation can be local or systemic.

Causes of inflammation
Inflammatory reactions may be triggered by a variety of stimuli:

 Infections…. (bacterial, viral, fungal, parasitic) and microbial toxins.

 Tissue necrosis elicits inflammation regardless of the cause of cell

death, which may include ischemia, trauma, physical and chemical
injury (e.g., thermal injury, as in burns; irradiation; exposure to some
environmental chemicals).
 Foreign bodies…. (splinters, dirt)

 Immune reactions….. autoimmune diseases, allergies.

o 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.
o These cells secrete inflammatory molecules
(cytokines and other mediators) that induce
and regulate the subsequent inflammatory
response.
o Leukocytes and plasma proteins are
recruited from the circulation to the site
where the offending agent is located.
o The leukocytes and proteins are activated
and work together to destroy and eliminate
the offending substance.
o The reaction is controlled and terminated.
o The damaged tissue is repaired.
The external manifestations of inflammation, often called its cardinal
signs, are :-
• heat (calor in Latin),
• Redness (rubor)
• Swelling (tumor)
• Pain (dolor)
• Loss of function (functio laesa).
 Acute inflammation is the initial, rapid response to infections and
tissue damage. It typically develops within minutes or hours and is of
short duration, lasting for several hours or a few days.

 If the initial response fails to clear the stimulus,

the reaction progresses to a prolonged type of
inflammation

 chronic inflammation

 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…
Examples….. rheumatoid arthritis, atherosclerosis, and lung fibrosis.
 Inflammatory mediators (i.e. molecules) are produced by resident
cells, recruited cells, 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.

 Some other mediators also activate the recruited leukocytes,

enhancing their ability to destroy and remove the offending agent.

Understanding the role of mediators is

important because most anti-
inflammatory drugs target specific
mediators.
1) Although normally protective, in 2) Inflammatory reactions to
some situations, the inflammatory infections are often accompanied by
reaction becomes the cause of local tissue damage and its
disease, and the damage it associated signs and symptoms
produces is its dominant feature. (e.g., pain and functional
impairment). Typically, however,
3) In contrast, there are many these harmful consequences are
diseases in which the inflammatory self-limited and resolve as the
reaction is misdirected:-autoimmune inflammation abates, leaving little
diseases, allergies, infections by or no permanent damage.
microbes that resist eradication.
4) inflammation may contribute to a
5) For this reason anti-inflammatory variety of diseases that are thought
drugs, ideally would control the to be primarily metabolic,
harmful sequela of inflammation yet degenerative, or genetic disorders,
not interfere with its beneficial such as type 2 diabetes, Alzheimer
effects. disease, and cancer.

***Defective inflammation is also responsible for serious illness. any

compromise of marrow function will diminish the generation of
mature leukocytes.
Recognition of microbes and damaged cells

• The first step in inflammatory responses is the recognition of

microbes and necrotic cells by cellular receptors and circulating
proteins.

- Cellular receptors for microbes. Phagocytes, dendritic 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).

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 like cytokines that induce inflammation, anti-viral cytokines
(interferons), and cytokines and membrane proteins that promote
lymphocyte activation.

-Sensors of cell damage: All cells have cytosolic receptors that

recognize molecules that are liberated or altered as a consequence of
cell damage called damage-associated molecular patterns (DAMPs)
like uric acid and ATP.

- Circulating proteins: Several plasma proteins recognize microbes and

function to destroy microbes and to stimulate inflammation at tissue
sites of infection like complement system.
Acute inflammation
Acute inflammation has three major components:
(1) Dilation of small vessels, leading to an increase in blood flow.
Is induced by the action of several
mediators, notably histamine….etc.

(2) Increased permeability of the microvasculature, enabling plasma

proteins and leukocytes to leave the circulation.
Is induced by histamine, kinins…etc

(3) Emigration of the leukocytes from the microcirculation, their

accumulation in the focus of injury, and their activation to eliminate
the offending agent.
• The most important leukocytes in typical inflammatory
reactions are the ones capable of phagocytosis, namely,
neutrophils and macrophages ingesting and destroy
bacteria and other microbes, as well as necrotic tissue and
foreign substances.
• Macrophages also produce growth factors that aid in repair.
*The journey of leukocytes from the vessel lumen to the tissue is a
multistep process that is mediated and controlled by adhesion molecules
and cytokines.
This process can be divided into phases:-

1. Adhesion of leukocytes to endothelium at the site of Inflammation.

This is mediated by complementary adhesion molecules (selectins
and integrins) on the two cell types (leukocytes and endothelial
cells) whose expression is enhanced by cytokines which are secreted
by cells in tissues in response to offending agents, thus ensuring that
leukocytes are recruited to the tissues where these stimuli are
present.

2. Transmigration of the leukocytes through the vessel wall, and

movement of the cells toward the offending agent.
 Selectins mediate the initial weak interactions between leukocytes
and
endothelium.
• E-selectin,…on endothelial cells
• P-selectin, …. present on platelets and endothelium
• L-selectin….. Found on the surface of most leukocytes.

