Overview of inflammation ,Definitions ,Historical highlights ,Causes of inflammation,Difference between infection and inflammation ,Cardinal signs ,Types of inflammation ,Acute inflammation ,Vascular events ,Haemodynamic changes ,Triple response ,Changes in vascular permeablity ,Difference betweeen transudate and exudate,Mechanism of altered vascularity,Cellular events ,Exudation of leucocytes Phagocytosis,Mediators of inflammation ,Cell derieved mediators ,Plasma derieved mediators ,Regulation of inflammation ,The Inflammatory cells Acute inflammation -Factors ,Morphology ,Effects ,Fate.

1. Basics of
Inflammation with
Applied Clinical
Aspects
Dr Nameeda. K. S

2. Contents
◂ Overview of inflammation
◂ Definitions
◂ Historical highlights
◂ Causes of inflammation
◂ Difference between infection and inflammation
◂ Cardinal signs
◂ Types of inflammation
◂ Acute inflammation
◂ Vascular events
◂ Haemodynamic changes
◂ Triple response
◂ Changes in vascular permeablity
◂ Difference betweeen transudate and
exudate
◂ Mechanism of altered vascular permeability 2

3. Contents
◂ Cellular events
◂ Exudation of leucocytes
◂ Phagocytosis
◂ Mediators of inflammation
◂ Cell derieved mediators
◂ Plasma derieved mediators
◂ Regulation of inflammation
◂ The Inflammatory cells
◂ Acute inflammation
◂ Factors
◂ Morphology
◂ Effects
◂ Fate 3

4. “
Inflammation is a protective response
of vascularised tissues to infections
and damaged tissues that brings cells
and molecules of host defence from
the circulation to the sites where they
are needed, in order to eliminate the
offending objects.
4
-Robbins and Cotran- pathologic basis of diseases, 9e

5. Historical Highlights
Sir thomas lewis-
histamine
1913
5
John hunter –
response
1793
Rudolf Virchow
19th century
Celcus
1st century
Egypt
3000 BC
Elie Metchnikoff-
phagocytosis
1880

6. 6
Infections
Bacterial
Viral
Fungal
Parasitic
Microbial toxins
Tissue necrosis
Ischemia
Trauma
Physical and
chemical injury
Immune
reactions
Hypersensitivity
Autoimmune
Allergy
Foreign bodies
• Splinter
• Dirt
• Suture
• Endogenous
substance-
• Ureate crystals,
Cholesterol
crystals and lipids

7. How is inflammation
distinct from
infection?
 Inflammation is a Protective response by the
body to various etiological agents- infectious
or non- infectious
 Whereas infection is invasion into the body
by harmful microbes and their resultant ill
effects by toxins.
7

8. 8
C
A
R
D
I
N
A
L
S
I
G
N
S

9. Types of Inflammation
9
Acute
Inflammation
Chronic
Inflammation
• Short duration- less than 2 months
• Represents early body reaction-
resolves quickly
• Main features - Accumulation of fluid
and plasma on the affected site
• Intravascular activation of platelets
• Polymorphonuclear neutrophils as
inflammatory cells
• Severe- fulminant acute inflammation
• Longer duration and causative agent
persists
• Presence of chronic inflammatory
cells – lymphocytes, plasma cells,
macrophages .
• Granulation tissue formation
• A variant – chronic active
inflammation.

10. Acute Inflammation
Mediators of Inflammation
Large and increasing number of endogenous
chemical substance.
Common properties
 Released from either cells or are derieved from
plasma proteins
 They are released in response to stimuli
 They act on different targets
 Range of action- increased vascular permeability,
vasodilation, chemotaxix, fever, pain and tissue
damage.
 Mediators have short lifespan after tgeir release.
It is a Continous process
A. Vascular events
B. Cellular events
Intimately linked to these two
processes is the release of mediators
of acute inflammation
10

11. 11

12. Vascular events
Alteration in the microvaculature- earliest response to tissue injury.
 Haemodynamic changes
 Changes in vascular permeability
12

13. 13
Haemodynamic changes
1. Transient vasoconstriction of arterioles (3-
5 sec to 5 min)
2. Persisitent progressive vasodilation (within
½ hour of injury- increased blood volume
in microvascuar bed of the area)
3. Elevation of the local hydrostatic pressure-
trasudation of fluid in extravascular spaces
4. Slowing or statis of microcirculation-
increased red cells concentration- raised
blood viscosity
5. Followed by leucocyte margination.

