This slides describes acute inflammation process

1. Acute Inflammation
DR I YUSUF
Pathology Department

2. Introduction
• Inflammation is the stereotyped response of living vascularized tissues to injury
• A complex tissue reaction consisting of response of blood vessels and leukocytes.
• The vascular and cellular events are mediated by soluble factors derived from cells
and plasma proteins.
• It is essentially a protective response that ensures the survival of the organism.
• Inflammation may be acute or chronic: depending of the stimulus and
effectiveness of the response.
• Serves to eliminate necrotic tissue and foreign invaders, terminated when
offending agents are removed. It is closely associated with tissue repair following
injury.
• Inflammation can be harmful and are associated with certain disease conditions.

3. Cardinal Signs of Localized
inflammation
• Rubor Redness
• Calor Heat (warmer than other
body parts)
• Tumor Swelling
• Dolor Pain (Tenderness)
• And in the past, a 5th one was added Functio
laesea (Loss of function)

4. • Acute inflammation is the response of living vascularized tissues to injury
usually of short duration and usually characterized predominantly by a
neutrophilic cellular infiltrates and serves to deliver leukocytes and
plasma protein to sites of infection or tissue injury.
• It is of rapid onset and short duration.
• It has 3 components:
1) Vasodilatation-alteration in vessel caliber leading to increased blood
flow.
2) Increased vascular permeability- structural changes in the vasculature
permitting exudation of plasma protein and leukocytes.
3) Leukocytes Emigration - to the site of injury.

5. Causes Acute of inflammation
1.Physical agents e.g heat, cold, radiations,
mechanical trauma
2. Chemical agents e.g cyanide, acids, alkali
3. Infections e.g bacterial, viral, fungal and parasitic
4. Immunological agents e.g cell-mediated and
antigen-antibody reactions
5. Foreign bodies e.g dirt, sutures, splinters
5

6. • Acute inflammation is centered around 2 events:
1) VASCULAR EVENTS
a) Vasodilatation-alteration in vessel caliber leading to increased
blood flow.
b) Increased vascular permeability- structural changes in the
vasculature permitting exudation of plasma protein and leukocytes.
2) CELLULAR EVENTS
a) Leukocyte emigration(Leukocyte extravasations)
b) Phagocytosis.

7. VASCULAR EVENTS OF ACUTE INFLAMMATION
Vasodilatation and Increased vascular permeability
• Blood vessel undergo changes to increase the movement of plasma
proteins and cells out of circulation to the site of injury.
• This escape of fluid, protein and cells from the vascular
compartment into the interstitium is referred to as exudation.
• Exudate is an inflammatory derived extracellular fluid that has
high protein concentration, cellular debris and hence high specific
gravity.
• In contrast, Transudate is an ultra filtrate of blood plasma and has
low protein concentration, low or no cellular debris and low specific
gravity.

8. 1) Vasodilatation: is induced by the action of several mediators, notably
histamine and Nitrous Oxide (NO) on vascular smooth muscle.
• Vasodilatation- Induced by Histamine, occurs early and may be preceded by
Transient Vasoconstriction. Vasodilatation results in increased blood flow which
is the cause of the heat and redness at the site of inflammation.
• And is followed immediately by increased vascular permeability and escape of
protein rich fluid.
• Loss of Protein rich fluid leads to increase viscosity of the blood, stasis and
vascular congestion.
• Stasis results in neutrophils migrating to vascular periphery and making contact
with vascular endothelium. Leukocytes adhere to vascular endothelium, and
subsequently migrate to the interstitium.

9. 2) Increased Vascular Permeability (Vascular Leakage)-Several mechanisms
are responsible for the increased permeability of postcapillary venules, a hallmark
of acute inflammation
• Contraction of endothelial cells resulting in increased interendothelial spaces is the
most common mechanism of vascular leakage.
• It is elicited by histamine, bradykinin, leukotrienes, and other chemical mediators.
• It is called the Immediate transient response ioccurs rapidly after exposure to the
mediator and is usually short-lived (15 to 30 minutes)
• Delayed prolonged leakage (appearing 2-12hrs, lasting hrs/days) may also be
caused by contraction of endothelial cells or mild endothelial damage. Late-
appearing sunburn is a good example of this type of leakage.

