Veterinary general pathology

1. Rajasthan university of veterinary and animal science
Department of veterinary pathology
Inflammation
presented by :
Dr Sanjana saini

2. Introduction
● Inflammation is a complex process of vascular and
cellular alterations occurs in body in response to
injury .
● Basically , it is the reaction of blood vessels
leading to accumulation of fluid and leukocytes in
extravascular tissues.
● Healing is the end result of of inflammation .
● inflammation serves to destroy ,dilute ,or
neutralize harmful agents (microbes ,toxins) and
repair the damaged tissues
● It is basically a protective response .

3. Types of inflammation
Inflammation is of 2 types:
1. Acute
2. chronic
Feature Acute inflammation Chronic inflammation
Duration Days or week Months or years
Types of cells Mainly neutrophils and
monocytes
,macrophages
Mainly lymphocytes,and
plasma cells
,macrophages,monocytes
cardinal signs All are present only some
Healing process complete resolution by fibrosis

4. Acute inflammation
● Acute inflammation is the immediate and early response to an
injurious agent.
● It is characterized by more intense vascular changes like
congestion ,oedema,haemorrhages,leakage of fibrinogen and
leucocytes.
Etiology
1. Infectious agents
2. chemical agents
3. physical agents
4. immunological reactions
5. nutritional imbalances
6. necrotic tissues

5. cardinal signs
● first 4 signs were given by Cornelius celsus
● The fifth sign was given by Rudolf virchow
1. Redness(rubor) = Due to a great increase of blood in the inflamed area
as a result of hyperaemia.
2. Swelling (tumor)= Outpouring of protein rich fluid containing blood cells
into the extravascular tissues called exudate .
3. Heat (calor)= Due to increase rate of metabolism at the inflammation
site and increase rate of blood flow through the area that carries
heat to periphery from interior body temperature.
4. Pain (dolor)= It occurs partly from increased pressure on sensory
nerve endings and by stretching of tissues from accumulation of
exudate .
Chemical mediators are released following injury and produce pain
5. Loss of function(functio-laeso) = Due to combination of pain , swelling ,
destruction of tissues

6. Tissue alterations in acute inflammation
2 grps
1. The vascular changes
2. The cellular events
● Julius Cohnheim was the first to describe vascular changes in
1877.
Vascular changes
1. Changes in blood vessels
● momentary vasoconstriction = Arterioles are constricted for a movement as a
result of action of irritants .
● Vasodilatation = momentary constriction is quickly followed by vasodilatation
of arterioles and results in opening of new capillary buds.
● - normally the capillaries which remain dormant or collapsed are opened up
● - due to this ,increased vascularity of the inflammed area
● -dilatation is caused by chemical mediators release locally .

7. 2. changes in the rate of flow
The early vasodilation results in increased blood flow soon followed
by slowing of the circulation .
The slowing is brought by increased permeability of the
microvasculatures leads to outpouring of protein rich fluid into the
extravascular tissues.
This results in concentration of RBC in small vessels and increased
viscosity of the blood leads to stasis .
● Increased vascular permeability
Endothelium of vessels becomes more permeable to proteins and
releases albumin , globulin, fibrinogen through leaky vessels .
The loss of protein from plasma reduces the intravascular
osmotic pressure and increase osmotic pressue of interstitial
fluid which causes marked outflow of fluid and its accumulation
causes oedema

9. Mechanism of increased cellular permeability
Formation of endothelial gaps in venules
● Inter endothelial junctions of vessels get loosened due
to chemical mediators of inflammation causing increase
vascular permeability .
● The inter endothelial gaps are produced by contraction
of actin and myosin endothelial cells results widening of
junction .
● Vascular leakage occurs which is reversible and short
lived hence called the ‘immediate transient response ‘.
● Here leakage affects only venules and capillaries not
arterioles becoz of relevant chemical mediator
receptors.

10. Endothelial cell retraction
● Structural reorganization of the endothelial cytoskeleton .
● Resulting, retraction of cells from each other leads to the
formation of gaps.
● Cytokine mediators, such as interleukin -1 , tumour necrosis
factor and interferon -gamma induce retraction .
● It takes 4-6 hours to develop and persists for 24 hours or
more
Direct endothelial injury
● It is usually seen after severe injury like burns and infections.
● leakage occurs immediately after injury and continue for long
time until the damaged vessels are thrombosed or repaired and
this reaction is called as immediate sustained response .
● venules , capillaries, arterioles all are affected

