aetiology of inflammation; types of inflammation; how inflammation occur; cells involve in inflammation; role of wbc in inflammation; outcome of inflammation; how inflammation associated with immunity, clotting system, complementary system kinin system, how inflammation is associated with oral cavity; disease associated with inflammatory system

1. PRESENTED BY:
Dr. Ranjana Das
1st year Resident
Department of periodontology and implantology
Mansarovar dental college

2. INTRODUCTION
What is inflammation ?
In general we can say that inflammation is a response
of vascular connective tissue towards injury.
Or we can define it as,
Inflammation is the process by which the immune
system defends the body from harmful agents .

3.  Definition
 Purpose of inflammation
 History
 Causes of injury/ inflammation
 How inflammation differ from infection
 Cardinal signs of inflammation
 Types of inflammation
 Acute inflammation
 Vascular events
 Hemodynamic changes
 Vascular permeability
 Difference between exudate, transudate and
edema
 Cellular events
 Leukocyte exudation
 Phagocytosis and tissue injury
Contents :
 Chemical mediators of inflammation
 Cells involved in acute inflammation
 Fate of acute inflammation
 Chronic inflammation
 Causes of chronic inflammation
 Types of chronic inflammation
 Mechanism of chronic inflammation
 Granulomatous inflammation
 Cells involved in chronic inflammation
 Fate of chronic inflammation
 Difference between acute and chronic
inflammation
 Systemic influence of chronic inflammation
 Consequences of impaired inflammation
 systemic effect of inflammation
 references

4. Definition of inflammation:
-It is a body defense reaction in order to eliminate or limit the spread of injurious agent as
well as to remove the consequent necrosed cell and tissues.
-The word “inflammation” originates from Latin word “inflammatio” which means “to set
on fire”.
-Inflammation is know by the suffix ‘itis’ to the end of the name of inflamed organ or tissue.
For example:
1.Inflammation in tongue is known as glossitis
2.Inflammation in gingiva is known as gingivitis.
-Although inflammation helps to clear infections and other noxious stimuli and initiate repair,
sometimes the inflammatory reaction and subsequent repair process can themselves cause
considerable harm too.

5. Purpose of inflammation:
1. To bring to the area certain phagocytic cells (neutrophilic
polymorphonuclear leukocytes, macrophages, histocytes)which engulf
and digest bacteria, dead cells or other debris.
2. To bring antibody to site (as antibody are altered gamma globulins, this
is achieved by escape of fluid and plasma proteins out of the blood
vessels and into the tissues) .
3. To neutralize and dilute the irritant(by edema).
4. To limit the spread of inflammation ( by fibrin formation, fibrosis, or
walling off with granulation tissue).
5. To initiate repair.

6. History -
• Egyptian papyrus in 3000BC introduced inflammation, which means burning.
• In 45AD Celsus gave (4)cardinal signs of inflammation and in 19century R. Virchow added the fifth sign.
• 18century application of microscope lead to description of blood flow changes in inflamed tissue and the proposal by
Gaubins that inflammation can promote “disposition to coagulation”.
• 1794 John Hunter first used the term angiogenesis to describe development of growing blood vessels in healing wounds.
• Dutrochet (1824) provided the first description of ‘sticking’ and emigration of WBC( described as ‘vesicular globules’) in
blood vessels during acute inflammation ,while the first explicit description of leukocyte rolling is attributed to Wagner in
1839.
• Cohnheim’s (1867) classical describes vascular events as thin, transparent tissues in vivo which lead him to postulate that
‘molecular alteration in the vessel walls’ underlies the sticking of leukocytes in inflamed microvessels, while their
subsequent emigration was attributed to mechanical filtration.
• Metchnikoff(1893) assigned important role of leukocyte in emigration process, stating that the migration is effected by the
amoeboid power of leukocytes.
• Cohnheim’s observation also lead him to speculate that augmented “porousness” of vessel wall explain enhanced fluid
and protein transudation in inflamed tissue.
• 20 century is marked by rapid advancements in understanding nature and underlying mechanisms of microvascular
responses to inflammation.

7. Causes of injury / inflammation:
• Infective agents: bacteria,viruses,fungi,parasites and their toxins.
• Physical agents: heat,cold,radiation,mechanical trauma.
• Chemical agents: organic and inorganic poisons.
• Immunological agents: cell mediated and antigen antibody reaction.
• Foreign bodies: splinters,dirt,sutures.

8. How inflammation differ from infection:
• The former being a protective response by the body while later is invasion
into the body by harmful microbes and their resultant ill effects by toxins.
• Inflammation involves two basic processes:
1. Inflammatory response
2. Followed by healing
Both these processes have protective role against injuries agent,
inflammation and healing may cause considerable harm to the body as well
e.g.-anaphylaxis to bites by insects or reptiles, drugs, toxins, atherosclerosis,
chronic rheumatoid arthritis, fibrous bands and adhesion in intestinal
obstruction.
-’Immunity or immune reaction’ and ‘inflammatory response’ by the host are
both interlinked protective mechanisms in the body-inflammation is the
visible response to an immune reaction, while activation of immune
response is almost essential before inflammatory response appears.

