II-Pharm.d, Pathophysiology, Inflammation

1. INFLAMMATION
T.SOUJANYA
PHARM-D

2. DEFINITION:-
Inflammation is defined as
the local response of living mammalian
tissues to injury due to any agent.It is a
body defence reaction in order to
eliminate or limit the spread of injurious
agent as well as to remove the
consequent necrosed cells and tissues.

3. CAUSES OF INFLAMMATION:-
The agents causing inflammation are as follows:-
1.Physical agents-heat,cold,radiation,mechanical trauma.
2.Chemical agents-organic & inorganic poisons.
3.Infective agents-bacteria,viruses & their toxins.
4.Immunological agents-cell mediated & antigen-anybody reactions.

4. SIGNS OF INFLAMMATION:-
The Roman writer “Celsus” in 1st century AD named the famous four
cardinal signs of inflammation as:-
1.Rubor (redness)
2.Tumor (swelling)
3.Calor ( heat)
4.Dolor (pain)
To these,the 5th sign “functio laesa” (loss of function) was later added
by Virchow.

7. TYPES OF INFLAMMATION:-
Depending upon the defence capacity of the host and duration
of response,inflammation can be classified as:-
1.Acute inflammation
2.Chronic inflammation

9. 1.ACUTE INFLAMMATION:-
It is of short duration and represents the early body reaction
and is usually followed by repair.It‘s main features are:-
• Accumulation of fluid and plasma at the affected site.
• Intravascular activation of platelets.
• Polymorphonuclear neutrophils as inflammatory cells.

10. 2.CHRONIC INFLAMMATION:-
It is of longer duration and occurs either after the causative
agent of acute inflammation persists for a long time or the stimulus is
such that it induces chronic inflammation from the beginning.
The characteristic features of chronic inflammation is presence
of chronic inflammatory cells such as lymphocytes,plasma cells and
macrophages.

13. CHEMICAL MEDIATORS
OF INFLAMMATION

14. They are also called as permeability factors or endogenous
mediators of increased vascular permeability,there are a large and
increasing number of endogenous compounds which can enhance
vascular permeability.
The substaces acting as chemical mediators of inflammation may
be released from the cells,the plasma or damaged tissue itself.They are
broadly classified into two groups:-
1.Cell derived mediators (mediators released by cells)
2.Plasma derived mediators (mediators originating from plasma)

15. I.CELL DERIVED MEDIATORS:-
1.Vasoactive amines
2.Arachidonic acid metabolites (Eicosanoids)
3.Lysosomal components
4.Platelet activating factor
5.Cytokines
6.Nitric oxide and oxygen metabolites

16. 1.VASOACTIVE AMINES:-
Two important
pharmacologically active amines that
have a role in early inflammatory
responses are:-
i)Histamine
ii)5-Hydroxy tryptamine (5-HT) or
serotonin

17. i)HISTAMINE:-
It is stored in the granules of mast cells,basophils and
platelets. Histamine is released from these cells by various agents as
follows:-
a)Stimuli or substances inducing acute inflammation.
Eg:-heat,cold,irradiation,trauma,irritant chemicals,immunologic
reactions etc.
b)Histamine-releasing factors from neutrophils,monocytes & platelets.
c)Neropeptides such as substance P.
d)Interleukins.

18. The main actions of histamine are:-
1.Vasodilation,increased vascular
permeability,itching & pain.
2.Stimulation of mast cells & basophils
also releases products of arachidonic acid
metabolism including the release of slow-
reacting substances of anaphylaxis (SRS-
As),which consists of various
interleukotrienes (LTC4,LTD4,LTE4).

19. ii)5-HYDROXY TRYPTAMINE (5-HT OR
SEROTONIN):-
It is present in tissues like chromaffin cells of GIT,spleen,
nervous tissue,mast cells and platelets.The actions of 5-HT are similar
to histamine but it is a less potent mediator of increased vascular
permeability and vasodilation than histamine.”Carcinoid tumour” is a
serotonin-secreting tumour.

20. 2.ARACHIDONIC ACID METABOLITES
(EICOSANOIDS):-
Arachidonic acid is a fatty acid,eicosatetraenoid acid.It‘s 2 main
sources are:-
• From diet directly
• Conversion of essential fatty acid,linoleic acid to arachidonic acid.
Arachidonic acid must be first activated by stimuli or other
metabolites like C5a so as to form arachidonic acid metabolites by one
of the two pathways via cyclo-oxygenase pathway and via lipo-
oxygenase pathway.