11. Delayed prolonged leakage
● It involves venules and capillaries and persist for several hours
or even days due to direct injury to endothelial walls like in
thermal injury
Leukocyte dependent endothelial injury
● Leukocyte accumulation at site release some toxic species and
proteolytic enzymes causes injury leads to increasing vascularity .
Increase transcytosis
● It occurs through channels formed by fusion of uncoated vesicles
by mediator like vascular endothelial growth factor (VEGF)
leakage from new blood vessels
● New vessels sprouts leaky until differentiation and form intercellular
junctions and have receptors for vasoactive mediators

12. 3.Change in the blood stream
● It consists of a redistribution of the cellular elements of the
bloodstream
● 2 distinct zone found in vessels , in the center cellular elements
(RBC and WBC ) called as axial part and elements are held in
center by centripetal force of the flowing blood .
● External to axial stream is the plasmatic stream, a clear zone
consist plasma , which is in close contact with wall of vessels.
● As the slowing of blood flow, centripetal force overcome by the
centrifugal force and the leukocytes fall out of the axial stream
and this adhesion of WBC to the endothelial walls of vessels is
called Margination .
● At this time , when the endothelium is virtually lined by White
blood cells , this appearance is called Pavementing .

13. 4. Exudation of plasma
● Following increased vascularity , fluid part of the blood
escapes into the inflamed area, called as exudation.
5. Emigration of leukocytes
● The process by which leukocytes come out of the blood
vessels into the extravascular space is called transmigration.
6.Diapedesis of erythrocytes
● Following emigration of WBC, red cells are also pushed out of
the vessel passively by intravascular pressure ,called as
diapedesis .
● In severe injuries , red cells may also enter the tissue by
rhexis ( break) of the vessel wall

14. Chemical mediators of inflammation
Origin
● Locally from cells ( cell derived mediators)
~~ they are preformed (eg histamin )
~ or newly synthesized ( eg prostaglandin)
● From liver (Plasma derived mediators) ~~
they are inactive or precursors forms that
must be activated to acquire their
biological properties

16. cell derived mediators
● preformed in secretory granules ~~vasoactive
amines ( serotonin , histamin)
● Newly synthesized ~~ 1 arachidonic acid
metabolites
2 cytokines
3 chemokines
4 plasma proteases
5 nitric oxide
6 oxygen derived free radicals
7 platelet activating factor ( PAF )

17. Histamine
● Produced by circulating basophils, platelets
and mass cells adjacent to vessels
● produced in response to physical injury ,
immune reactions , anaphylotoxins (C3a ,C5a)
histamine releasing proteins derived from
neutrophils , cytokines(IL~1,IL~8) and
neuropeptides (substance P)
● functions= vasodilatation, increase vascular
permeability , venules endothelial contraction

18. Serotonin
● Also called as 5~ hydroxytryptamine
● It is present only in the mast cells of rat and
mouse
● Its presence in the chicken mast cells is
suspected
● Produced mainly within platelets dense
granules
● released during platelet aggregation
● cause vasodilatation , increase vascular

19. Arachidonic Acid metabolites
They are short range hormones( autocoids) that act locally and
decay spontaneously
● 2 pathways
~ Cyclooxygenase pathway synthesise Prostaglandin and
thromboxanes
function = vasodialation , potentiates edema formation
1. PGI2 produced by prostacyclin synthase in endothelial cell
causes vasodialation and inhibits platelet aggregation
2. TxA2 produced by thromboxane synthase in platelets
causes vasoconstriction and stimulates platelets
aggregation

20. ● Lipoxygenase pathway
~ 1LTB4 produced by neutrophils and some macrophages
~it is a potent chemotactic agent and causes aggregation
of neutrophils
~LTC4 ,LTD4,LTE4 produced by mast cells causes
vasoconstriction , bronchospasm ,and increased vascular
permeablity only in venules
● Lipoxins
~ synthesized by transcellular pathway that is cell ~cell
interaction
~ They are formed by platelets when platelets interact
with neutrophils derived LT4
~ antagonists of leukotrienes.

21. 5HPETE -
hydroperoxyeicosatetrae
noic acid

22. Platelet activating
factor
● Produced by WBCs and endothelial cells
by the action of phospholipase A2
● At low concentration induces
vasodilation and increase permeability
● PAF induces vasoconstriction ,
increased leukocyte adhesion to
endothelium ,chemotaxis ,degranulation
,and oxidative burst

23. Cytokines
● They are proteins produced from many cells
mainly lymphocytes and macrophages
● some play role in inflammation (tumour necrosis
factor ,interleukin ~1 )
● IL~1 and TNF are produced by macrophages
● IL~1 and TNF- alpha , TNF -beta induce
endothelial effects increses leukocyte adherence
,fibroblastic proliferation due to release of
proteolytic enzymes ,induction of systemic acute
phase reactions

