This document describes inflammation, including its causes, mechanisms, and effects. It defines acute and chronic inflammation and outlines the vascular and cellular events of acute inflammation. This includes increased blood flow, vascular permeability, exudation of fluid, and migration of neutrophils. It also discusses the various chemical mediators involved, such as histamine, prostaglandins, leukotrienes, and cytokines. These mediators cause effects like vasodilation, increased permeability, and chemotaxis. The document notes both local and potential systemic manifestations of inflammation, such as fever, acute phase response, and changes in white blood cell count.

1. Inflammation
Acute
inflammation

2. Inflammation
 Describe the causes and mechanisms of
acute and chronic inflammation
 Describe the chemical mediators of
inflammation
 Understand the systemic effects of
inflammation

3. Inflammation
local physiological response to tissue injury
Not a disease, usu a manifestation of d’se
beneficial effects:
 destruction of invading microorganisms
 walling off of an abscess cavity
Prevent spread of infection

4. Inflammation
produce disease
abscess in the brain: SOL
Compress vital surrounding structure
 fibrosis from CI may distort the tissues
permanently alter their function
purpose to localize and eliminate the
causative agent
 limit tissue injury and restore tissue to normality

5. Inflammation
classified according to its time course as:
 acute inflammation
 chronic inflammation

6. Causes of acute inflammation
 physical agents, e.g. trauma, heat, cold,
ultraviolet light, radiation
 irritant and corrosive chemical subst, e.g. acids,
alkalis
 Biological agents, e.g. pyogenic bacteria
 immune-mediated hypersensitivity reactions, e.g.
immune-mediated vasculitis, seasonal allergic
rhinitis (hay fever)

7.  Endogenous causes:
 tissue necrosis, e.g. ischaemia resulting
in a myocardial infarction
 Circulation disorders: thrombosis,
infarction, hemorrhage
 Enzymes activation – e.g. acute
pancreatitis
 Metabolic products deposals – uric acid,
urea
Causes of acute inflammation

8. Cardinal signs
essential physical characteristics of AI
formulated by Celsus
30 BC to AD 38 using the Latin words
 rubor, calor, tumor and dolor
rubor (redness)
tumor (swelling)
calor (heat)
dolor (pain)
 functio laesa, or loss of function
 second century AD: Greek physician Galen

9. are produced by a rapid vascular
response and cellular events
characteristic of AI
main function of these events is to
bring elements of the immune system
to the site of injury
prevent further tissue damage
Cardinal Signs

10. Early stages of AI
In the early stages, oedema fluid, fibrin
and neutrophil polymorphs accumulate in
the extracellular spaces of the damaged
tissue
 presence of the cellular component: the
neutrophil polymorph
essential for a histological diagnosis
AI response involves three processes:

11. Vascular response
1. changes in vessel calibre:
2. increased vascular permeability and
formation of the fluid exudate
Cellular events
3. formation of the cellular exudate –
emigration of the neutrophil polymorphs into
the extravascular space
Early stages of AI

12. Vascular response
Vasodilatation
 BF to the capillary bed is normally limited
by the precapillary sphincters
 In AI vasodilatation occurs when the
arterioles and precapillary sphincters
relax
results in increased blood flow to the
injured area

13. Increased vascular permeability
 Endothelial intracellular proteins contract
under the influence of chemical
inflammatory mediators:
 histamine, bradykinin, nitric oxide, C5a
leukotriene B4 and platelet activating factor
Endothelial contraction results in:
increased fenestrations between endothelial
cells
increased permeability of vessels to plasma
proteins
Vascular response

14. Increased vascular permeability
Proteins leak out of the plasma into the
interstitial spaces
 includes circulating components: immunoglobulins and
coagulation factors
 decreases in the plasma oncotic pressure
 escape of plasma proteins into interstitial S
increases the colloid osmotic pressure there

15. The Vascular Response
 Phase I = vasoconstriction
 momentary constriction of small blood vessels in
the area
 Vascular spasm begins very quickly (30 sec.)
after the injury at it last a few minutes
 mechanism of spasm is nervous – thru
catecholamine liberated from sympatic nerves
endings

16. The Vascular Response
 Phase II = active vasodilation
 thru catabolism products that act thru receptors and
directly stimulates vascular dilation – nervous
mechanism
 Dilation of arterioles and capillaries (redness =
rubor)
 Blood flow increases and gives pulsate sensation
 Active hyperemia in skin territory and increased
metabolism leads to higher local temperature (heat =
calor)

