Inflammation

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 1 st 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 5 th sign “functio laesa” (loss of function) was later added by Virchow.

5. 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

6. 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.

7. 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.

8. CHEMICAL MEDIATORS OF INFLAMMATION

9. 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)

10. 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

11. 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

12. 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.

13. 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 (LTC 4 ,LTD 4 ,LTE 4 ).

14. 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.

15. 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 C 5a so as to form arachidonic acid metabolites by one of the two pathways via cyclo-oxygenase pathway and via lipo-oxygenase pathway.

16. 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 (PGG 2 )” which is enzymatically transformed into “PGH 2 ” with generation of free radical of oxygen.PGH 2 is further activated upon by enzymes and results in the formation of following 3 metabolites. a)Prostaglandins (PGD 2 ,PGE 2 and PGF 2 ) b)Thromboxane A 2 (TXA 2 ) c)Prostacyclin (PGI 2 )

17. 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)

18. 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.

19. 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

20. 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)

21. 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

22. Oxygen-derived metabolites:- They are released from activated neutrophils and include superoxide oxygen (O 2 ),H 2 O 2 ,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

23. 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.

24. 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

25. 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

26. 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 C 3 to form C 3a which is a permeability factor. Degrades fibrin to form fibrin split products which increase vascular permeability and are chemotactic to leucocytes.

27. 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 C 3a ,C 4a and C 5a ,and membrane attack complex (MAC).The relative potencies of anaphylatoxins are in the descending sequence of C 3a ,C 5a ,C 4a .

28. The actions of anaphylatoxins in inflammation are:- Release of histamine from mast cells and basophils. Increased vascular permeability causing oedema in tissues. C 3b augments phagocytosis. C 5a is chemotactic for leucocytes. The action of MAC is to cause pores in the cell membrane of the invading micro organisms.

29. INTER-RELATION BETWEEN 4 SYSTEMS:-

30. ACUTE INFLAMMATION

31. 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

32. 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

33. 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

34. 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

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

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

37. 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”.

38. CHRONIC INFLAMMATION

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

40. 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.

41. 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.

42. 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.

43. REPAIRS OF WOUNDS IN THE SKIN

44. 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

45. 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.

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

47. 2.CONTRACTION OF WOUNDS:- The wound starts contracting after 2-3 days and the process is completed by the 14 th 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.

48. FACTORS INFLUENCING HEALING OF WOUNDS

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

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

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