ACUTE INFLAMMATION

Def: local response of living mamalian tissues to injury

Def:to
due local
anyresponse
agent. it of
is aliving mamalian
body’s defence tissues
reactiontoininjury
order
due to any agent.
to eliminate it is
or limit thea body’s
spreaddefence reaction
of injurious agentinas
order
to
to eliminate
remove or limit the necrosed
the consequent spread ofcells
injurious agent as to
and tissue.
remove the consequent necrosed cells and tissue.
“Inflame”–to set fire.
Inflammation is“A dynamic response of vascularised
tissue to injury.”
It is a protective response.
It serves to bring defense & healing mechanisms to the
site of injury
Etiologies
-Physical agents: heat,cold,trauma or radiation
-Chemical agents: organic and inorganic poisons
-Infective agents: bacterial,viral toxins
-Immunological agents: cell mediated, antigen and
antibody reactions
TYPES
1) ACUTE
2) CHRONIC
Signs of inflammation
a) rubor
b) tumour
c) calor
d) dolor
e) functio laesa
ACUTE INFLAMMATION
1) VASULAR EVENTS

 2) CELLULAR EVENTS
1) VASCULAR EVENTS
a) haemodynamic changes

b) vascular permeability
Series of events that takes place in haemodynmic
changes that includes:
First- Transient vasoconstriction
Second- Persistent progressive vasodilation

elevate the local hydrostatic pressure

results in transudation of fluid into the extracellular space


responsible for swelling at the local site of acute
inlammation

slowing or stasis of microcirculation occurs next

increased permeability of microvasculature

increased concentration of red blood cells

 raises blood viscocity

stasis or slowing is followed by leucocytic migration

(mainly neutrophils along the vascular endothelium)

 these move and migrate through the gaps between the
endothelium (emigration)
VASCULAR PERMEABILITY:
pathogenesis:
MECHANISM OF INCREASED
VASCULAR PERMEABILITY
Contraction of endothelial cells - most common
 eg: mild thermal injury of forearm

Retraction of endothelial cells- structural reorganisation of

the cytoskeleton of endothelial cells.
 eg: invitro experimental work only
 Direct injury to endothelial cells
 eg: severe bacterial infections

 Endothelial injury mediated by leucocytes.

 eg: in pulmonary veins and capillaries

 Neo vascularisation
 eg: During the process of repair.
CELLULAR EVENTS

1) exudation of leukocytes

2) phagocytosis
EXUDATION OF LEULOCYTES
1) changes in the formed elements of blood
2) rolling and adhesion
3) emigration
1) changes in the formed elements of blood:
- margination
- pavementing
pics
2) ROLLING AND ADHESION:
- rolling phage
- adhesion (transient bond between leucocytes and
endothelium)
pics
Molecules that bring about adhesion and rolling phases:
1) SELECTINS:P-selectins,E-selectins,L-selectins
2) INTEGRINS:
3) IMMUNOGLOBULIN SUPERFAMILY ADHESION
MOLECULE: Such as ICAM-1,2
PICS
EMIGRATION:
- neutrophils throw out cytoplasmic pseudopods
Pic
DIAPEDESIS- escape of red cells through gaps between
the endothelial cells- a passive process,by raised
hydrostatic presure
pic
Sequence of events in exudation of
leucocytes
CHEMOTAXIS
boyden’s experiment:In this, a millipore filter(3 microns
pore size)seperates the suspension of leucocytes from the
test solution in tissue culture chamber.if the test solution
contains chemotactic agent,the leucocytes migrate
through the pores of filter towards the chemotactic
agent.
Various chemokines are:
- leukotriene B4
- platelet factor 4
- components of compliment system(C3,C4 in particular)
- cytokines(interleukines IL-1,IL-5,IL-6)
- soluble bacterial products (eg :formylated peptidases)
- monocyte chemoattractant protein(MCP-1)
Chemotactic factor for CD4 +T cells
- Eotaxin chemotactic for eosinophills
PHAGOCYTOSIS
- it is the process of engulfment of solid particulate
matrial by the cells(cell eating).
Types of phagocytic cells(phagocytes)
1) pmn’s or microphages
2) circulating monocytes-macrophages
The process includes 4 steps
1) Recognition and attachment stage(opsonisation)
2) Engulfment stage
3) Secretion (degranulation)stage
4) Digestion (degradation)stage
1) RECOGNITION and ATTACHMENT STAGE
- phagocytes are reconised and attracted by bacterial
products as well as tissue proteins.

Opsonins – naturally ocurring factors in the serum

Opsonins present in the serum and their corresponding
receptors on the surface of phagocytic cells are;
1) IgG opsonin:
 - it is the Fc fragment of immunoglobulin G.
- it is the naturally occuring antibody in the serum that
coats the bacteria.
2) C3b opsonin:
- it is the fragment of complement.
- generated by activation of compliment pathway.
- it is strongly chemotactic for attracting PMN’S to
bacteria.
3) LECITHINS:
-These are carbohydrate binding proteins in the plasma
which bind to bacterial cell wall.
pic
2) ENGULFMENT STAGE:
- The opsonised particle bound to the surface of
phagocyte is ready to be engulfed, sequence of events
taking place..
 Formation of cytoplasmic pseudopods around the
parcticle due to activation of actin filaments beneath the
cellwall,enveloping it in a phagocytic vacuole.

 eventually, the phagocytic vacuole breaks from
the cell surface so that membrane lined phagocytic
vacuole lies free in the cytoplasm.

