series of events which takes place at the time of acute inflammation includes two different kinds of, one at the vascular level and other one is at the cellular level. which works as the primary level of immunity protection and leads to the phagocytosis of the pathogenic microbes. The presence of foreign bodies such as bacteria within the bodies provokes a protective inflammatory response...characterized by redness, swelling, warmth and the pain at the site of infection. These signs are due to increased blood flow, increased capillary permeability and the escape of fluid and cells into the tissue spaces. The increased permeability is due to several chemical mediators of which histamines, prostaglandins and leukotriens are the most important ones.

1. AnjanaTandon
2nd Yr Pathology 2010

2.  Is a protective response
 The body’s response to any injury.
 Involves the repair process
 Protective response needed for survival
 Battle between enemy( injurious agents)
and defence( leukocytes, antibodies,
compliment etc.)

3.  Recognition…of the injurious agent
 Recruitment…of leukocytes
 Removal …of injurious agent
 Regulation…control of inflammatory
responses
 Repair…Resolution

4.  Two Types
 Acute (sec, mins, hrs). Immediate and early
response to tissue injury (physical, chemical,
microbiologic, etc.)
 Chronic (days, weeks, months, yrs)…body is on
high alert all the time.This prolonged state of
emergency can cause lasting damage to your
heart, brain and other organs . Less dramatic but
more destructive then acute inflammation.

5. ACUTE
 Rapid in min/hrs
 Neutrophils( leucocytes)
 Tissue injury mild, self
limited
 Signs are prominent
CHRONIC
 Slow, days/months
 Lymphocytes,
monocytes/macrophages
 Tissue injury severe and
progressive
 Signs are less prominent

6.  Bacterial
 Viral
 Protozoal
 Metazoal
 Fungal
 Immunological
 Tumours
 Chemicals, toxins etc
 Radiation
 INJURY

8. RUBOR …Redness
CALOR….Heat
TUMOR….Swelling
DOLOR….Pain
FUNCTIO LAESA….Loss of function

10.  Redness (rubor) – secondary to vasodilatation and
increased blood flow
 Heat (calor) – localised increase in temperature, also
due to increased blood flow
 Swelling (tumour) – results from increased vessel
permeability, allowing fluid loss into the interstitial
space
 Pain (dolor) – caused by stimulation of the local
nerve endings, from mechanical and chemical
mediators
 Pain and swelling result in loss of function.

11. M….Margination
R….Rolling…..Selectins ( CD 62…..P, E , L )
A….Adhesion…..Integrins ( B1 integrins..bind to
VCAM 1, B2 integrins …bind to ICAM 1)
T….Transmigration/ Diapedesis( CD 31/ PECAM 1)
C….Chemotaxis
O….Opsonization ( Ig G, C3b )
P…..Phagocytosis

12. CENTER MOST COLUMN….RBC, WBC
PERIPHERAL…..Plasma
NORMAL LAMINAR BLOOD FLOW

13.  Movement of fluid in and out of arterioles,
capillaries and venules is regulated by the
balance between
 1.Intravascular hydrostatic pressure – tends to
force fluid out of vessels.
 2.Osmotic pressure of the plasma proteins –
tends to retain fluid within the vessels.

14. VASCULAR CHANGES
 Increase in blood flow
 To bring cells and proteins
to the site of injury.
 By vasodilation and
increased vascular
permeability
CELLULAR EVENTS
 Recruitment of leukocytes
 Activation of leukocytes
leading to the process of
destruction of invaders and
production of mediators
 By phagocytosis.

16. 2nd Yr Pathology 2010
Components of acute and chronic inflammation
Players of Inflammation

18. • Brief arteriolar vasoconstriction followed by vasodilation
• Accounts for warmth and redness
• Opens microvascular beds
• Increased intravascular pressure causes an early transudate
(protein-poor filtrate of plasma) into interstitium (vascular
permeability still not increased yet)
VASCULAR EVENTS
VASCULAR DILATATION followed by exudation of
protein-rich edema fluid which floods the area, dilutes toxins,
allows immunoglobulins to opsonise bacteria and provides
substrate (fibrinogen) for fibrin scaffold.