17. The Vascular Response
 Phase III = passive vasodilation
 Blood vessels in the affected area loose their
reactivity to nervous and humoral stimuli and
passive vasodilation occurs
 Progressively fluid move into the tissues (increased
vascular permeability and structural alteration of
blood vessels) and cause swelling (tumor), pain,
and impaired function

18. The Vascular Response
 Phase III = passive vasodilation
 exudation of the fluid out of the capillaries and into
the tissue spaces dilutes the offending agent
 As fluid moves out of the capillaries, stagnation of
flow and clotting of blood in the small capillaries
occurs at the site of injury
 This aids in localizing the spread of infectious
microorganisms

19. Inflammatory oedema
capillary hydrostatic pressure increased
much more fluid leaves the vessels than is
returned to them
 net escape of protein-rich fluid is called
exudation
 called the fluid exudate

20. combined increase in hydrostatic
pressure and the decreased oncotic
pressure (from leakage of proteins into
ECS) causes net fluid movement from
plasma into tissues
this is inflammatory oedema
Inflammatory oedema

21. Advantages of I oedema
Fluid increase in the damaged tissue dilutes
and modifies the action of toxins
Protein levels increase in the tissue—these
include protective antibodies and fibrin
Non-specific antibodies act as opsonins for
neutrophil mediated phagocytosis and
function to neutralize toxins

22. If the antigen is coated with antibody or
complement, its adherence is increased
because of binding to complement
This process of enhanced binding of an
antigen caused by antibody or complement
is called opsonization
Advantages of I oedema

23. Phagocytosis

24. Advantages of I oedema
formation of a fibrin net acts as a scaffold for
inflammatory cells
 prevent the spread of microorganisms
Circulation of the exudate into the lymphatic
system assists in antigen presentation
 helps mount a specific immune response

25. Cellular events
Formation of the cellular exudate
 accumulation of neutrophils within the ECS
diagnostic histological feature of AI
 Neutrophils pass between endothelial cell
junctions and invade damaged tissue to
combat the effects of injury
 The movement of leucocytes out of the vessel
lumen is termed extravasation

26. Extravasation
achieved in five stages
1. Margination to the plasmatic zone
This is assisted by the slowing of the blood
2. ‘Rolling’ of leucocytes due to the repeated
formation and destruction of transient
adhesions with the endothelium

27. 3. Adhesion: ‘pavementing’—leucocytes
eventually firmly adhere to the endothelium
due to the interaction of paired molecules on the
leucocyte and endothelial cell surface, e.g. β2-
integrin and ICAM-1
4. Transmigration: diapedesis—leucocytes pass
between the endothelial cell junctions, through
the vessel wall into tissue spaces
Extravasation

28. 5. Chemotaxis—
After exiting the circulation, neutrophils move
in the tissues toward the site of injury by a
process called chemotaxis
neutrophils migrate are possibly activated by
chemical substances: chemotaxins
released at sites of tissue injury
thought to be leukotrienes, complement
components and bacterial products
Extravasation

29.  Steps in neutrophil emigration
 Neutrophils
 (1) marginate into the plasmatic
zone
 (2) adhere to endothelial cells
 (3) pass between endothelial
cells
 (4) pass through the basal
lamina and migrate into the
adventitia

30. Phagocytosis and intracellular killing
predominant cell type of AI is the
neutrophil
Lymphocytes, plasma cells and MØs
are the cells found in CI

31. Neutrophils and monocytes ingest debris
and foreign particles at the site Cellular
pseudopodia engulf the foreign particle and
fuse
 phagocytic vacuole or phagosome
Phagocytosis is assisted by opsonization
with immunoglobulins and complement
components
Phagocytosis and intracellular killing

32.  Phagocytosis of foreign particle by leucocyte
 (A) Attachment of foreign particle
 (B) Pseudopodia engulfing particle
 (C) and (D) Incorporation within the cell in a
vacuole: phagosome

33. Following phagocytosis, leucocytes attempt to
destroy phagocytosed material:
 discharge of lysosomal enzymes into the
phagosome
 oxygen-dependent mechanisms:
H2O2, O2−, •OH
 oxygen-independent mechanisms:
lactoferrin, lysozyme and hydrolases
Phagocytosis and intracellular killing

34.  actions of neutrophils in
AI process
 events mediated by:
 Selectins
 ICAM-1: intercellular
adhesion molecule 1
 CD31
 C5a and leukotriene B4
 C3b and IgG
 Myeloperoxidase,
lysozyme