9. Cardinal signs of inflammation:
• Roman writer C. Celsus in 1st century AD named the famous four cardial signs of inflammation are-
1.Rumor (Redness): Because of arterioles dilatation, increase blood is coming to site that produces redness
2.Tumor (swelling): Micro circulation become more permeable that will produce excessive escape of fluid
from microcirculation to local extravascular area or interstitial area.
3.Calor (heat): Release of inflammatory mediators and increase flow of blood increases the temp. Locally.
4.Dolar (pain): Due to swelling and some chemical mediators produce at site of inflammation which irritate
nerve ending.
later R. Virchow added fifth sign-
5. Functio laesa (loss of function): Local cell don’t perform normal function because of disruption of tissue
structure so loss of function.
RUBOR,CALOR,TUMOR are mediated by HISTAMINE
DOLOR is mediated by PGE2 and BRADYKININ

11. -The vascular and cellular reactions of both acute and chronic
inflammation are mediated by chemical factors.
-Subacute inflammation: is used for a state of inflammation between
acute and chronic.
INFLAMMATION
ACUTE CHRONIC

12. Components of acute and chronic inflammatory response:

13. Components of acute and chronic inflammatory response
1. Neutrophil or polymorphonuclear leukocyte (PMN)
• First cell to emigrate to the site of injury
• Primary cell involved in acute inflammation
• Capable of phagocytosis
2. Monocyte or macrophage
• Second white blood cell to emigrate to injured tissue, where it
becomes a macrophage
• Capable of phagocytosis; helper during the immune response

14. 3. Lymphocytes and plasma cells
• Involved in both chronic inflammation and immune response
4. Eosinophil
• Involved in immune reactions and parasitic infections
5. Mast cells
• Involved in both acute and chronic inflammatory reactions (releasing
chemical mediators) and in immune response

16. Acute inflammation:
-Acute inflammation is a rapid response to an injurious agent that
serves to deliver mediators of host defense-leukocytes and plasma
proteins -to the site of injury.
- Acute inflammation is for short duration.
Immediately after injury there is vasoconstriction that is followed by
vasodilatation and increased rate of blood flow through the
arterioles, capillaries and venules.

18. • Major events of acute inflammation:
Vascular events
1.Hemodynamic changes 1.leukocytes exudation
2. Increased vascular permeability 2. phagocytosis
VASCULLAR EVENT CELLULAR EVENT

19. Vascular events-
Hemodynamic changes :
After injury :-
1.There will be immediate vascular response i.e. Transient vasoconstriction of arterioles.
-in mild form of injury blood flow reestablishment in 3-5sec. And for sever injury it may last for 5mint.
2.Persistent progressive vasodilation which involves mainly arterioles but microcirculation like venules and capillaries too.
Vasodilatation result in increase blood volume in microvascular bed of area
which result in redness and warmth at site of inflammation
3.Progressive vasodilation, elevate the local hydrostatic pressure
resulting in transudation of fluid into extracellular space.
which is responsible for swelling at local site.

20. 4. Slowing or stasis of microcirculation occur next, slowing is attributed to
increased permeability of microvasculature that result in increased
concentration of red cells thus raised blood viscosity.
5. Leucocyte margination or peripheral orientation of leucocytes(mainly
neutrophils) along the vascular endothelium.
-the leucocytes stick to the vascular endothelium, and then move and migrate
through the gaps between the endothelial cells into the extravascular space.
This process is known emigration.

22. ALTERED VASCULAR PERMIABILITY:
• In and around inflamed tissue
There is accumulation of edematous fluid in the interstitial
compartment which comes from blood plasma by its escape through
endothelial wall of peripheral vascular bed.
Initially, escape of fluid is due to vasodilation and consequent elevation
in hydrostatic pressure. This is transudate in nature.
-Subsequently, characteristic inflammatory edema swelling appears by
increased vascular permeability of microcirculation: Exduate.

25. MECHANISMS OF INCREASED VASCULAR PERMEABILITY:
1.Contraction of endothelial cells
2.Contraction or mild injury to endothelial cells
3.Direct injury to endothelial cells
4.Endothelial injury mediated by leucocytes
5.Neovascularisation

28. Contraction of endothelial cells:
• This is the most common mechanism of increased leakiness that
affects venules while capillaries and arterioles remain unaffected.
• The endothelial cells develop temporary gaps between them due to
their contraction resulting in vascular leakiness.
• It is mediated by release of histamine, bradykinin and other chemical
mediator.
• This response begins immediately after injury and is reversible and for
short duration i.e.15-30 mints.