14. Triple response
Also called as red line response.
Features of haemodynamic
changes – LEWIS EXPERIMENT
 Red line- within a few seconds-
due to local vasodilation of
capillaries
 Flare- bright reddish appreance or
flush surrounding the red line from
vasodilation of adjacent arterioles
 Wheal- swelling or oedema of
surrounding skin
14
Blunt object on inner side of forearm

15. Altered vascular permeability
Pathogenesis-in and around the inflamed tissue, there is accumulation of oedema fluid
which comes from blood plasma by its escape through the endothelial wall of peripheral
vascular bed.
◂ In the initial stage the escape of fluid is due to vasodilation and consequent elevation
in hydrostatic pressure- this is transudate in nature.
◂ But subsequently the characteristic inflammatory oedema- exudate, appears by
increased vascular permeability of microcirculation.
15
Outward
movement
of fluid
intravascuar
hydrostatic pressure,
colloidal osmotic
pressure of
interstitial fluid.
intravascular
colloidal osmotid
pressure
hydrostatic pressure of
interstitial fluid
Inward
movement
of fluid

16. Features Transudate Exudate
Definition
Filtrate of blood plasma without changes
in endothelial permeability
Oedema of inflamed tissue associated
with increased vascular permeability
Character Non inflammmatory oedema Inflammatory oedema
Protein content
Low- less than 1gm/dl; low fibrinogen- no
tendency to coagulate
High- 2.5- 3.5 gm/dl; high fibrinogen-
coagulates
Glucose content Same as plasma Less( <60 mg/dl )
Specific gravity < 1.015 > 1.018
pH > 7.3 < 7.3
LDH Low High
Efffusion LDH/ serum LDH ratio < 0.6 > 0.6
Cells Few- mainly mesothlial and cellular debris
Many cells- inflammatory and
parenchymal
Example Oedema in congestive heart failure Purulent exudate- pus
16

17. 17

18. Examples
18

19. One fluid that is both
exudate and
transudate in Oral
Cavity
19

20. Mechanism of increased vascular
permeability
◂ Contraction of endothelial cells
◂ Contraction or mild endothelial damage
◂ Direct injury to endothelial cells
◂ Leucocyte mediated endothelial injury
◂ Leakiness in neovascularization
20

21. 21

22. 22
Cellular
events
Exudation of
leucocyte
1. Changes in formed elements of
blood
2. Rolling and adhesion
3. Emigration
4. Chemotaxix
Phagocytosis
1. Recognition and attachment
2. Engulfment
3. Killing and degradation

23. Changes in the formed elements of blood
◂ Early stage,blood flow increased- vasodilation
◂ Slowing or statis of blood- changes in axial flow
of blood
◂ Normally
◂ Central stream- leucocyte and RBCs
◂ Periperal cell free layer of plasma
◂ Due to statis
◂ Central stream of cells widen
◂ Peripheral cell free layer of plasma narrows
because of loss of plasma – MARGINATION
◂ Redistribution – neutrophils from centre to
vessel wall- PAVEMENTING
23

24. Rolling and Adhesion
◂ Peripheral marginated and pavemented neutrophils slowly roll over the endothelial
cells lining vessel wall- ROLLING PHASE
◂ Followed by transient bond between the leucocyte and endothelial cells becoming
further firmer- ADHESION PHASE
Cell adhesion molecules bring about the following.
24

25. 25
.
Cell Adhesion Molecules (CAM)
1. Selectins
 Expressed on the surface of endothelial cells and are structurally composed of
lecithin or lecithin like protein molecules the most important of which is s-lewis
X molecule
 Their role is to recognise and bind to the glycoproteins and gylcolipids on the
cell surface of neutrophils.
P- selectin
Preformed and stored in
endothelial cells and platelets
also called CD62
Involved in rolling
E- selectin
Synthesized by cytokine-
activated endothelial cells, also
named ECAM
Associated with both rolling
and adhesion
L- selectin
Expressed on the surface of
lymphocytes and neutrophils,
also called as LCAM.
Responsible for homing of
circulating lymphocytes to the
endothelial cells in lymph
nodes