35. Chemical mediators of inflammation
Several different inflammatory mediator
systems interact to produce inflammation
No chemical mediator alone can be entirely
responsible for any single feature of the IR
Regulatory mechanisms exist in all mediator
systems

36. Chemical mediators of inflammation
chemicals called endogenous chemical
mediators, cause:
 vasodilatation
 emigration of neutrophils
 chemotaxis
 increased vascular permeability
 itching and pain

37. Endogenous chemical mediators of the acute IR

38. TNF-a and IL-1 are responsible for
 fever and the release of stress hormones
norepinephrine, vasopressin, activation of the
renin-angiotensin-aldosterone system
 synthesis of IL-6, IL-8, and interferon gamma
Cytokines, esp IL-6, stimulate the release of
acute-phase reactants such as C-reactive protein
(CRP)
Chemical mediators of inflammation

39. The proinflammatory interleukins
either function directly on tissue
work via secondary mediators to activate:
 the coagulation cascade
 complement cascade
 the release of nitric oxide, platelet-activating
factor, prostaglandins, and leukotrienes
Chemical mediators of inflammation

40.  Complement fragments and cytokines
 stimulates chemotaxis of neutrophils, eosinophils
and monocytes
 C3a, C5a increase vascular permeability;
 Cytokines
 Interleukins (IL1, IL 6, IL8)
Stimulates the chemotaxis, degranulation of
neutrophils and their phagocytic activity
Induce extravascularization of granulocytes
Fever
 Tumor necrosis factor (TNF) and IL 8
Leukocytosis
Fever
Stimulates prostaglandins production
Chemical mediators of inflammation

41. Prostaglandins
lipid soluble molecules derived from
arachidonic acid, a fatty acid liberated from
cell membrane phospholipids, through the
cyclooxygenase pathway
contribute to vasodilation, capillary
permeability, and the pain and fever that
accompany inflammation
Chemical mediators of inflammation

42. Stable prostaglandins: PGE1 and PGE2
induce inflammation
potentiate the effects of histamine and other
inflammatory mediators:
cause the dilation of precapillary arterioles
lower the blood pressure
modulates receptors activity
affect the phagocytic activity of WBC
prostaglandin thromboxane A2 promotes
platelet aggregation and vasoconstriction
Chemical mediators of inflammation

43. Leukotrienes
are formed from arachidonic acid
thru the lipoxygenase pathway
Histamine and leukotrienes are
complementary in action
Histamine is produced rapidly and transiently
while the more potent leukotrienes are being
synthesized
Chemical mediators of inflammation

44. Leukotrienes
 C4 and D4 are recognized as the primary
components of the slow reacting substance of
anaphylaxis (SRS-A)
causes slow and sustained constriction of the
bronchioles
Leukotrienes affect
permeability of the postcapillary venules
adhesion properties of endothelial cells
stimulates the chemotaxis
extravascularization of neutrophils, eosinophils,
and monocytes
Chemical mediators of inflammation

45. cyclooxygenase and lipoxygenase pathways

46. Histamine
 found in high concn in platelets, basophils, and
mast cells
 Causes dilation and increased permeability of
capillaries:
causes dilatation of precapillary arterioles
contraction of endothelial cells
dilation of postcapillary venules
 It acts through H1 receptors
Chemical mediators of inflammation

47. Platelet-activating factor (PAF)
 generated from a lipid complex stored in cell
membranes
 affects a variety of cell types and induces platelet
aggregation
 activates neutrophils and is a potent eosinophil
chemoattractant
 contributes to extravascularization of plasma
proteins and so, to edema
Chemical mediators of inflammation

48. Plasma Proteases: consist of:
 Kinins
Bradykinin - causes increased capillary
permeability: (implicated in hyperthermia and
redness) and pain
 Clotting factors
clotting system contributes to the vascular phase
of inflammation
mainly thru fibrin peptides that are formed during
the final steps of the clotting process
Chemical mediators of inflammation

49. Metabolic changes in inflammation
Protein metabolism
 Is increased – cell destruction, metabolic products
lead o increased osmotic pressure in interstitial space
which attracts water and contributes to edema
(swelling = tumor)
 metabolic changes: including skeletal muscle
catabolism, provide amino acids that can be used in
the immune response and for tissue repair
Glucose metabolism
 Anaerobe utilization of glucose is increased because
of hypoxia with increased formation of lactic and
pyruvic acid

50. Metabolic changes in inflammation
Lipid metabolism
 Increased formation of ketons and fatty acids
Mineral metabolism
 Increased extracellular K+ concentration
Acid – base balance
 Metabolic acidosis (ketons, lactic acid)