 Firm adhesion of leukocytes to endothelium is mediated by integrins.

** Chemokines are chemoattractant cytokines that are secreted by

many cells
at sites of inflammation.
3. Transmigration leukocytes in the tissue

 After exiting the circulation, leukocytes move in the tissues toward

the site of injury by a process called chemotaxis.

 Both exogenous and endogenous substances can act

achemoattractants,
including the following:-

• Bacterial products
• Cytokines, especially those of the chemokine family.
• Components of the complement system, particularly C5a

 These chemoattractants are produced by microbes and by host cells

in response to infections and tissue damage and during immunologic
reactions.
 ‫ﻟﻼطﻼع‬
Just to understand the process
 In most forms of acute inflammation, neutrophils predominate in the
inflammatory infiltrate during the first 6 to 24 hrs and are gradually
replaced by macrophages over 24 to 48 hrs.

 After entering tissues, neutrophils are short-lived; they undergo

apoptosis and disappear within 24 to 48 hours.

 Macrophages not only survive longer but also may proliferate in the
tissues, and thus they become the dominant population in prolonged
inflammatory reactions.

Phagocytosis and cytokine production

There are, however, exceptions to this pattern of cellular infiltration.

 In certain infections—for example, those produced by Pseudomonas

bacteria—the cellular infiltrate is dominated by neutrophils for
several days.

 In viral infections, lymphocytes may be the first cells to arrive.

 Some hypersensitivity reactions are dominated by activated

lymphocytes, macrophages, and plasma cells (reflecting the immune
response).

 In allergic reactions, eosinophils may be a prominent cell type.

Some T lymphocytes, which are cells

of adaptive immunity, also contribute to
acute inflammation like TH17 cells.
Leukocyte-Mediated Tissue Injury

• In some infections that are difficult to eradicate, such as tuberculosis

and hepatitis, the prolonged host response contributes more to the
pathology than does the microbe itself.

• When the inflammatory response is inappropriately directed against

host tissues, as in certain autoimmune diseases.

rheumatoid arthritis

When the host hyper-reacts against usually harmless environmental

substances, as in allergic diseases, including asthma, and some drug
reactions.
Termination of the Acute Inflammatory Response
Anti-inflammatory mediators terminate the acute inflammatory
reaction when it is no longer needed.

Examples of anti-inflammatory cytokines, including transforming growth

factor-β (TGF-β) and IL-10.
Chronic inflammation

o Is a response of prolonged duration (weeks or months) in which

inflammation, tissue injury, and attempts at repair coexist.

Causes of Chronic Inflammation

 Persistent infections by microorganisms that are difficult to eradicate,

such as mycobacteria and certain viruses, fungi, and parasites.

 Unresolved acute inflammation evolves into chronic one, such as

when an acute bacterial infection of the lung progresses to a chronic
lung abscess.

 In auto immune diseases like rheumatoid arthritis and multiple

sclerosis in which immune response induce against self and non self
Ags.
 In allergic diseases, as in bronchial asthma. Such diseases may show
morphologic patterns of mixed acute and chronic inflammation.
Fibrosis may dominate the late stages.

 Prolonged exposure to potentially toxic agents, either exogenous or

endogenous.

Example
agent is particulate silica,
Example results in an inflammatory lung
Atherosclerosis thought to be disease called silicosis
induced, at least in part, by
excessive production and tissue
deposition of endogenous
cholesterol and other lipids.
Chronic inflammation

 Is mediated predominately by macrophages lymphocytes, plasma

cells, and other leukocytes.

 Cytokines produced by macrophages and lymphocytes (notably T

lymphocytes) are mostly involved.

 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.
 ‫ﻟﻼطﻼع‬
Just to understand the process
The acute-phase response consists of several clinical and pathologic
changes:
 Fever:- Substances that induce fever are called pyrogens like TNF .
Acute-phase proteins: Are plasma proteins, their plasma concentrations
may increase several hundred-fold as part of the response to
inflammatory stimuli. Examples:-
1. C-reactive protein (CRP)
2. Fibrinogen
3. Serum amyloid A (SAA) protein.
 Leukocytosis is a common feature of inflammatory reactions,
especially those induced by bacterial infections.

 Sepsis and septic shock: In some severe infections, Fall in blood

pressure, disseminated intravascular coagulation, metabolic
abnormalities, induced by high levels of TNF and other cytokines
Repair by scar formation

 Repair occurs by deposition of connective tissue and scar formation if

the injured tissue is not capable of regeneration.

 Macrophages are critical for orchestrating the repair process, by

eliminating offending agents and producing cytokines and growth
factors that stimulate the proliferation of the cell types involved in
repair.
 ‫ﻟﻼطﻼع‬
Just to understand the process
REFERENCES
• Robbins Basic pathology. Vinay Kumar, Abul K. Abbas, and Jon C.
Aster.10th ed., 2018