29. Retraction of endothelial cells:
• This is structural re-organization of the cytoskeleton of endothelial
cells that causes reversible retraction at intercellular junctions.
• This too affects venules and is mediated by cytokines such as
interleukin 1 and TNF.
• Onset of response takes 4-6hours after injury and last for 24hours or
more(somewhat delayed and prolonged leakage).

30. Direct injury to endothelial cells:
• It cause cell necrosis and appearance of physical gaps at sites of
detached endothelial cells.
• Change affects all microvasculatine i.e.venules,capillaries and
arterioles.
• Either appear immediately after injury and last for several hours or
days(immediate sustained leakage) or may occur after a delay of 2-12
hours and last for hours or days (delayed prolonged leakage).

31. Endothelial injury mediated by leucocytes:
• Adherence of leucocytes to endothelium at site of inflammation
causes activation of leucocytes.
• Activation of leucocytes release proteolytic enzymes and toxic oxygen
species which may cause endothelial injury and increased vascular
leakiness.
• Affects mostly venules and is a late response.

32. Neovascularisation:
• Newly formed capillaries under the influence of vascular endothelial
growth factor(VEGF) during the process of repair and in tumors are
excessively leaky.

35. Cellular events:
The cellular phase of inflammation consist of 2processes:
1. Exudation of leucocytes
2. phagocytosis

36. Exudation of leucocytes:
It is the most important feature of inflammatory response.
In acute inflammation, polymorphonuclear neutrophils(PMNs)comprise
the 1st line of body defense followed later by monocytes and
macrophage.
1.Changes in the formed elements of blood.
2.Rolling and adhesion
3.Emigration
4.chemotaxis

38. Changes in the formed elements of blood:
- In early stage, there is increased in blood flow due to
vasodilation but subsequently there is slowing or stasis
of bloodstream.
- With stasis, normal axial flow of blood in
microcirculation take place.
- Normal axial flow consist of central sheath of cells
comprised by leucocytes and RBCs and peripheral cell
free layer of plasma close to vessel wall.
- Later, central stream of cells widens and peripheral
plasma zone becomes narrower because of loss of
plasma by exudation and this phenomenon is called
margination.
- As a result, neutrophils of central column come
close to vessel wall known as pavementing.

40. Rolling and adhesion:
• Peripherally marginated and pavemented
neutrophils slowly roll over the endothelial
cells lining the vessel wall(rolling phase).
• Transient bond between the leucocytes and
endothelial cells becoming firmer(adhesion
phase).
• The following molecules bring about rolling
and adhesion phase:
1.Selectins
2.Integrins
3.Immunoglobulin gene superfamily adhesion
molecule

42. 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.
• Subsequently, the neutrophils lodged between
endothelial cells and basement membrane by
damaging it locally-collagenases and escape out
into the extravascular space-emigration.
• Simultaneous to emigration of leucocytes,
escape of red cells through gaps between the
endothelial cells, diapedesis, takes place.it is a
passive phenomenon- RBCs being forced out
either by raised hydrostatic pressure or may
escape through the endothelial defects left
after emigration of leucocytes. It gives
hemorrhagic appearance to the inflammatory
exudate.

43. Chemotaxis:
• After extravasating from the blood,
leukocytes migrate toward sites of
infection or injury along a chemical
gradient by a process called
chemotaxis.
• Following agent act as potent
chemotactic substances or
chemokines for neutrophils:.
1.Leukotriene B4(LT-B4)product of
lipoxygenase pathway of arachidonic
acid metabolites.
2.Components of complement
system(C5a and C3a in particular).
3.cytokines(interleukins,in particular
IL-8).
4.Solube bacterial products(like
formylated peptides).

44. Phagocytosis:
• It is define as the process of engulfment of soild
particulate material by the cells(cell-eating). The cells
performing this function are called phagocytes.
• There are 2main types of phagocytic cells:
1.PMNs
2.Circulating monocytes and fixed tissue mononuclear
phagocytes,i.e.macrophage.
Neutrophils and macrophages on reaching tissue spaces
produce several proteolytic enzymes-
lysozymes,protease,collagenase,elastase,lipase,proteinease,
gelatinase,and acid hydrolases.
-These enzymes degrade collagen and extracellular matrix.
-Phagocytosis of the microbe by polymorphs and
macrophages involves the following 3 steps:
1.Recognition and attachment
2.Engulfment
3.Killing and degradation.