26. 26

27. 2. Integrins
 Family of endothelial cell
surface proteins having alpha
CD11 or beta CD18 subunits.
 These bring about firm
adhesion between leucocyte
and endothelium
3. Immunoglobulin gene
superfamily adhesion molecule
 These partake in cell to cell contact
through various other CAMs and
cytokines.
 Major role in recognition and
binding.
 Intracellular adhesion molecule 1
(ICAM1 Or CD54)
 Vascular cell adhesion molecule-1
( VCAM-1 or CD106)
 Platelet endothelial cell adhesion
molecule 1 (PECAM-1 or CD31)
27

28. Emigration
◂ After sticking of neutrophils to endothelium, the former move along the
endothelial surface till a suitable site between the endothelial cells is found
where the neutrophils throw out cytoplasmic pseudopods.- Cross the basement
membrane by damaging it locally – collagenases and escape out into the
extravascular space EMIGRATION.
◂ Diapedesis - escape of red cells through gaps between the endothelial cells
◂ passive phenomenon.
◂ raised hydrostatic pressure
◂ haemorrhagic appearance to the inflammatory exudate
28

29. Chemotaxis
◂ After extravasating from the blood,
Leukocytes migrate toward sites of
infection or injury along a chemical
gradient by a process called
CHEMOTAXIS
◂ They have to cross several barriers -
endothelium, basement membrane,
perivascular myofibroblasts and
matrix.
◂ Other inflammatory cells too respond
and partake in inflammation – NK
cells and MCP-1.
29
Potent chemotactic
substances for neutophils.
Leukotriene B4 (LT-B4) - arachidonic
acid metabolites.
Components of complement system -
C5a and C3a in particular.
Cytokines- Interleukins, in particular IL-8
Soluble bacterial products-
formaldehyde peptides

30. Phagocytosis
◂ The process of engulfment of solid
particulate material by the cells.
◂ 2 main types of phagocytic cells
◂ Polymorphonuclear neutrophils
(PMNs) : early in acute
inflammatory response, also known
as microphages
◂ Macrophages : Circulating
monocytes and fixed tissue
mononuclear phagocytes
30
Phagocytic cell
• proteolytic enzymes
• lysozyme
• protease
• collagenase
• elastase
• lipase
• proteinase
• gelatinase
• acid hydrolases

31. ◂ The microbe undergoes the process of
phagocytosis in following 3 steps :
◂ Recognition and attachment
◂ Engulfment
◂ Killing and degradation

32. Recognition and Attachment
◂ Phagocytosis is initiated by the expression of surface
receptors on macrophages.
◂ Its further enhanced when the microorganisms are
coated with specific proteins, opsonins.
◂ Establish a bond between bacteria and the cell
membrane of phagocytic cell.
◂ Major opsonins are
◂ IgG opsonin .
◂ C3b opsonin
◂ Lectins
32

33. Engulfment
◂ Formation of cytoplasmic pseudopods around
the particle due to activation of actin filaments
around cell wall enveloping it into a phagocytic
vacuole.
◂ Eventually plasma membrane gets lysed and
fuses with nearby lysosomes- phagolysosome.
33

34. 34

35. 35
Killing and Degradation
 Killing of microorganisms take place by Antibacterial substances further
degraded by hydrolytic enzymes
 Sometimes this process fails to kill and degrade some bacteria like tubercle
bacilli.
 Then the following mechanisms are involved in disposal of microorganisms.
35
• Oxidative bacterial mechanism by oxygen free radicles
• MPO- dependent
• MPO- independent
• Oxidative bacterial mechanism by lysosomal granules
• Non oxidative bactericidal mechanism
Intracellular mechanism
• Granules
• Immune mechanisms
Extracellular mechanism

36. Intracellular Mechanism
◂ Kill microbes by oxidative mechanism and less oftennon-oxidative
pathways
◂ Oxidative bactericidal mechanism by oxygen free radicals.
◂ production of reactive oxygen metabolites (O’2 H2O2, OH’, HOCl, HOI,
HOBr)
◂ activated phagocytic leucocytes requires the essential presence of NADPH
oxidase
◂ present in the cell membrane of phagosome reduces oxygen to superoxide
ion (O’2)
36