20. Exudation of fluid leads to a net loss of fluid from the
vascular space into the interstitial space, resulting
in oedema (tumour).
The formation of increased tissue fluid acts as a
medium for which inflammatory proteins (such as
complement and immunoglobulins) can migrate
through. It may also help to remove pathogens and
cell debris in the area through lymphatic drainage.
VASCULAR EVENTS

21. Mechanism of exudation

22. EXUDATE

23. VASCULAR DILATION
VASODILATION: Leads to greater blood flow to the area of
inflammation, resulting in redness and heat.
VASCULAR PERMEABILITY: endothelial cells become leaky from
either direct endothelial cell injury or via chemical mediators
EXUDATION: fluid, proteins, and white blood cells escape from the
intravascular space as a result of increased osmotic pressure
extravascularly and increased hydrostatic pressure intravascularly.
VASCULAR STASIS: slowing of the blood in the bloodstream with
vasodilation and fluid exudation to allow chemical mediators and
inflammatory cells to collect and respond to the stimulus.

24. VVVVVVVVVVV
Chemical mediators producing endothelial contraction
include, histamine, leukotrienes, bradykinin, platlet
activating factor and the C3a and C5a components from
complement activation.
Mediators of this process over a longer term include
tumor necrosis factor and interleukin 1
Chemical mediators that promote vasodilation include
histamine, prostaglandine and nitric oxide.
CHEMICAL MEDIATORS for
VASOCONSTRICTION & VASODILATION

25.  Leukocytes leave the vasculature routinely through the
following sequence of events:
1. Margination and rolling
2. Adhesion and transmigration
3. Chemotaxis , opsonisation and phagocytosis
 They are then free to participate in:
Phagocytosis and degranulation
Leukocyte-induced tissue injury

26.  With increased vascular permeability, fluid leaves the vessel
causing leukocytes to settle out of the central flow column and
“marginate” along the endothelial surface
 Endothelial cells and leukocytes have complementary surface
adhesion molecules which briefly stick and release causing the
leukocyte to roll along the endothelium like a tumbleweed until
it eventually comes to a stop as mutual adhesion reaches a
peak
 CD marker for endothelial cells is CD 34
 CD marker for selectin is CD 62
MARGINATION

28. Selectins: molecules on leukocytes (L-selectin) and endothelium
(E-selectin, P-selectin) act as receptors to provide loose binding for
rolling.
P selectin….Platelet, Endothelial cells…Sialyl- lewis X.(on
leucocytes)
E selectin….Endothelial cells…. Sialyl- lewis X.
L selectin….leucocytes…CD 34/ GlyCAM 1, MedCAM 1( on
endothelial cells )

29.  P-selectins are found intracellularly inWeibel-Palade bodies,
which once stimulated by mediators such as histamine are
distributed over the cell surface.
 E-selectins are expressed at low levels or are not present at
all on normal cells.They are upregulated after stimulation by
specific mediators. eg.IL-1 andTNF.

 L-selectins interact with carbohydrate molecules known as
vascular addresins (eg.sialomucin) on the luminal surface of
endothelial cells.This brief interaction manifests itself as
rolling of the leukocyte along the luminal surface of endothelium.

31.  Rolling comes to a stop and adhesion results.
 Other sets of adhesion molecules participate:
Endothelial: ICAM-1,VCAM-1
Leukocyte: LFA-1, Mac-1,
 ICAM-1: intercellular adhesion molecule 1 provides more firm
adhesion of the neutrophil, via integrins on neutrophil surfaces,
to the endothelium. (ICAM-1 binds LFA-1/Mac-1,
 VCAM-1 bindsVLA-4

32. INTEGRINS for ADHESIN
Beta 1 Integrin on WBC( VLA 4 )….binds to VCAM 1 on
endothelial cell
Beta 2 Integrin on WBC…binds to ICAM 1 on endothelial
cells…CD marker is CD11/ CD18.

33. VCAM 1….vascular cell adhesion molecule on
endothelial cells
ICAM 1…..intracellular adhesion molecule on
endothelial cells.