24. ● Released from neutrophils and
macrophages after exposure to
chemotactic agents , immune complexes,
phagocytic activity
● Superoxide , hydrogen peroxide ,hydroxyl
radical are the major species produced
within the cell
● They cause endothelial cell damage
resulting increased vascular permeability

25. Nitric oxide
● NO is formed from the amino acid arginine ,
molecular oxygen , NADPH by the enzyme nitic oxide
synthatase(NOS)
● 3 types of NOS - 1. Type1 (nNOS) =neuronal
2. Type2( eNOS)= endothelium
3. Type3(iNOS)= inducible enzyme
which is produced when cells are activated by cytokine
● It is a potent vasodialator
● It reduces platelet and leukocyte adhesion
● It also act as a microbial agent in activated
macrophages

26. Lysosomal Components
The inflammatory cells neutrophils and monocytes contain
lysosomal granules
1.Granules of monocytes and tissue
macrophage
● On degranulation these cells release
acid proteases ,collagenase ,
elastase and plasminogen activator

27. Granules of neutrophils
1.primary
granules(azurophil)=myeloperoxidase ,
bacterial factors,acid hydrolases.
2.secondary granules(specific
granules)=lysozyme,collagenase,alkaline
phosphatase, lactoferrin,plasminogen
activator, histaminase.
3.neutral proteases= elastase, cathepsin G
, non specific collagenases, proteinase 3

28. Chemokines
They are proteins that act mainly as activators and
chemoattractants for specific types of leukocytes
● The 2 major groups are
1. CXC 2. CC chemokines
● CXC chemokines act mainly on neutrophils
– IL8 is a typical of this group and it is produced by activated
macrophages , endothelium , or fibroblast in response to IL-1 and
TNF
● CC chemokines include monocyte chemoattractant protein -1(MCP-
1) and macrophage inflammatory protein -1(MIP-1alpha)
- both are chemotactic mainly for monocytes
Chemokines play a role in regulating leukocyte
recruitment and activation during inflammation

29. Plasma protein derived mediators
Complement system
Clotting / fibrinolytic system
Kinin system

30. Clotting /fibrinolytic system
This system is activated by Hageman factor (Xll)
● Activated Hageman factor initiates 4 systems
1.Kinin system =producing vasoactive kinins
2.Clotting system = Inducing activation of
thrombin ,fibrinopeptides, and factor X
3.Fibrinolytic system = producing plasmin and
degrading thrombin
4.Complement system = producing anaphylotoxins
C3a and C5a

32. ● Hageman factor initiates the
clotting system resulting in
formation of fibronogen which is
acted upon by thrombin to form
fibrin and leads to
1.Increased vascular permeability
2.Chemotaxis for leucocyte
3.Anticoagulant activity

33. ● The fibrinolytic system activated by plasminogen
activator the source of which include kallikrein of
the kinin system , endothelial cells and leucocytes .
● Plasminogen activator acts on plasminogen tp form
plasmin and further breakdown of fibrin by plasma
forms fibrinopeptides or fibrin split products
Actions of plasmin
1. Activation of hageman factor
2. Splits C3 to form C3a which is a permeability factor
3. Degrades fibrin to form fibrin split products which
increases vascular permeabilty and are chemotactic to
leucocytes.

34. Complement system
● It consists of 20 proteins in an inactive form
in plasma and body fluids
● Complement system activated in one of the 2
ways classic or alternate pathway
● Both pathways converge to produce a
membrane attack complex(MAC) which is
responsible for lysis of bacterial cell
membrane and also results in mediating
inflammation.

36. Complement derived factors effects on inflammation
1. Vascular effects =C3a and C5a [anaphylotoxins] increase
vascular permeability and vasodialation by releasing histamine
from mast cells
–C5a also activates the lipoxygenase pathway of AA metabolism
in neutrophils and monocytes causing release of mediators
1. Leukocyte activation , adhesion , chemotaxis = C5a activates
leucocytes and increases the affinity of integrins thereby
increases adhesion to endothelium
–It is also a potent chemotactic agent for neutrophils,
monocytes, eosinophils, basophils
1. Phagocytosis= C3b and C3bi act as opsonins and favour
phagocytosis by neutrophils and macrophages

37. Kinin system
● This system on activation by factor generates bradykinin
● It is present in a glycoprotein precursor form called High
molecular weight kininogen [HMWK]
● This precursor is split by kallikrein proteolytic enzyme
● Kallikrein is activated from its own precursor prekallikrein
activated by hageman factor
Bradykinin effects
1.Smooth muscle contraction
2.vasodialtation
3.Increased vascular permeability
4.Pain

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