21. i)METABOLITES VIA CYCLO-OXYGENASE
PATHWAY:-
Prostaglandins and related compounds are also called
“autocoids”.Cyclo-oxygenase is a fatty acid enzyme which acts on
arachidonic acid to form “prostaglandin endoperixide (PGG2)” which is
enzymatically transformed into “PGH2” with generation of free radical
of oxygen.PGH2 is further activated upon by enzymes and results in the
formation of following 3 metabolites.
a)Prostaglandins (PGD2,PGE2and PGF2)
b)Thromboxane A2 (TXA2)
c)Prostacyclin (PGI2)

23. ii)METABOLITES VIA LIPO-OXYGENASE
PATHWAY:-
The enzyme,lipo-oxygenase acts on activated arachidonic acid
to form hydroperoxy compound,5-HPEPE (Hydro peroxy eico-sate
traenoic acid) which on further peroxidation forms the following 2
metabolites:-
a)5-HETE
b) Leukotrienes (LT)

26. 3.LYSOSOMAL COMPONENTS:-
The inflammatory cells-neutrophils and monocytes,contain
lysosomal granules which on release elaborate a variety of mediators of
inflammation. They are as follows:-
i)Granules of neutrophils.
ii)Granules of monocytes and tissue macrophages.

27. 4.PLATELET ACTIVATING FACTOR (PAF):-
It is released from IgE-sensitised basophils or mast cells,other
leucocytes,endothelium and platelets.Apart frimfrom it‘s action on
platelet aggregation and release reactions,the action of PAF as
mediation of inflammation are:-
• Increased vascular permeability
• Vasodilation in low concentration & vadoconstriction otherwise
• Broncho constriction
• Adhesion of leucocytes to endothelium
• Chemotaxis

28. 5.CYTOKINES:-
These are polypeptide substances produced by activated
lymphocytes (lymphokines) and activated monocytes
(monokines).These agents may act on self cells producing them or on
other cells.The main cytokines acting as mediators of inflammation
are:-
• Interleukin-1 (IL-1)
• Tumour necrosis factor (TNF)-alpha
• TNF-beta
• Interferon (IF)-gamma
• Chemokines (IL-8,PF-4)

29. 6.NITRIC OXIDE AND OXYGEN METABOLITES:-
Nitric oxide metabolites:-
Nitric oxide was originaly described as vascular relaxation
factor produced by endothelial Nitric oxide plays the following role in
inflammation:-
• Vasodilation
• Anti-platelet activating agent
• Posibly microbicidal action

30. Oxygen-derived metabolites:-
They are released from activated neutrophils and include
superoxide oxygen (O2),H2O2,OH and toxic NO products. They have the
following action in inflammation:-
• Endothelial cell damage and thereby increased vascular permeability
• Activation of protease and inactivation of anti protease causing tissue
matrix damage
• Damage to other cells

31. II.PLASMA DERIVED MEDIATORS:-
These include the various products derived from activation and
interaction of four interlinked systems.
1.Kinin system
2.Clotting system
3.Fibrinolytic system
4.Complement system
Hageman factor (factor XII) of clotting system plays a key
role in interactions of the four systems.

32. 1.THE KININ SYSTEM:-
This system on activation by factor XIIa generates bradykinin,which
induces the slow contraction of smooth muscle.First “kallikrein” is formed
from “plasma kallikrein” by the action of prekallikrein activator,which is a
fragment of factor XIIa.Kallikrein that acts on a higher molecular weight
kininogen to form bradykinin.Bradykinin acts in the early stage of
inflammation and its effects include:-
• Smooth muscle contraction
• Vasodilation
• Increased vascular permeability
• Pain

34. 2.THE CLOTTING SYSTEM:-
Factor XIIa initiates the cascade of the clotting system
resulting in the formation of fibrinogen which is acted upon by the
thrombin to form fibrin & fibrinopeptides.
The actions of fibrinopeptides in inflammation are:-
• Increased vascular permeability
• Chemotaxis for lecocyte
• Anti coagulant activity

37. 3.THE FIBRINOLYTIC SYSTEM:-
It is activated by plasminogen activator which acts on
plasminogen present as component of plasma proteins to form
plasma.Further breakdown of fibrin by plasmin forms fibrinopeptides
or fibrin split products.
The actions of plasmin in inflammation are:-
• Activation of factor XII to form prekallikrein activator that stimulates
the kinin system to form bradykinin.
• Splits off complement C3 to form C3a which is a permeability factor.
• Degrades fibrin to form fibrin split products which increase vascular
permeability and are chemotactic to leucocytes.

39. 4.THE COMPLEMENT SYSTEM:-
The activation of complement system can occur either:-
i)By “classic pathway” through antigen-anybody complexes or
ii)By “alternate pathway” via non-immunologic agents such as bacterial
toxins,cobra venoms and IgA.
Complement system on activation by either of these two
pathways yields anaphylatoxins C3a,C4a and C5a,and membrane attack
complex (MAC).The relative potencies of anaphylatoxins are in the
descending sequence of C3a,C5a,C4a.

40. The actions of anaphylatoxins in inflammation are:-
• Release of histamine from mast cells and basophils.
• Increased vascular permeability causing oedema in tissues.
• C3b augments phagocytosis.
• C5a is chemotactic for leucocytes.
The action of MAC is to cause pores in the cell membrane
of the invading micro organisms.