46. Recognition and attachment:
-Phagocytosis is initiated by the expression of cell
surface receptors on macrophages which recognize
microorganisms: mannose receptor and scavenger
receptor. The process of phagocytosis is further
enhanced when the microorganisms are coated
with specific proteins, opsonins, from the serum
and the process is called opsonisation.
-Opsonins establish bond between bacteria and the
cell membrane of phagocytic cell.
-the main opsonins present in the serum and their
corresponding receptors on the surface of
phagocytic cellsi.e.PMNs and macrophages are:
1.IgG opsonin
2.C3b opsonin
3.Lectins

47. Engulfment:
• The opsonized particle or microbe bound to
the surface of phagocyte is ready to be
engulfed. This is done by formation of
cytoplasmic pseudopods around the particle
due to activation of actin filaments beneath
cell wall, enveloping it in a phagocytic
vacuole.

48. • Plasma membrane enclosing the particle breaks
from the cell surface so that membrane-lined
phagocytic vacuole or phagosome becomes
internalized in the cell and lies free in the cell
cytoplasm.

49. • The phagosome fuses with one or
more lysosomes of the cell and form
bigger vacuole called phagolysosome.

50. Killing and degradation:
• In this stage microorganism is dispose off which is the major function of phagocytes as scavenger
cells.
• Microorganisms after being killed by antibacterial substances are degraded by hydrolytic
enzymes.
• Sometimes it fails to kill some bacteria like tubercle bacilli.
• Following mechanisms are involved in disposal of microorganism:
A.INTRACELLULAR MECHANISMS:
i)Oxidative bactericidal mechanism by oxygen free radicals-
a)MPO-dependent
b)MPO-independent
ii)Oxidative bactericidal mechanism by
lysosomal granules
iii)non-oxidative bactericidal mechanism
B)Extracellular mechanism:
i)Granules
ii)Immune mechanism

52. Intracellular mechanisms:
• This involves killing of microbes mainly by oxidative mechanism.
i)Oxidative bactericidal mechanism by oxygen free radicals:
-production of reactive oxygen metabolites (O2,H2O2,OH,HOCL,HOI,HOBr)
-activated phagocytic leucocytes requires the essential presence of NADPH
oxidase.
-NADPH-oxidase present in the cell membrane of phagosome reduces
oxygen to superoxide ion(O2)

54. a)MPO DEPENDENT KILLINGS:
-MPO acts on H2O2 in the presence of halides-from hypohalous acid(HOCl,HOI,HOBr)
b)MPO INDEPENDENT KILLINGS:
-Mature macrophages lack the enzyme MPO.
-Bactericidal activity by producing OH- ions and superoxide singlet oxygen(O-).
-H2O2 in presence of O2(Haber-Weiss reaction) or in presence of Fe++(Fenton reaction).
ii)OXIDATIVE BACTERICIDAL MECHANISM BY LYSOSOMAL GRANULES:
-Performed granule-stored products of neutrophils and macrophages are secreted into the phagosome and the extracellular environment.
-progressive degranulation of neutrophils and macrophages with oxygen free radicals degrades proteins i.e. induces proteolysis.
III)NON-OXIDATIVE BACTERICIDAL MECHANISM:
-some agents released from the granules of phagocytic cells do not require oxygen for bactericidal activity. they are:
a)GRANULES: Cause lysis of within phagosome,ex:lysosomal hydrolases, permeability increasing factors, cationic
proteins(defensins),lipases,ptoteases,DNAases.
b)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.

55. Extracellular mechanisms:
• Following mechanisms explain
bactericidal activity at
extracellular level:
i)GRANULES: degranulation of
macrophages and neutrophils
ii)IMMUNE MECHANISMS:
immune mediated lysis of
microbes takes place outside the
cells by mechanisms of cytolysis,
antibody mediated lysis and by cell
mediated cytotoxicity.

57. CHEMICAL MEDIATORS OF INFLAMMATION:
Two main groups of substances acting are:
a)Cell derived mediators are release either from their stroge in the cell
granules or are synthesized in the cells.
b)Plasma derived mediators is synthesized in liver and after release it
requires activation.
- Some mediators are drived from necrotic cells.

61. Cell-derived mediators:
Various cell derived mediators are:
1.Vasoactive amines
2.Arachidonic acid metabolites
3.Lysosomal component
4.Platelet activating factor(PAF)
5.Cytokines
6.Reactive oxygen species(ROS) and nitrogen oxide(NO)
7.Neuropeptides

62. Vasoactive amines:
-two imp. active amines that have role in early acute inflammatory
response(first 1 hour)are histamine and 5hydroxytryptamine(5-HT)or
serotonin, additional is neuropeptides.
i) HISTAMINE: stored in granules of mast cells, basophils and platelets.
-main action of histamine are : vasodilatation, increases vascular
(venular) permeability, itching and pain.