37. ◂ Bactericidal activity is carried out either via enzyme
myeloperoxidase (MPO) or MPO independent.
37

38. 38
Oxidative bactericidal mechanism by lysosomal granules
preformed granule-stored products of neutrophils and macrophages.
secreted into the phagosome and the extracellular environment.
• Non-oxidative bactericidal mechanism
– Some agents released from the granules of phagocytic
cells do not require oxygen for bactericidal activity
• Granules : cause lysis of within phagosome, ex: lysosomal
hydrolases, permeability increasing factors, cationic proteins
(defensins), lipases, ptoteases, DNAases.
• Nitric oxide : reactive free radicals similar to oxygen free radicals
– potent mechanism of microbial killing
– produced by endothelial cells as well as by activated macrophages

39. Extracellular mechanism
◂ Granules
◂ Degranulation of macrophages and
neutrophils
◂ Immune mechanisms
◂ immune-mediated lysis of microbes
◂ takes place outside the cells
◂ by mechanisms of cytolysis, antibody-
mediated
◂ lysis and by cell-mediated cytotoxicity
39

40. Chemical mediators
◂ Chemical mediators that are responsible for
vascular and cellular events.
◂ Knowledge of this mediators basis of anti-
inflammatory drugs.
◂ Cell Derived – produce locally by cells at the
site of inflammation
◂ Plasma derived – mainly from liver
◂ Some mediators are derived from Necrotic
cells
40

41. 41
• Vasoactive amines
• Arachidonic acid
metabolites
• Lysosomal
component
• Platelet activating
factors (PAF)
• Cytokines
• Reactive Oxygen
Species (ROS) and
nitrogen oxide (NO)
Cell derived
mediators

42. 42
Histamine
Serotonin ( 5-
HT)
Neuropeptides
• Mast cells, basophils, platelets
• Vasodilation, increased
permeability, itching and pain.
• Stimulation of mast cells to release
arachidonic acid metabolites
• Released from platelet dense body
granules during platelet
aggregation
• Less potent than former
• Example- substance P
• Proinflammatory actions.

43. 43

44. 44

45. 45
LYSOSOMAL
COMPONENTS
Granules of
neutrophils
Primary or azurophil -
myeloperoxidase, acid hydrolases,
acid phosphatase, lysozyme
Secondary or specific- alkaline
phosphatase, lactoferrin
Tertiary-C particles gelatinase and
acid hydrolases
Granules of
monocytes
and tissue
macrophages
acid proteases, collagenase, elastase
and plasminogen activator; more
active in chronic inflammation

46. Platelet activating factor
◂ Released from Ig-E- sensitized basophils or mast
cells.
◂ Functions of PAF
◂ increased vascular permeability
◂ Vasodilation in low concentration and
vasoconstriction otherwise
◂ Bronchoconstriction
◂ Chemotaxix
46

47. 47

48. 48
1. Vasodilation
2. Anti-platelet
activating
agent
3. Possibly
microbial
action
1. Endothelial cell
damage
2. Activation of
protease
3. Damage to other
cell

49. Plasma protein derived mediators
◂ Circulating proteins of three interrelated systems
◂ The Kinin system
◂ The Clotting system
◂ The Fibrinolytic system
◂ The Complement system
◂ Inactive precursors that are activated at the site of
inflammation – action of enzyme.
◂ Each of these systems has its inhibitors and accelerators in
plasma - negative and positive feedback mechanisms
respectively.
◂ Hageman factor (factor XII) of clotting system – a key role in
interactions of the four systems. 49

50. 50

51. Pathway of Kinin system
◂ Bradykinin acts in early
stage of inflammation
◂ Smooth muscle
contraction
◂ Vasodilation
◂ Increased vascular
permeability
◂ Pain
51

52. The clotting system
52
Action of fibrinopeptide
 Increased vascular
permeability
 Chemotaxix for
leucocyte
 Anticoagulant
activity

53. The
Fibrinolytic
System
53

54. The
Complement
System
54

55. Regulation of inflammation
◂ The onset on inflammation may be potentially
damaging to the host tissues.
◂ So, self damaging effects are kept in check by
host regulatory mechanisms in order to
resolve inflammation
I. Acute phase reactants
II. Glucosteroids
III. Free cytokine receptor
IV. Anti- inflammatory chemical mediators
55