42. INTER-RELATION BETWEEN 4 SYSTEMS:-

44. ACUTE
INFLAMMATION

45. PATHOGENESIS OF ACUTE INFLAMMATION:-
Acute inflammatory response by the host to any agent is a
continuous process.It can be divided into following two events:-
1.Vascular events
2.Cellular events

47. 1.VASCULAR EVENTS:-
Alternation in the microvascular (arterioles,capillaries and
venules) is the earliest response to tissue injury.These alternations
include:-
i)Haemodynamic changes
ii)Changes in vascular permeability

48. i)HAEMODYNAMIC CHANGES:-
The earliest features of inflammatory response result from
changes in the vasular flow and calibre of small blood vessels in the
injured tissue.The sequence of these changes is as under:-
• Transient vadoconstriction
• Vasodilation
• Local hydrostatic pressure
• Slowing or stasis
• Leucocytic margination

50. ii)ALTERED VASCULAR PERMEABILITY:-
In and around the inflamed tissue,there is accumulation of
oedema fluid in the interstitial compartment 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

52. 2.CELLULAR EVENTS:-
The cellular phase of inflammation consists of two
processes:-
i)Exudation of leucocytes
ii)Phagocytosis

53. i)EXUDATION OF LEUCOCYTES:-
The sequence of these leucocytic events can be divided into:-
• Margination
• Adhesion
• Emigration
• Chemotaxis

54. ii)PHAGOCYTOSIS:-
Phagocytosis is defined as the process of engulfment of solid
particulate material by the cells (cell-eating).The cells performing this
function are called phagocytes.There are 2 main types of phagocytic
cells:-
• Polymorphonuclear neutrophils (PMNs) which appear early in acute
inflammatory response,sometimes called as “microphages”.
• Circulating monocytes and fixed tissue mononclear phagocytes called
as “macrophages”.

57. CHRONIC
INFLAMMATION

58. DEFINITION:-
Chronic inflammation is
defined as prolonged process in
which tissue destruction and
inflammation occur at the same
time.

59. CAUSES:-
Chronic inflammation can be caused by one of the following three
ways:-
1.Chronic inflammation following acute inflammation:-
When the tissue destruction is extensive,or the bacteria survive and
persist in small numbers at the stage of acute inflammation.
Eg:- in osteomyelitis,pneumonia terminating in lung abscess.
2.Recurrent attacks of acute inflammation:-
When repeated bouts of acute inflammation culminate in chronicity
of the process.
Eg:- in recurrent urinary tract infection leading to chronic pyelonephritis.

60. 3.Chronic inflammation of starting de novo:-
When the infection with organisms of low pathogenecity is
chronic from the beginning.
Eg:- infection with Mycobacterium tuberculosis.

61. TYPES OF CHRONIC INFLAMMATION:-
Histological features are used for classifying chronic
inflammation into 2 corresponding types:-
1.Chronic non-specific inflammation:-
It is characterised by non-specific inflammatory cell infiltration.
Eg:- chronic osteomyelitis,lung abscess.
2.Chronic granulomatous inflammation:-
It is characterised by formation of granulomas.
Eg:- tuberculosis,leprosy,syphilis,actinomycosis,sarcoidosis etc.

62. REPAIRS OF WOUNDS
IN THE SKIN

63. REPAIR:-
Repair is the replacement of injured tissue by fibrous
tissue.Two processes are involved in repair:-
1.Granulation tissue formation
2.Contraction of wounds

64. 1.GRANULATION TISSUE FORMATION:-
The following 3 phases are observed in the formation of
granulation tissue:-
i)Phase of inflammation:-
Following trauma,blood clots at the site of injury,there is acute
inflammatory response with exudation of plasma,neutrophils and some
monocytes within 24 hours.
ii)Phase of clearance:-
Combination of proteolytic enzymes liberated from,autolytic
enzymes from dead tissue cells and phagocytic activity of macrophages
clear off the necrotic tissue debris and red blood cells.

65. iii)Phase of ingrowth of granulation tissue:-
This phase consists of 2 main processes:-
• Angiogenesis or neovascularisation
• Fibrogenesis

66. 2.CONTRACTION OF WOUNDS:-
The wound starts contracting after 2-3 days and the process
is completed by the 14th day.During this period,the wound is reduced
by approximately 80% of it‘s original size.
In order to explain the mechanism of wound contraction,a
number of factors have been proposed.These are as under:-
1.Dehydration as a result of removal of fluid.
2.Contraction of collagen
3.Discovery of myofibroblasts appearing in active granulation tissue.

67. FACTORS INFLUENCING
HEALING OF WOUNDS

68. Two types of factors influencing the wound healing are:-
1.Factors acting locally-local factors
2.Factors acting in general-systemic factors

69. 1.LOCAL FACTORS:-
These include the following factors:-
• Infection
• Poor blood supply
• Foreign bodies
• Movement
• Ionising radiation
• UV light
• Type,size & location of injury

70. 2.SYSTEMIC FACTORS:-
These are as follows:-
• Age
• Nutrition
• Systemic infection
• Administration of glucocorticoids
• Uncontrolled diabetes
• Haematologic abnormalities