34. 2nd Yr Pathology 2010

35. CD31: this cell to cell adhesion molecule aids in
transmigration.
TRANSMIGRATION

36. • Vascular permeability (leakiness) commences
•Transudate gives way to exudate (protein rich)
•Increases interstitial osmotic pressure contributing to edema (water
and ions)
• Fluid escapes from vessels because of endothelial cell (EC)
retraction, opening up gap-junctions.
•The vessels which are normally involved are the post-capillary
venules where the EC have high affinity receptors for histamine.
•Severe EC injury leads to leakiness of all vessels
capillaries, venules and arterioles - giving acute local edema, e.g.
blister formation after a burn.
Vascular Leakage

40.  Leukocytes follow chemical gradient to site of injury
(chemotaxis)
 Soluble bacterial products
 Unidirectional
 Pathogen is itself is exogeneous chemotaxis factor
 Internal Chemotaxis factors ,Cytokines (chemokine family e.g.,
IL-8)
LTB4 (AA metabolite, C5a)
 Chemotactic agents bind surface receptors inducing calcium
mobilization and assembly of cytoskeletal contractile elements
CHEMOTAXIS

41. C5a and LTB4: chemotaxis is aided by the C5a component from
complement activation, along with leukotriene B4, a product of
the lipo-oxygenase pathway of arachidonic acid metabolism
CHEMOTAXIS

42.  Soon after bacteria enters our tissues,
macrophages recognize them.
 With the help of opsonize C3b they
phagocytose them.
 As they degrade these bacteria, cellular
components are released, which stimulate
the macrophages to release cytokines.
 These cytokines signal other components of
immune system to have local effects.

43. C3b and IgG: opsonins such as the C3b component from
complement activation, as well as immunoglobulin G, coat
foreign objects such as bacteria to aid in phagocytosis by
binding to leukocyte receptors.
OPSONISATON

44. Myeloperoxidase, lysozyme: after engulfment, killing
of bacteria occurs via generation of toxic oxygen
species (superoxide) converted to hydrogen peroxide
and further converted to a hypochlorous radical by
myeloperoxidase from neutrophil granules. In the
absence of oxidation, lysozyme from neutrophil
granules can form holes in microbial membranes.
PHAGOCYTOSIS

45.  Bradykinin….A vasoactive protein that is
able to induce vasodilation, increase vascular
permeability, cause smooth muscle
contraction, and induce pain.

46.  C3Complement system Cleaves to
produce C3a and C3b. C3a stimulates
histamine release by mast cells, thereby
producing vasodilation.
 C3b is able to bind to bacterial cell walls and
act as an opsonin, which marks the invader as
a target for phagocytosis.

47.  C5aComplement system Stimulates histamine
release by mast cells, thereby producing
vasodilation.
 It is also able to act as a chemoattractant to
direct cells via chemotaxis to the site of
inflammation.

48.  Histamine Mast cells and basophils Stored in
preformed granules, histamine is released in
response to a number of stimuli. It
causes arteriole dilation,
increased venous permeability, and a wide
variety of organ-specific effects.

49.  Leukotriene B4 secreated by Leukocytes,
Able to mediate leukocyte adhesion and
activation, allowing them to bind to the
endothelium and migrate across it. In
neutrophils, it is also a potent
chemoattractant, and is able to induce the
formation of reactive oxygen species and the
release of lysosomal enzymes by these cells.

50.  Prostaglandins Mast cellsA group of lipids
that can cause vasodilation, fever, and pain.

51.  Nitric oxideSoluble gas….Macrophages,
endothelial cells, some neuronsPotent
vasodilator, relaxes smooth muscle, reduces
platelet aggregation, aids in leukocyte
recruitment, direct antimicrobial activity in
high concentrations.

52. Zinc is a key micronutrient for both microbial pathogens and
human host cells, particularly immune cells. Zinc can be
concentrated by phagocytic cells, particularly neutrophils
containing a cytoplasmic protein call calprotectin. These
phagocytes can then signal T lymphocytes for an adaptive
immune response, and they can concentrate free zinc toxic to
microbes. Measurement of calprotectin can provide a means
for assessing the magnitude of an inflammatory reaction, such
as stool calprotectin measurement to gauge inflammatory
bowel disease.