10. • Direct endothelial injury: resulting in endothelial
cell necrosis and detachment is encountered in
severe injuries.
• Direct endothelial injury is seen in burns,
chemical injury or mediated by leukocytes
attached to the endothelium or microbial toxins.
• Leakage begins immediately and sustained until
damaged vessels are thrombosed or repaired.

11. • Transcytosis: involves increased transport of
fluids and proteins, through the endothelial
cell.
• This process involves intracellular channels
that may be stimulated by certain factors,
such as VEGF, that promote vascular leakage.

13. CELLULAR EVENTS IN ACUTE INFLAMMATION
Leukocyte Adhesion to the Endothelium
• Margination- implies the peripheral displacement of WBC along the endothelial surface due to
stasis and hemodynamic changes.
• Rolling- Subsequently, leukocytes adhere transiently to the endothelium, detach and bind again,
thus rolling on the vessel wall. The cells finally come to rest at some point where they adhere firmly
to the endothelial surface.
• Adhesion- The attachment of leukocytes to endothelial cells is mediated by complementary
adhesion molecules on the two cell types. Expression of adhesion molecules are induced by
cytokines are secreted by sentinel cells in tissues in response to microbes and other injurious
agents, thus ensuring that leukocytes are recruited to the tissues where these stimuli are present
.
• The two major families of molecules involved in leukocyte rolling and adhesion are: Selectins and
Intergrins.

15. Selectins: Selectins are involve in Rolling. They are receptors
expressed on cell surface. There are three types of
selectins:
• L-selectin, expressed on leukocytes.
• E-selectin), on endothelium
• P-selectin, on endothelium and leukocytes.
Ligands: for selectins are sialylated oligosaccharides.
• The expression of selectins and their ligands is regulated by
cytokines produced in response to infection and injury.

16. Integrins
• Adhesion is mediated by a family of leukocyte
surface proteins called integrins:
VLA-4 β1 integrin: ligand VCAM-1, on endothelial
surface.
LFA-1 β2 integrins : ligand ICAM-1on endothelial
surface.
• TNF and IL-1 released at site of infection or injury
induce endothelial expression of ligands for
integrins on leukocyte surfaces.

17. Rolling, Adhesion, Emigration

18. • 3) Leukocyte Emigration: Occurs through a process of migration
of the leukocytes through the endothelium called Transmigration
or Diapedesis.
• Adherent leukocytes migrate through interendothelial spaces
toward the chemical concentration gradient to the site of injury or
infection (Chemotaxis).
• Adhesion molecules in interendothelial space such as PECAM 1 aid
in leukocyte extravasation.
• After traversing the endothelium, leukocytes pierce the basement
membrane, probably by secreting collagenases, and enter the
extravascular tissue.

20. • Chemotaxis : which is defined as locomotion along a
chemical gradient. Both exogenous and endogenous
substances can act as chemoattractants.
• Bacterial products: LPS, Proteoglycans including peptides
that possess an N-formylmethionine terminal amino acid
and some lipids.
• Chemical mediators:
(1) Cytokines,e.g, IL-8.
(2) Components of the complement system, particularly C5a
(3) Arachidonic acid (AA) metabolites e.g LTB4.

21. • The nature of the leukocyte infiltrate varies with the age of
the inflammatory response and the type of stimulus.
• Neutrophils predominate in the inflammatory infiltrate
during the first 6 to 24 hours and are replaced by
macrophages in 24 to 48 hours.
• However, others cells may dominate in other acute
inflammatory responses
– Lymphocytes: esp in Viral infections
– Eosinophils: Parasitic and
Hypersensitivity reaction

22. 4)Phagocytosis: Process of engulfment of solid particulate
matter. (Cell eating). The cells involved in phagocytosis are
called Phagocytes.
• 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.