63. ii) 5-hydroxytryptamine(5-HT or serotonin):
-it is present in tissues like chromaffin cells of git,spleen,nervous tissue,mast cells and
platelets.
-the action of 5-HT is similar to histamine but it is less potent mediator of increased
vascular permeability and vasodilatation than histamine.
-carcinoid tumour is a serotonin-secreating tumour.
iii) Neuropeptides:
-it include substance P, neurokinin A, vasoactive intestinal polypeptide(VIP) and
somatostatin.
-these are produce in central and peripheral nervous systems.
The major proinflammatory action of neuropeptides are:
1.Increased vascular permeability
2.Transmition of pain stimuli
3.Mast cell degradation

64. ARACHIDONIC ACID METABOLITES(EICOSANOIDS):
• Arachidonic acid is released from the cell membrane by phospholipases.
• It is then activated to form arachidonic acid metabolites or eicosanoids by one of
following 2pathways:via cyclo-oxygenase pathway or via lipo-oxygenase pathway.
i)METABOLITES VIA CYCLO-OXYGENASE PATHWAY:prostaglandins, thromboxanea2,
prostacyclin:-
-it is a fatty acid enzyme present as COX-1 and COX-2,acts on activated arachidonic acid to
form prostaglandin endoperoxide(PPG2).
-PGG2 is enzymatically transformed into PGH2 with generation of free radical of oxygen.
-PGH2 is further acted upon by enzymes and results in formation of following
3metabolites:
a)prostaglandins(PGD2,PGE2 AND PGF2-alfa)
b)Thromboxane A2(TXA2)
c)Prostacyclin(PGI2)
d)Resolvins

65. Metabolites via lipo oxygenase pathway: 5-HETE,leukotrienes,lipoxins:
-predominant enzyme in neutrophils.
-acts on activated AA to form hydroperoxy eicosatetraenoic acid(5-
HETE) which on further peroxidation forms following 2 metabolites:
1. 5-HETE(hydroxyl compound)
2. Leukotrienes(LT)
3. Lipoxins(LX)

66. LYSOSOMAL COMPONENTS
The inflammatory cells- neutrophils and monocytes,contain lysosomal
granules which on release elaborate variety of mediators of inflammation.
These are:
i)Granules of neutrophils: neutrophils have 3types of granules-
a)Primary or azurophil granules: contain functionally active enzymes.these are
myeloperoxidase,acid hydrolases,acid phosphatase,lysozyme,defensin(cationic
protein),phospholipase,cathepsin G,elastase,and protease.
b)Secondary or specific granules: contain alkaline
phosphatase,lactoferrin,gelatinase,collagenase,lysozyme,vitamin-B12 binding
proteins, plasminogen activator.
c)Tertiary granules or C particles: contain gelatinase and acid hydrolases.
ii)Granules of monocytes and tissue macrophages: release mediators like acid
proteases,collagenase,elastase and plasminogen activator. They are more
active in chronic inflammation.

67. CYTOKINES
They are polypeptide substances produced by activated
lymphocytes(lymphokines) and activated
monocytes(monokines).
-chemokine is used for a family of substances which act as
chemoattractants for inflammatory cells.
Major cytokines in acute inflammation are:
i)TNF and IL-1
ii)chemokine
In chronic inflammation:interferon-ꝩ and IL-12

68. FREE RADICALS: OXYGEN METABOLITES AND NITRIC OXIDE
• FREE RADICALS ACT AS POTENT MEDIATOR OF INFLAMMATION:
i)oxygen-derived metabolites are released from activacted neutrophils and macrophages abd
include superoxide oxygen(O2),H2O2, OH,and toxic NO products.
-these oxygen derived free radicals have following actions on inflammation:
a) Endothelial cell damage and thereby increased vascular permeability.
b) Activation of protease and inactivation of antiprotease causing tissue matrix damage.
c) Damage to other cells.
ii)Nitric oxide(NO):it is formed by activated macrophages during the oxidation of arginine by
action of enzyme,NO synthase.
-NO plays following role in mediating inflammation:
a)Vasodilatation
b)anti-platelet activating agent
c)Possibly microbicidal action.

69. Plasma protein-derived mediators(plasma proteases):
• These include various products derived from activation and
interaction of 4 interlinked systems:kinin,clotting,fibrinolytic and
complement.
• Each of these system has its inhibitors and accelerators in plasma with
negative and positive feedback mechanisms.
• Hageman factor(factor XII)of clotting system plays a key role in
interactions of 4systems.

71. The kinin system:
• On activation by factor XIIa generates bradykinin.
• First kallikrein is formed from plasma prekallikrein by the action of
prekallikrein activator which is a fragment of factor XIIa.
• Kallikrein then acts on high molecular wt.kininogen to form
bradykinin.
• Bradykinin act in early stage of acute inflammation and gives:
a)Smooth muscle contraction
b)Vasodilatation
c)Increased vascular permeability
d)Pain

72. The clotting system:
• Factor XIIa initiates the cascade of clotting system resulting in
formation of fibrinogen which is acted upon by thrombin to form
fibrin and fibrinopeptides.
• Action of fibrinopeptides in inflammation are:
a)Increased vascular permeability
b)Chemotaxis for leucocyte
c)Anticoagulant activity.

