Inflammation process

Chap.2

1
 Acute inflammation as a readily first line of
defense

Infectious agents, such as bacteria or viruses, can grow very

rapidly (can produce up to 500 million offspring within 24h).

So time is critical and delay is fatal.

The body needs to use fast-reacting preexisting immune

mechanisms as its first line of defense whereby the most
important one is the process of “acute inflammation”.

2
 Acute inflammation as a readily first line of
defense

It involves the activation and migration of cells (esp.

neutrophils and macrophages) from the bloodstream to sites of
invasion to attack and destroy invaders.

Later, following elimination of invaders, the repair of

damaged tissues can begin.

3
 How invaders are recognized??
Recognition* is due to warning signals or “Alarmins” sent by
2 major groups:

a.“DAMPS” (or damage associated molecular patterns): are

the internally generated molecules from dead or dying cells.

b. “PAMPs”(or pathogen associated molecular patterns): are

the externally generated molecules by invading
microorganisms.

Together, the DAMPS and PAMPs can then be recognized and

detected by “sentinel cells” (**such as macrophages, dendritic
cells (DC) and mast cells). 4
5
 What are “Dendritic cells” and “Mast cells”??

DC: produced by BM stem cells which migrate throughout the

body and form lattice-like networks in nearly all tissues.

“Mast cells”: large, round cells scattered in body (CT,

mucosae, skin and around nerves) close to blood vessels to be
able to regulate blood flow and influence cell migration)

6
7
DC: produced by BM stem cells which migrate throughout
the body and form lattice-like networks in nearly all tissues.

8
9
Mast cells detect injury to nearby cells and release “histamine”
increasing blood flow to the wound site, and increased vascular
permeability allows fluid, proteins, phagocytes, and other immune cells
to enter infected tissue.

10
 Toll-like receptors (TLRs)

Sentinel cells have “pattern-recognition receptors” or PRR that

can bind DAMPS, and PAMPs expressed by bacteria, fungi
and viruses.

The most important of the pattern-recognition receptors are:

a. The “scavenger receptors” or “ScR” which recognize the
DAMPS.
b. The “toll-like receptors” or “TLRs” which recognize the
PAMPS..

Microbes are highly diverse and can mutate and change their molecular
structure. Sentinel cells receptors are not designed to recognize all
possible microbial molecules but only the highly conserved ones found in
these M.O. 11
 Cytokines
The various types of PAMP/DAMP-PRR (or TLRs) binding result
in the triggering of a variety of produced cytokine mixtures
(antibacterial, antiviral…).
Cytokines also “turn on” or stimulate the acquired immune system.
https://www.youtube.com/watch?v=qCpWXPSMBIY
(only from 2:50 to 8:05 min)
Cytokines (such as TNF- α and IL I) are proteins that regulate the
activities of cells involved in the defense of the body.
They are synthesized and secreted by sentinel cells when exposed
to infectious agents.
When released in sufficient quantities, these cytokines cause a
fever and sickness behavior and promote an inflammatory response
in order to remove invaders.
12
innate inflammation mechanism as
triggered by microbial invasion and tissue
damage
Infections of pathogenic bacteria or viruses
(or when cells are stressed or injured)
cause release of PAMPs that bind to PRRs
such as TLRs or ScRs, on immune cells
and stimulate an innate immune response
that is accompanied by inflammation,
activation of adaptive immunity aiming to
resolve the infection and allow for tissue
repair.
The immune cells that participate in these
processes include, for example, DC and
macrophages. DAMPs may also stimulate
adaptive immunity and participate in
autoimmune responses and tissue repair.
13
 What are “macrophages”(greek: large eaters)

These not only act as “sentinel cells” by detecting invaders but

also kill them and stimulate (by their secreted cytokines)
acquired I and further innate I.

They would then contribute to the healing process of damaged

tissues by removing dead, dying and damaged cells.

14
15
Macrophage

16
 Monocyte vs Macrophage
Phagocytic cells are called monocytes (when in blood
stream) and macrophages (when in tissues).

