1. Biology of Disease CH0576 The Inflammatory Response I Dr Stephen Todryk

2. Inflammation: Painful Unsightly Essential process Response to a foreign object or to damage

6. Major cells Neutrophil 50-70% (5000/mm 3 ) Eosinophil 1-3% Basophil <1% polymorphonuclear

7. Major cells Monocyte 1-6% macrophage

8. mast cell (tissue) platelets

10. Inflammation - Introduction Inflammation is the local physiological tissue response to injury, cell death, infection and is classified according to duration Acute inflammation:- Initial and often transient response. Short-lived. Chronic Inflammation:- Subsequent and often prolonged response that follows acute stages. Associated with / cause: cancer, atherosclerosis, asthma, psoriasis, arthritis

11. Inflammation - Introduction Inflammation is a reaction to trauma e.g.the invasion of microorganisms through the skin or through the epithelial layers of the respiratory, digestive, or urinary system characterized by four signs:

13. Acute Inflammation  The ‘cardinal signs’ of inflammation were first described some 2000 years ago by the Roman Physician Celcus. Calor = Heat Rubor = Redness Tumor = Swelling Dolor = Pain These normally give rise to a fifth: loss of function Table 4. Cardinal Signs EnglishGreek/LatinCaused By RednessRuborHyperemia WarmthCalorHyperemia SwellingTumor Increased permeability PainDolorLow pH Loss of function Functio laesaPain, swelling

14. Inflammation Usually localised, but can get whole body effects Multiple injuries Systemic infection Multiple organ failure

15. Causes of Acute Inflammation The causes of acute inflammation are 1. Physical agents (physical trauma, radiation, burns). 2. Chemical agents (corrosive chemicals). 3. Immunological mechanisms (hypersensitivity reactions - certain allergies). 4. Tissue necrosis (death of tissue from lack of nutrients or oxygen due to lack of blood flow – INFARCTION). 5. Microbial Infections (viruses, bacteria, fungi and parasites)

16. Acute Bronchitis Medlineplus, National Library of Medicine, U.S.A.

17. Inflammatory Response Inflammatory response The body's reaction to trauma includes an increase in blood flow to the affected area (controlled by “chemicals”) release of “chemicals” to attract white blood cells (Neutrophils) an increased flow of plasma the arrival of monocytes to clean up the debris.

18. Functions of Acute Inflammation The acute inflammatory response is relatively non-specific (primitive program; innate) and has three main functions: 1.Damaged tissue is broken down and dead cells and debris are removed from the site. 2. If an infective agent is present (bacteria) it can be destroyed and eliminated 3. Allows the immune response (cells and molecules) access to the damaged site. Focusing the immune response.

19. Effects of Acute Inflammation BENEFICIAL EFFECTS: 1.Dilutes toxins 2. Allows entry of antibodies to site of inflammation 3. Delivers nutrients and oxygen to site of inflammation (essential for cells such as neutrophils which have a high metabolic activity)

20. BENEFICIAL EFFECTS : 4. Fibrin formation (Exuded fibrinogen, clot, may impede the movement of microorganisms, limiting their spread; facilitating phagocytosis) 5. Stimulation of the immune response (Drainage of fluid exudate to the lymphatics allows antigens to reach the local lymph nodes) 6. Promotes repair and healing Effects of Acute Inflammation

21. Acute Inflammation

22. Effects of Acute Inflammation HARMFUL EFFECTS: 1.Release of lysosomal enzymes by inflammatory cells can digest normal tissues (collagenases and proteases) as well as damaged tissue 2. Swelling of acutely inflamed tissue may be harmful e.g. Swelling of the epiglottis due to Haemophilus influenzae infection may obstruct airway and cause death. In Acute Meningitis inflammatory swelling is especially serious as it may impair blood flow to brain 3. Inappropriate inflammatory responses. (Type I hypersensitivity reactions to harmless antigen - allergy )

23. Inflammatory Response The inflammatory response consists of: a)Vasodilation - causing increased blood flow (hyperaemia) b) Increased vascular permeability - causing vessels to become leaky c) Leakage of plasma from blood to tissues (fluid exudate) d) Emigration of inflammatory cells (mostly neutrophils) from blood to tissues (cellular exudate)

24. Steps in the Inflammatory Response Steps involved in the acute inflammatory response a)Small blood vessels adjacent to the area of tissue damage become dilated with increased blood flow which then slows down b) Endothelial cells swell and partially retract so they no longer form a completely intact internal lining.

25. Steps in Inflammatory Response c) The vessels become leaky, allowing the passage of water, salts and some small plasma proteins into the damaged area ( EXUDATION ) d)Circulating neutrophils adhere to swollen endothelial cells ( MARGINATION ) then migrate through the vessel basement membrane ( EMIGRATION ) passing into area of tissue damage e) Small numbers of macrophages and lymphocytes migrate in a similar way as do neutrophils.

26. Chemical Mediators in Acute Inflammation Vascular response to injury is mediated by a wide range of soluble mediators generated at the site of tissue injury PHASE CHEMICAL MEDIATOR Vascular Dilation Histamine, Prostoglandins, Complement components: C3a and C5a. Increased vascular Histamine, Kinins, Prostaglandins. permeability Emigration of C5a, leukotrienes, IL-8, cationic proteins leukocytes of neutrophils.

27. Fluid Movement Across Capillaries Under physiological conditions there is a continuous movement of fluid between capillaries and extravascular tissues. The movement of fluid is dependent upon differential pressure gradients across the vessel wall. The high colloid osmotic pressure inside the vessel (due to plasma proteins) favours fluid return to the vessel. Normally there is fluid movement OUT of capillary at arteriolar end and INTO it at the venous end.

28. Non-inflammatory Oedema In certain circumstances fluid can move into the tissues at a greater rate than it can be removed. This results in OEDEMA e.g. pulmonary oedema due to left ventricular cardiac failure.

29. Non-inflammatory Oedema Obstruction to lymphatic drainage from a particular site can also result in oedema – LYMPHODEMA – following surgery, in tumour metastasis or elephantiasis due to parasitic worm infection e.g. filiarisis

31. Inflammatory Oedema Oedema which occurs due to increased vascular permeability following tisssue injury. Various vasoactive mediators originating from plasma and cellular sources, also from injured cells, are generated at the site of tissue injury. Their main site of action is at the post capillary venule

32. Inflammatory Oedema The mediators induce changes in endothelial cell wall of vessels, altering its permeability Binding of vasoactive mediators to their specific receptors on endothelial cells results in endothelial cell retraction and formation of gaps The integrity of the endothelial cell layer is lost. Endothelial cell retraction and gap formation are reversible processes

33. Inflammatory Oedema Experimental studies have shown three patterns of oedema which occur at different times following injury: 1.IMMEDATE - This is transient and lasts for 30-60 minutes after injury and is mediated by HISTAMINE acting on endothelium.

34. Inflammatory Oedema 2. DELAYED - starts 2-3 hours after injury and lasts for up to 8 hours. This is mediated by factors synthesised by local cells e.g. BRADYKININ, Complement breakdown products and factors released by dead neutrophils 3. An immediate response that is prolonged for over 24 hours and is seen if there has been severe direct injury to the endothelium e.g. by burns or caustic chemicals.

35. Mediators of Increased Vascular Permeability The primary sources of these mediators are either plasma or various cells types e.g. Platelets, