Inflammation

QUESTIONS
How did cells recognize the presence of potentially
harmful agents?
Inflammation
is a protective response involving host cells, blood
vessels, and proteins and other mediators that is
intended to eliminate the initial cause of cell injury, as
well as the necrotic cells and tissues resulting from the
original insult, and to initiate the process of repair.

can cause considerable harm

 Goal of the inflammatory reaction is to bring cells and
molecules of host defense to the site of infection or
tissue damage.

Normally its controlled and self-limited.

 Classification
 Inflammation is induced by chemical mediators that are
produced by host cells in response to injurious stimuli.
 The external manifestations of inflammation (cardinal
signs)
1. Heat (calor)
2. Redness (rubor)
3. Swelling (tumor)
4. Pain (dolor)
5. Loss of function (functio laesa)
 The steps of the inflammatory response can be
remembered as the five Rs:
I. Recognition of the injurious agent
II. Recruitment of leukocytes
III. Removal of the agent
IV. Regulation (control) of the response
V. Resolution (repair).
ACUTE INFLAMMATION
Has two major components
1. Vascular changes
Vasodilation: vessel caliber increased blood flow
Increased vascular permeability: vessel wall permit plasma
proteins to leave the circulation
Activation of endothelial cells adhesion & migration of the
leukocytes through the vessel wall.
2. Cellular events
Cellular recruitment: emigration & accumulation
Leukocyte activation: eliminator
 The principal leukocytes in acute inflammation are
neutrophils (PMN leukocytes).
Stimuli for Acute Inflammation
1. Infections
2. Trauma
3. Various physical & chemical agents
4. Tissue necrosis
5. Foreign bodies
6. Immune reactions
Recognition of Microbes, Necrotic Cells, and Foreign
Substances
pattern recognition receptors
1. Toll-like receptors (TLRs)
microbial sensors
recognize products of bacteria, viruses, and other pathogens
activates transcription factors
2. Inflammasome
is a multi-protein cytoplasmic complex that recognizes
products of dead cells, such as uric acid and extracellular ATP
results in activation of caspase-1 activate IL-1 recruit
leukocyte leukocytes phagocytose and destroy dead cells.
Vascular Changes
1. Vascular Caliber and Flow
.Transient vasoconstriction arteriolar vasodilation
blood flow and engorgement of the down-stream
capillary beds redness (erythema) and warmth
2. Vascular Permeability
Mechanisms
I. Endothelial cell contraction (most common)
intercellular gaps in postcapillary venules
binding of histamine, bradykinin, leukotrienes, and many other
mediators to specific receptors, and is usually short-lived (15 to
30min)
cytokines (TNF & IL-1) changes in the cytoskeleton slower
and more prolonged retraction of endothelial cells taking 4 to 6
hours to develop after the initial trigger & persist for 24 hours or
more.
II. Endothelial injury
necrosis and detachment
leakage begins immediately after the injury and persists for
several hours (or days) until the damaged vessels are
thrombosed or repaired.
Venules, capillaries, and arterioles can all be affected,
depending on the site of the injury.
III. Increased transcytosis
.Leakage of proteins through channels formed by fusion
of intracellular vesicles VEGF exposure augments
venular permeability
IV. Leakage from new blood vessels
.During angiogenesis vessel sprouts remain leaky
deficient intercellular junctions
Responses of Lymphatic Vessels
Drain edema fluid, leukocytes, & cell debris from the
extravascular space
Disseminate microbes inflammation of lymphatics
(lymphangitis) and LN (lymphadenitis)
Cellular Events
Leukocyte Recruitment
Sequence of events
1. Margination and rolling along the vessel wall
2. Firm adhesion to the endothelium
3. Transmigration between endothelial cells; and
4. Migration in interstitial tissues toward a chemotactic
stimulus
1. Margination and Rolling
Margination blood flow & cell size
Rolling weak and transient adhesion selectin fx receptors
Selectins
3 members
E-selectin (CD62E), expressed on endothelial cells IL-1
and TNF
L-selectin (CD62L), on the surface of most leukocytes
P-selectin (CD62P), present on platelets and
endothelium histamine/thrombin
bind sialylated oligosaccharides
2. Adhesion
.mediated by integrins (transmembrane heterodimeric
glycoproteins)
3. Transmigration
.Leukocytes migrate through the vessel wall primarily by
squeezing between cells at intercellular junctions
(diapedesis) driven by chemokines.
.Mediated by platelet endothelial cell adhesion molecule-
1 (PECAM-1) (also called CD31)
.Collagenase???
4. Chemotaxis
.A process by w/c leukocytes move toward sites of infection or
injury along a chemical gradient.