73. The fibrinolytic system:
• This system is activated by plasminogen activator,it act on
plasminogen present as component of plasma proteins to form
plasmin.further breakdown of fibrin by plasmin forms fibrinopeptides
or fibrin split products.
• Action of plasmin are:
a)Activation of factor XII to form prekallikrein activator that stimulates
the kinin system to generate bradykinin.
b)Splits off complement C3 to C3a(permeability factor)
c)Degrades fibrin to fibrin split products which increase vascular
permeability and chemotactic to leucocytes.

75. The complement system:
• Activation of it can be either:
a)By classic pathway i.e.antigen-antibody
complexes,or
b)By alternate pathwayi.e.non-immunologic
agents such as bacterial toxins,cobra venoms
and IgA.
-Action of activated complement system in
inflammation are:
i)C3a.C5a,C4a(anaphylatoxins) activate mast
cells and basophils to release of
histamine,cause increased vascular
permeability causing oedema in
tissues,augments phagocytosis.
ii)C3b is an opsonin.
iii)C5a ischemotactic for leucocytes
iv)Membrane attack complex(MAC)(C5b-C9)is
lipid dissolving agents and causes holes in
phospholipid membrane of cell.

77. Regulators of inflammation:
• Normally,inflammation is kept in check by inbuilt regulatory system to
resolve its harmfull effects.
• These substancesare acute phase reactant proteins,endogenous
glucocorticoids,cytokine receptors and certain anti-inflammatory
mediators like prostacyclin.

78. Inflammatory cells:
-cells participating in acute and chronic inflammation are circulating leucocytes, plasma
cells, tissue macrophages and inflammatory gaint cells.
-polymorphs or neutrophils are the first line of defense against invading agents and
perform initial phagocytosis.
-Eosinophils participate in allergic conditions,parasitic infestations and certain skin
diseases.
-basophils and mast cells are involved in immediate and delayed type of hypersensitivity
reactions.
-lymphocytes are immunocompetent cells-Bcells in humoral immunity and Tcells in cell-
mediated immunity. Lymphocytes are dominant in chronic inflammation.
-plasma cells develop from Bcells are immunoglobulin-synthesizing cells and are seen in
chronic inflammation.
-mononuclear phagocytes system is comprised by circulating monocytes and tissue
macrophages. These are scavenger cells of body.
-different types of gaint cells are seen in different inflammatory conditions.the types of
gaint cells are foreign body,langhans’touton and aschoff giant cells.

81. Systemic effects of acute inflammation:
• Fever: due to bacteraemia.
• Leucocytosis:usually in the range of 15000-20000/µl.
• Lymphangitis-lymphadenitis:the lymphatics and lymph nodes that
drain inflamed tissue show reactive inflammatory changes in form of
lymphangitis and lymphadenitis.
• Shock:may occur in severe cases.

82. FATE OF ACUTE INFLAMMATION:

83. Fate of acute inflammation:
1.Resolution: it is the complete return to normal tissue. This occour when tissue changes
are slight and cellular changes are reversible. e. g. resolution in lobar pneumonia.
2.Healing: tissue loss is superficial, healing takes place by regeneration. When tissue
destruction is extensive, then healing occurs by fibrosis.
3.Suppuration: when pyogenic bacteria it will result in severe tissue necrosis, the process
progresses to suppuration. Initially there is intense neutrophilic infiltration.
Subsequently,mixture of neutrophils,bacteria,fragments of nectrotic tissue,cell debris and
fibrin comprise pus which is contained in a cavity to form an abscess. The abscess,if not
drained,may get organized by dense fibrous tissue,and in time,get calcified.
4.Chronic inflammation: persisting or recurrent acute inflammation may progress to
chronic inflammation in which the process of inflammation and healing proceed side by
side.

88. Chronic inflammation
• Chronic Inflammation is defined as a prolonged process (weeks to
months to years)in which tissue destruction and inflammation occur
at the same time.
• Chronic inflammation is characterized by:
1.Mononuclear cell infiltration
2.Tissue destruction or necrosis
3.Proliferative changes

89. CAUSES OF CHRONIC INFLAMMATION
1.Persistent infection
2.immune-mediated inflammatory disease
3.Toxic agents/foreign body
4.Progression from acute inflammation

90. Causes of chronic inflammation:
• 1.PERSISTENT INFECTIONS: infection such as tuberculosis,leprosy,certain fungi etc.
• -persistent suppuration as result of uncollapsed abscess cavities,sequesterum of
• osteomyelitis.
• -these organisms are of low toxicity and evoke delay hypersensitivity reactions.
• 2.AUTOIMMUNITY: autoimmune diseases such as rheumatoid arthritis and systemic lupus
• erythematosus are chronic inflaamations from the onset.
• 3.TOXIC AGENTS: either endogenous lipid components which result in atherosclerosis or
• exogenous substances such as silica, asbestos.
• 4.PROGRESSION FROM ACUTE INFLAMMATION: it will always progresses to chronic inflammation in
persistent suppuration as a result of collapsed abscess cavities, foreign body material (dirt, cloth,
wool etc), sequestrum in osteomyelitis.