56. Acute phase reactants
Major role is to protect
the normal cells from
harmful effects of toxic
molecules generated in
inflammation and to clear
away the waste material
56

57. 57
Cellular protection factors
• α2 antiplasmin
• α2 antitrypsin
Coagulation proteins
• Fibrinogen
• vWF, factor VIII
Transport proteins
• Ceruloplasmin
• Haptoglobulin
Immune agents
• C reactive protein
Stress proteins
• Heat shock proteins
Anti oxidants
• Ceruloplasmin

58. The Inflammatory Cells
58

59. ◂ Lymphocytes
◂ Role in antibody formation and cell mediated immunity
◂ Take part in inflammatory response
◂ In tissues- dominant in chronic inflammation and
late acute inflammation
◂ In blood- increased in chronic infections such as
tuberculosis
◂ Plasma cells
◂ Develop from B lymphocytes and are rich in RNA and γ
globulin.
◂ their number increases
◂ Prolonged infection – syphilis , rheumatoid arthritis
◂ Hypersensitivity states
◂ Multiple myeloma 59

60. Reticuloendothelial
system
◂ This system includes cells
derived from 2 sources with
common morphology, function
and origin.
◂ Blood monocytes ( 4-8%
circulating leucocytes )
◂ Tissue macrophages
60

61. 61

62. Giant cells
◂ In chronic inflammation when the
macrophages fail to deal with particles to be
removed- they fuse together and form
multinucleated giant cells.
62
• Foreign body giant cells
• Langhans giant cell
• Tuton giant cell
• Aschoff giant cell
Giant cell in
inflammation
• Anaplastic cancer giant cell
• Reed- Sternberg cells
• Osteoclastic giant cells
Giant cell in
tumors

63. Factors determining variation in
inflammatory response
◂ Although acute inflammation is typically characterised by emigration of neutrophilic
leucocyte not all cases of acute inflammation show infiltration of neutrophils.
63
• Type of injury and infection
• Virulence
• Dose
• Portal of entry
• Product of organisms
Factors involving the Organism
• Systemic diseases
• Immune status
• Congenital neutrophil defects
• Leukopenia
• Site and type f tissue involved
• Local host factors
Factors involving the Host

64. Morphology of acute inflammation – “itis”
◂ Type of exudate
1. Serous - pleural effusion in TB, blister
formation in burns
2. Fibrinous – pneumococcal and rheumatic
pericarditis
3. Purulent or suppurative exudate – abscess,
acute appendicitis
4. Haemorrhagic – acute haemorrhagic
pneumonia in influenza
5. Catarrhal – common cold 64

65. Pseudomembranous
inflammation
◂ Inflammatory response to mucous
surface to toxins of diphtheria or
irritating gases.
◂ As a result of denudation of
epithelium, plasma exudates on the
surface where it coagulates and
together with necrosed epithelium,
forms false membrane
65

66. Suppuration
◂ Acute pyogenic bacterial infection accompanied by intense
neutrophilic infiltrate in the in the inflamed tissue results in
tissue necrosis.
◂ A cavity is formed- abscess- filled with purulent exudate.
◂ Due to tissue destruction- resolution does not occur but
instead healing by fibrous scarring takes place.
◂ Examples- furuncle, carbuncle.
66

67. Cellulitis
◂ It is diffuse inflammation of the
soft tissues resulting from
spreading effects of substance
like hyaluronidase released by
some bacteria
67
Ulcer
◂ Local defects on the surface on the
organ.

68. 68
Bacterial infection of the blood
◂ Bacteraemia – presence of small number of bacteria which do not
multiply significantly.
◂ Septicaemia – presence of rapidly multiplying bacteria.
Accompanied by systemic effects like toxaemia, disseminated
intravascular coagulation
◂ Pyaemia – dissemination of small septic thrombi in blood which
cause their effect at the site where they are lodged.
◂ Pyaemic abscess
◂ Septic infarcts

69. 69
Systemic effects of Acute Inflammation
Fever Leucocytosis
Lymphangitis
–
lymphadenitis
Shock

70. Fate of acute inflammation
70

71. References
1. Textbook of pathology-
Harsh Mohan- 7th edition
2. Pathology basis of disease-
Robbins and Cotran-volume
1
71