17
 Types of Macrophages
Immature macrophages circulate in the blood, where they are called
“monocytes”.

When monocytes mature they migrate into tissues and become

“macrophages” where they are named differently based on the tissues
where they are found:

•Alveolar macrophages: lungs alveoli

•Kuppfer’s cells: liver
•Osteoclasts: bones
•Dendritic cells: found in all organs (especially in lymph nodes, skin
and mucosal surfaces, where invading microbes are most likely to be
encountered) except the brain, eye and testes.
•Splenic macrophages: spleen
•Histiocytes: connective tissue
•Microglia: brain 18
19
20
 Inflammation

Acute inflammation can develop within minutes after a tissue is

damaged and has 5 main signs:

heat, redness, swelling, pain and possible loss of function.

All are due to changes (vasodilation, vascular permeability and
fluid and neutrophils leakage) in nearest small blood vessels.

https://www.youtube.com/watch?v=Fbzb75HA9M8

https://www.youtube.com/watch?v=uc6IV85mf3s

21
Inflammation Process

22
Neutrophils migration

23
 The coagulation system

When fluid leaks from the bloodstream into the tissues, blood
coagulation is activated. Platelets aggregation accelerates this
process.
This would lead to production of large quantities of
“thrombin”, the main clotting enzyme.

Thrombin acts on fibrinogen in tissue fluid and plasma to

produce insoluble fibrin.

Fibrin is then deposited in inflamed tissues where it forms a

barrier to the spread of infection. 24
 Coagulation Cascade (1)
The process by which blood clots are formed involves a complex
set of reactions collectively called the “coagulation cascade”

This cascade is stimulated by “clotting factors” released from

damaged cells (extrinsic pathway) and platelets (intrinsic pathway).

The coagulation cascade involves many intermediary steps,

however the principal events are as follows:

Clotting factors cause platelets to become sticky and adhere to the

damaged region to form a solid plug.

These factors also initiate localized vasoconstriction to reduce

blood flow through the damaged region.
25
 Simplified coagulation cascade
This cascade is stimulated by clotting factors released from damaged
cells (extrinsic pathway) and platelets (intrinsic pathway)

26
 Coagulation Cascade (2)
https://www.youtube.com/watch?v=j9Hdl9w-K0M

Additionally, clotting factors trigger the conversion of the

inactive zymogen prothrombin into the activated
enzyme thrombin.

Thrombin in turn catalyses the conversion of the soluble

plasma protein fibrinogen into an insoluble fibrous form
called ”fibrin”.

The fibrin strands form a mesh of fibers around the platelet

plug and traps blood cells to form a temporary clot.

When the damaged region is completely repaired, an enzyme

(plasmin) is activated to dissolve the clot.
27
Components of a Blood Clot (Scanning Electron
Microscopy)

28
 Fibrinolysis

Fibrinolysis is the enzymatic breakdown of fibrin in blood

clots preventing uncontrolled thrombosis* and
embolism*. There are 2 types of fibrinolysis:

- Primary fibrinolysis is a normal body process.

- Secondary fibrinolysis is the breakdown of clots due to

medicine, disorder, or other cause.

29
 The initiation stage of fibrinolysis is just as complex as that of
coagulation and is based on the transformation of the zymogen
“plasminogen” into its active serine protease form of “plasmin”.

30
 Fibrinolysis

Thrombosis* is the process of a blood clot, also known as a

thrombus, forming in a blood vessel.

This clot can block (embolism*) or obstruct blood flow in the

affected area, as well as cause serious complications if the clot
moves to a crucial part of the circulatory system, such as the
brain or the lungs.

31
 Fibrinolysis cascade
Plasmin is produced in an inactive form, plasminogen, in the
liver. Plasminogen cannot cleave fibrin and circulates in the
bloodstream.
During clotting, some plasminogen is trapped in clot. So it is
incorporated into the clot when it is formed and then activated
into plasmin later and initiated and catalyzed by fibrin
presence in clot .

Plasminogen is activated to plasmin by tissue plasminogen

activator (t-PA) and urokinase. However in normal situations
there are inhibitors of plasmin formation in healthy blood
vessels.

https://www.youtube.com/watch?v=zOvq1x9rbt4
The second until 4:18 only
32
 Fibrinolysis
Plasmin cleaves fibrin at various places, leading to the production
of circulating fragments that are cleared by phagocytosis by
macrophages and eosinophils

33
Coagulation and fibrinolysis cascades
During clotting, some plasminogen is trapped in clot. So it is
incorporated into the clot when it is formed and then activated into
plasmin later and initiated and catalyzed by fibrin presence in clot .
Plasminogen is activated to plasmin by tissue plasminogen activator (t-
PA) and urokinase

34