93. Applied aspects of chronic inflammation:
• Lichen planus
• Leukoplakia
• Oral submucous fibrosis
• Periodontal disease

94. Types of chronic inflammation:
Chronic non-specific inflammation: when irritant produces non-specific chronic inflammatory
reaction with formation of granulation tissue and healing by fibrosis.
e.g. chronic osteomyelitis, chronic ulcer, lung abscess.
Chronic granulomatous inflammation: injurious agent causes a characterstic histologic tissue
response by formation of granulomas.
e.g. tuberculosis, leprosy,syphilis,actinomycosis,sarcoidosis ect
Chronic non-specific inflammation Chronic granulation inflammation

95. Mechanism of chronic inflammation:

96. Granulomatous inflammation
• It is a cellular attempt to contain an offending agent that is difficult to
eradicate.
• A granuloma is a focus of chronic inflammation consisting of a
microscopic aggregation of macrophages that are transformed into
epithelium-like cells principally lymphocytes and occasionally plasma
cells.

97. Granuloma:
• Bacilli/foreign body are inhaled by droplets
• They are phagocytosed by alveolar macrophages
• After amassing substances that they cannot digest macrophages lose their motility,
accumulate at the site of injury and transform themselves into nodular collections
• A localized inflammatory response recruits more mononuclear cells
• The granuloma consist of a kernel of infected macrophages surrounded by foamy
macrophages and a ring of lymphocytes and a fibrous cuff(containment phase)
• Containment usually fails when the immune status of the patient changes; the
granuloma caseates, ruptures and spills into the airway

102. Chronic inflammatory cells and mediators:
-Macrophages
-Lymphocytes
-Plasma cells
-Eosinophils
-Mast cells

103. Macrophages:
-Dominant cells of chronic inflammation.
-Derived from circulating blood
monocytes.
MACROPHAGES present in:
-Liver: Kuffer cells.
-Spleen
-Lymph nodes: sinus histiocytes
-Central nervous system: microglial cells
-Lungs: alveolar macrophages

105. Lymphocytes:
-T and B LYMPHOCYTES-
-Antigen-activated(via-macrophages)
-Release macrophage-activating
cytokines(in turn, macrophages release
lymphocyte-activating cytokines until
inflammatory stimulus is removed
-Lymphocytes and macrophages
interact in a bidirectional way which is
important role in chronic inflammation.

107. Eosinophils:
• Inflammatory sites especially around parasitic infections or as part of
immune reactions mediated by IgE.
• Associated with allergies
• Induced by specific chemokines-eotaxin
• Granules contain major basic protein- highly charged cationic protein
- Toxic to parasites
- Also causes epithelial cell necrosis

109. Systemic influence of chronic inflammation:
1.Fever: invariably there is mild fever, often with loss of weight and
weakness.
2.Anaemia: chronic inflammation is accompanied by anaemia of
varying degree.
3.Leucocytosis: as in acute inflammation also has leukocytosis but
generally there is relative lymphocytosis in these cases.
4.ESR: ESR is elevated in all cases of chronic inflammation.
5.Amyloidosis: long-term cases of chronic suppurative inflammation
may develop secondary systemic(AA) amyloidosis.
6. Scarring and fibrosis within the organ → damage and loss of function
7. Continuous inflammation → neoplasm

110. Mast cells:
• Sentinel(watch) cells widely distributed in connective tissues
throughout the body.
• Both acute and chronic inflammatory responses.
• Elaborate cytokines such as TNF and chemokines.
• Atopic individuals: individuals prone to allergic reactions
-mast cells armed with IgE antibody.
-as the environmental antigens enters-it releases histamines and AA
metabolites-anaphylactic shock.

111. Outcomes of chronic inflammation:
 Continued chronic inflammation
 Change in tissue function:
-atrophy
-metaplasia(=change in cell type)
 Resolution: damaging stimulus removed, healing can occur
 Scarring with dysfunction: cirrhosis in viral hepatitis
 Catastrophe:
-damaging stimulus increases/tissue healing response
-weaken>tissue insult worsens
e.g. perforated gastric ulcer