.Both exogenous and endogenous substances can be chemotactic

for leukocytes
Bacterial products (peptides with N-formylmethionine termini)
Cytokines
Components of the complement system (C5)
Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism
(LTB4)
 The type of emigrating leukocyte varies with the age of the
inflammatory response and with 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 replaced by monocytes in 24 to 48 hours.
Exceptions
In certain infections (e.g., Pseudomonas organisms) neutrophils
viral infections lymphocytes
hypersensitivity reactions eosinophils
Leukocyte Activation
Recognition of microbes or dead cells induces several responses
in leukocytes that are collectively called leukocyte activation

results in the enhancement of the following functions

Phagocytosis of particles
Intracellular destruction of phagocytosed microbes and dead cells
Liberation of substances that destroy extracellular microbes and dead
tissues
Production of mediators
1. Phagocytosis
.consists of three steps
a) recognition and attachment of the particle to the ingesting
leukocyte
b) engulfment, with subsequent formation of a phagocytic
vacuole
c) killing and degradation of the ingested material.
 There are 2 main types of phagocytic cells
1. Polymorphonuclear neutrophils (PMNs) which appear
early in acute inflammatory response, sometimes
called as microphages.
2. Circulating monocytes and fixed tissue mononuclear
phagocytes, commonly called as macrophages.
Recognition and attachment
Initiated by the expression of surface receptors on
macrophages which recognise microorganisms: mannose
receptor and scavenger receptor enhanced by opsonins.
Opsonins establish a bond between bacteria and the cell
membrane of phagocytic cell. The main opsonins are:
1. IgG opsonin
2. C3b opsonin
3. Lectins
Engulfment
Opsonisation formation of cytoplasmic pseudopods
around the particle the plasma membrane enclosing
the particle breaks from the cell surface phagocytic
vacuole free in the cell cytoplasm fuses with one or
more lysosomes form bigger vacuole called
phagolysosome
Killing and degradation
Mechanisms: two
Intracellular mechanisms:
Oxidative bactericidal mechanism by oxygen free radicals
MPO-dependent HOCl, HOI, HOBr
MPO-independent OH ions and superoxide singlet oxygen (O)
Oxidative bactericidal mechanism by lysosomal granules
Non-oxidative bactericidal mechanism (hydrolase & NO)
Extracellular mechanisms:
Degranulation & immune mediated
Morphologic patterns
1. Serous inflammation
.Cxd by the outpouring of a watery, relatively protein-
poor fluid that, depending on the site of injury, derives
either from the plasma or from the secretions of
mesothelial cells lining the peritoneal, pleural, and
pericardial cavities.
Low-power
view of a
cross-
section
of a skin
blister
showing
the
epidermis
separated
from the
dermis by a
focal
collection
of serous
effusion.
2. Fibrinous inflammation
.severe injuries greater vascular permeability
allows large molecules (such as fibrinogen) to pass the
endothelial barrier

.Histologically
appears as an eosinophilic meshwork of threads or sometimes
as an amorphous coagulum
Deposits of fibrin on the
pericardium
A pink meshwork of fibrin
exudate (F) overlies the
pericardial surface (P)
3. Suppurative (purulent) inflammation and abscess
formation
.manifested by the collection of large amounts of
purulent exudate (pus) consisting of neutrophils,
necrotic cells, and edema fluid.
Purulent inflammation
with abscess
formation. Multiple
bacterial abscesses in
the lung (arrows) in a
case of
bronchopneumonia
The abscess contains
neutrophils and
cellular debris and is
surrounded by
congested blood
vessels.
4. Ulcer
. is a local defect, or excavation, of the surface of an
organ or tissue that is produced by necrosis of cells and
sloughing (shedding) of necrotic and inflammatory
tissue.
A chronic duodenal
ulcer
Low-power crosssection of a duodenal ulcer crater
with an acute inflammatory exudate in the base
Chemical mediators & regulators
N:B
Mediators may be produced locally by cells at the site of
inflammation, or may be derived from circulating
inactive precursors (typically synthesized by the liver)
that are activated at the site of inflammation.
Most mediators act by binding to specific receptors on
different target cells.
The actions of most mediators are tightly regulated and
shortlived.
Cell-Derived Mediators
Vasoactive Amines
Histamine
mast cells adjacent to vessels, as well as circulating
basophils and platelets.
arteriolar dilation and rapidly increases vascular permeability
inducing
venular endothelial contraction and formation of
interendothelial gaps.
Serotonin (5-hydroxytryptamine)
platelet
Arachidonic Acid Metabolites