51. Systemic manifestations of inflammation
 IR remains confined to a localized area
 local injury can result in prominent systemic
manifestations
 inflammatory mediators are released into the
circulation
 most prominent systemic manifestations are:
 acute phase response
 Alterations in WBC count
 leukocytosis or leukopenia
 Fever
 Sepsis and septic shock: systemic inflammatory
response
 severe systemic manifestations of inflammation

52. The acute phase response
 Usually begins within hours or days of the onset of
inflammation or infection
 Includes:
 changes in the concns of plasma proteins - liver
dramatically increases the synthesis of acute-phase
proteins such as fibrinogen and C-reactive protein
 increased erythrocyte sedimentation rate
 fever
 increased numbers of leukocytes
 skeletal muscle catabolism
 negative nitrogen balance

53. The acute phase response
 responses are generated after the release of the
cytokines, IL-1, IL-6, and TNF:
 cytokines affect the thermoregulatory center in the
hypothalamus to produce fever
 IL-1 and other cytokines induce an increase in the
number and immaturity of circulating neutrophils by
stimulating their production in the bone marrow
 Lethargy
a common feature of the acute-phase response
results from the effects of IL-1 and TNF on the CNS

54. Outcomes of AI
 Resolution
 complete restoration of the inflamed tissue back to a
normal status
 Inflammatory measures such as vasodilation,
chemical production, and leukocyte infiltration cease,
and damaged parenchymal cells regenerate
 limited or short lived inflammation: usual outcome
 Fibrosis
 Large amounts of tissue destruction, or damage in
tissues unable to regenerate
 Fibrous scarring occurs in these areas of damage
 forming a scar composed primarily of collagen
scar will not contain any specialized structures
 parenchymal cells, hence functional impairment may occur

55. Outcomes
 Abscess formation
 A cavity is formed containing pus, an opaque liquid
containing dead WBCs and bacteria with general
debris from destroyed cells
 Chronic inflammation
 if the injurious agent persists then chronic
inflammation will ensue
 infln lasting many days, months or even years
 may lead to the formation of a chronic wound

56. Outcomes
 Chronic inflammation
 characterised by the dominating presence of
macrophages in the injured tissue
 are powerful defensive agents of the body
 but the toxins they release (including reactive oxygen
species) are injurious to the organism's own tissues as
well as invading agents
 almost always accompanied by tissue destruction

57. Resolution of inflammation
IR must be actively terminated
Failure to do so results in CI, and cellular
destruction
Resolution occurs by different mechanisms in
different tissues
 Short half-life of inflammatory mediators in vivo
 Production and release of TGF beta from MØs
 Downregulation of pro-inflammatory molecules, such
as leukotrienes
 Upregulation of anti-inflammatory molecules such as
the IL-1 receptor antagonist or the soluble TNF
receptor

58. Resolution of inflammation
Mechanisms of resolution in different tissues
 Apoptosis of pro-inflammatory cells
 Downregulation of receptor activity by high concns of
ligands
 IL-4 and IL-10 are cytokines responsible for
decreasing the production of TNF-a, IL-1, IL-6, and IL-
8

59. Resolution of inflammation
 Production of anti-inflammatory lipoxins
 Evidence now suggests that an active, coordinated
program of resolution initiates in the first few hours
after an IR begins
 After entering tissues, granulocytes promote the
switch of arachidonic acid–derived prostaglandins
and leukotrienes to lipoxins
 initiate the termination sequence
 Neutrophil recruitment thus ceases and apoptosis is
engaged

60. Resolution of inflammation
 Production of anti-inflammatory lipoxins
 These events coincide with the biosynthesis,
from omega-3 polyunsaturated fatty acids, of
resolvins and protectins
 critically shorten the period of neutrophil
infiltration by initiating apoptosis
 apoptotic neutrophils undergo phagocytosis by
MØs, leading to neutrophil clearance and release
of anti-inflammatory and reparative cytokines
such as TGF -β1
 anti-inflammatory program ends with the
departure of MØs thru the lymphatics

61. Outcomes of AI

62. Beneficial effects
 Beneficial effects of the fluid exudate are:
 Dilution of toxins
 Entry of antibodies
 Transport of drugs
 Fibrin formation: from exuded fibrinogen
 impede the movement of microorganisms
 trap them and so facilitate phagocytosis
 serves as a matrix for the formation of granulation tissue
 Delivery of nutrients and oxygen: essential for cells such
as neutrophils that have high metabolic activity
 Stimulation of immune response by drainage of this fluid
exudate into the lymphatics