23. a) Recognition and Attachment: Phagocytic cell a
recognize and attach to bacteria products and tissue
proteins via;
• 1) Mannose receptors-binds glycoprotein & lipids on
bacterial cell wall.
• 2) Scavenger receptors bind a variety of microbes in
addition to modified LDL particles. Macrophage
integrins Mac-1 (CD11b/CD18), may also bind microbes
for phagocytosis.
• 3) Opsonins- IgG, C3b breakdown product of
complement and lectins are recognized by specific
receptors on leukocytes.

24. b) Engulfment
After binding to phagocyte
receptors, pseudopod extends
around the particle, forming a
vescicle (phagosome).
The phagosome fuses with a
lysosome forming
phagolysosome, into which the
lysosomal granules are
discharged.

26. • Degradation/ Killing
• The killing and degradation of microbes and dead cell debris
within neutrophils and macrophages occur most efficiently
after activation of the phagocytes.
–Oxygen-dependent mechanisms
–Oxygen-independent mechanisms

28. OXYGEN DEPENDENT KILLING
1) NADPH-Oxidase system (ROS)

29. OXYGEN DEPENDENT KILLING
2) Myeloperoxidase-Halide system

30. H202-MPO-Halide system
is the most efficient bactericidal system of neutrophils.

32. (3) Peroxy-Nitrite system
NO, a soluble gas produced from arginine
by the action of nitric oxide synthase (iNOS), also participates
in microbial killing.
Induced when macrophages and neutrophils are activated
by cytokines.
These nitrogen-derived free radicals, attack and
damage the lipids, proteins, and nucleic acids of microbes

36. CHEMICAL MEDIATORS OF INFLAMMATION
• General properties of chemical mediators
a. These mediators can be produced Locally, by the CELLS and are called CELL-
DERIVED. Derived from inactive precursors present in plasma which are referred
to as PLASMA -DERIVED .
The cell derived mediators are preformed mediators where as the plasma derived
are the ones which are synthesized de-novo.
b. They can be produced only in response to agents that stimulate inflammation
c. They can stimulate the release of another mediator.
d. They have short lifespan: as they are degraded by enzymatic action very rapidly.
e. They can act on wide variety of cells and may have similar action on different
targets or different actions on similar targets.

40. CELL DERIVED MEDIATORS-Preformed(stored)
Vasoactive Amines
HISTAMINE: -In mast
cells, basophils &
Platelets.
Vasodilatation and
increase vascular
permeability.
SEROTONIN-in platelets.
Increase vascular
permeability.

41. • Arachidonic acid metabolites: Prostaglandins,
Leucotrienes & Lipoxins. Released from in membrane
Phospholipid by the action of phospholipase A2.

42. Actions of AA Metabolites

43. Cytokines
Cytokines are biologically active substances secreted by mono-cytes, lymphocytes, and
other cells and are actively involved in innate immunity, adoptive immunity, and
inflammation. They actively take part in a wide range of biological activities varying
from chemotaxis to activation of specific cells

44. Cytokines in Inflammation

48. PLASMA DERIVED
• Complement System

50. • Kinnin System
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.
The action of bradykinin is short-lived, because it is quickly inactivated
by an enzyme called kininase. Bradykinin has been implicated as a
mediator in some forms of allergic reaction, such as anaphylaxis .

51. Role of the inflammatory response
• Drainage of fluid exudate into the Iymphatics allows
particulate and soluble antigens to reach the local Iymph
nodes where they may stimulate the immune response.
• Enables cells of the inflammatory response get to the
desired site
• Increased heat at the site of infection activates enzymes
used in the response.
• Prepare grounds for wound healing

52. What is the outcome of Acute
inflammation?
• Resolution
• Healing with scarring (fibrosis)
• Ulceration
• Abscess formation
• Fistula formation
• Sinus formation
• Progression to chronic inflammation