112. Difference between acute and chronic inflammation
acute inflammation chronic inflammation
Causative agent Pathogens, injured tissues Persistent acute inflammation, persistent infection, foreign bodies,
autoimmune reactions.
Major cells involved Neutrophils, mononuclear cells(monocytes, macrophages) Mononuclear cells(monocytes, macrophages, lymphocytes, plasma
cells), fibroblasts
Primary mediators Vasoactive amines, eicosanoids IFN-ꝩ and other cytokines, growth factors reactive oxygen species,
hydrolytic enzymes
Onset Immediate Delayed
Duration Few days Up to few months or years
Specificity Nonspecific Specific( where immune response is activated)
Vascular changes Active vasodilation ,increased permeability New vessel formation(granulation tissue)
Fluid exudation and edema Present Absent
Cardinal clinical signs Present Absent
Tissue necrosis Generally absent
If present(suppurative and necrotizing inflammation)
Continuous
Fibrosis(collagen deposition) Present Absent
Operative host responses Plasma factors: complement ,immunoglobulins etc; neutrophils
,nonimmune phagocytosis
Immune response, phagocytosis, repair
Systemic manifestations Fever, often high Low-grade fever, weight loss, anemia
Changes in peripheral Neutrophil leukocytosis: lymphocytosis(in viral infection) Frequently none: variable leukocytic changes increased
Outcomes Resolution, abcess formation, chronic inflammation Tissue destruction, fibrosis

114. Consequences of impaired inflammation:
DEFECTIVE INFLAMMATION
-increase susceptibility to infection.
-delay in wound healing
-tissue damage
EXCESS INFLAMMATION
-allergies
-important in:
*cancer
*atherosclerosis
*fibrosis as a sequel of chronic infections,
metabolic conditions

115. Systemic effect of inflammation:
• Also known as acute-phase reaction.
• Cytokines TNF,IL-1, IL-6
• The acute-phase response consist of several clinical and pathological changes:
-increase Bp and pulse
-decrease sweating
-Chills, anorexia
-fever
-elevated plasma levels of acute-phase proteins:
*C-reactive protein(CRP),
*Fibrinogen,
*Serum amyloid A(SAA) protein
-leukocytosis
-septic shock

116. Clinical Relevance
Examples of inflammation becoming a pathologic response:
• Atherosclerosis: common form of arterial disease in which lipid deposition
forms a plaque in the blood vessel walls. Atherosclerosis starts with
endothelial injury secondary to turbulent flow and is followed by lipid
retention through monocytic response, leading to the formation of foam
cells. This process ultimately results in the formation of a fibrous plaque. The
plaque narrows the lumen and can cause ischemia, resulting in MI,
stroke, CKD, and other organ compromise.
• Multiple sclerosis (MS): chronic inflammatory autoimmune disorder leading
to demyelination of the CNS. Inflammation occurs when the oligodendrocyte
recognizes self myelin as a foreign antigen and results in the removal of the
myelin sheath. Symptoms arise owing to the swelling plus loss of tissue
function and include neurologic symptoms affecting vision, motor functions,
sensation, and autonomic function.

117. • Pulmonary fibrosis: type of interstitial lung disease. Environmental
exposure to minute inhalants such as smoke, pollutants, and dust causes
an inflammatory process within the lung tissue, resulting in fibrosis on
injury repair. Individuals often present in a moderate-to-advanced stage
with progressive dyspnea and nonproductive cough. The diagnosis is made
on the basis of imaging findings and pulmonary function testing. Lung
transplantation is the only curative intervention.

118. Disorders due to deficiency in some mediators of the inflammatory
response:
• Defects in adhesion: Leukocyte adhesion deficiency I (LAD I) is due to defective
synthesis of integrin in the cellular response phase and deficient binding
to immunoglobulins, which result in recurrent infections.
Leukocyte adhesion deficiency II (LAD II) is a rare disorder in which neutrophils are
deficient in the expression of sialyl-Lewis X, which is needed for rolling in the
cellular response phase of inflammation. Leukocyte adhesion deficiency II is
characterized by recurrent infections, persistent leukocytosis, and severe deficits
in development and growth.
• Defect in phagolysosome formation: Chediak-Higashi syndrome is an autosomal
recessivedisorder caused by mutations affecting a lysosomal trafficking regulator
protein, whereby phagocytosed bacteria are not destroyed by
lysosomal enzymes. Chemotaxis is also disrupted, resulting in poor neutrophil
recruitment and function. Individuals exhibit recurrent pyogenic infections, easy
bleeding and bruising, and neurologic manifestations. The diagnosis is based on
analysis of the individual’s blood or bone marrow smear and genetic testing.

119. • Defect in microbicidal activity: Chronic granulomatous disease (CGD),
seen in individuals with a genetic mutation for NADPH oxidase, which is
responsible for the respiratory burst in
phagocytic leukocytes. Infections may be contained; however, lysis does
not occur, thus resulting in chronic granuloma formation. Individuals with
CGD are at increased risk of life-threatening infections
with fungi and catalase-positive bacteria.

120. References:
• Harsh mohan- textbook of pathology 6th edition.
• Synopsis of oral pathology by S.N.Bhaskar 7th edition
• Robbinson’s basic pathology 8th edition
• Color atlas of pathology