 the lysosomes of the cell fuse with the phagocytic

vacuole and form phagolysosome or phagosome
3) DEGRANULATION STAGE:
- During this process,the preformed granules stored products
of PMN’s are dischared into the phagosome and the
extracellular environment, in particular the lysosomes,while
azurophilic granules are fused with phagosomes.
- besides this,mononuclear phagocytes synthesize and
secrete certain enzymes,(eg:interleukin 2,6) arachidonic acid
metabolites(eg:prostaglandins,leukotrienes,PAF’S) and
oxygen metabolites(eg:super oxide oxygen,
H2O2,hypochlorous acid
KILLING or DEGRADATION STAGE:
The microbes after being killed by anti bacterial
substances are degraded by hydrolytic enzymes.
- however this mechanism fails to kill some bacteria like
tubercle bacilli.
- These antimicrobial agents acts by either of the
following mechanisms:
1) oxygen-dependant bactericidal mechanism
2) oxygen-independant bactericidal mechanism and
3)nitric oxide mechanism
CHEMICAL MEDIATORS OF INFLAMMATION
Time course Acute inflammation:Less than 48hours
Chronic inflammation:Greater than
48hours(weeks,months,years)

Cell type Acute inflammation:Neutrophils

Chronic inflammation:Mononuclear
cells(Macrophages,Lymphocytes,Plasmacells).
Histamine(& serotonin)
Histamine mainly stored in mast cells,basophills and
platelets, it is released by various agents like,
Stimuli inducing acute inflammation eg: heat,
cold,irradiation,trauma,irritant chemicals.
Anaphylotoxins like fragments of complement C3a,and
C5a, which increase vasucular permeability and cause
oedema in tissues
Histamine-releasing factors from neutrophils, monocytes
and platelets.
Neuropeptides such as substance p.
Interleukines.
Role of Mediators in Different Reactions of
Inflammation
Vasodilatation Prostaglandins
Nitric oxide
Histamine
Increased vascular permeability Vasoactive amines
C3a and C5a (through liberating amines)
Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
Chemotaxis,
leukocyte recruitment and activation C5a
Leukotriene B4
Chemokines
IL-1, TNF
Bacterial products
Fever IL-1, TNF
Prostaglandins
Pain Prostaglandins
Bradykinin
Tissue damage Neutrophiland macrophage lysosomalenzymes
Oxygen metabolites
Nitric oxide
Actions of histamine
- vasodilation, increased vascular permeability,itching and
pain
ARACHIDONIC ACID METABOLITES
•In both physiologic and pathologic processes (inflammation)
•produced by endothelial cells, leukocytes and platelets
•act locally on smooth muscle, endothelium and platelets
•can mediate most of the steps in acute inflammation!
•origin:
arachidonic acid derived from membrane phospholipids (eg linoleic acid)
must first be released by activated phospholipases (in injury)
•two important pathways:
cyclooxygenase (COX)
lipoxygenase
ARACHIDONIC ACID METABOLITES
LYSOSOMAL CONSTITUENTS
Degradation of ECM
•collagenase, hydrolase, protease (trypsin), elastase

Kill infectious organisms &/or infected cells

•lactoferrin, lysozyme, myeloperoxidase, major basic
protein
•granzyme/perforin in cytotoxic T lymphocytes
PLATELET ACTIVATING FACTOR
produced by platelets, endothelial cells, leukocytes
functions:
platelet aggregation and release
bronchoconstriction & vasoconstriction [high]
vasodilation and vascular permeability [low]
increases leukocyte adhesion & chemotaxis
increases leukocyte degradation / oxidative burst
 CYTOKINES
Polypeptide transmitters for cell-to-cell chatting
modulate cell functions
•primarily from activated macrophages & lymphocytes
•esp. IL-1 & TNF-α
IL-1 and TNF - “Master Cytokines”
Other Cytokines
IL-5
eosinophils (chemotaxis, activation, proliferation)
•IL-6
B and T cells proliferation (master cytokine)
•IL-8
attracts neutrophils (chemokine)
•IF-γ
activates macrophages & T lymphocytes (in viral infections)
•PDGF
chemotactic to fibroblasts and leukocytes
•TGF-β & VEGF
important in repair
NITRIC OXIDE (NO)
nitric oxide (NO) synthesized from L-arginine by NOS
(iNOS in inflammation)
•effects: - smooth muscle relaxation → vasodilation
- reduce platelet aggregation & adhesion
- bactericidal (forms peroxynitrite)
•uncontrolled NO production (sepsis) → massive
vasodilation → shock
 CHEMICAL MEDIATORS OF INFLAMMATION
Definition: any messenger that acts on blood vessels, inflammatory
cells or other cells to contribute to an inflammatory response.
PLASMA PROTEASES
Complement system
•killing system
•vasoactive
•chemotactic

Kinin system
•highly vasoactive
•pain

Clotting / fibrinolytic system

•vasoactive
•cleaves C3
All 3 systems are interrelated
COMPLEMENT SYSTEM

Three pathways:
•Classical pathway (antibodies)
•Alternate pathway (microbe LPS)
•Lectin pathway (sugar on microbes
KININ SYSTEM

Bradykinin
•activated by Hageman factor (XIIa)
•generated from plasma proteins (kininogens)
•actions:
potent vasodilator
stimulates release of histamine ( vasc. perm.)
contraction of non-vascular smooth muscle
produces pain
activates the arachidonic acid cascade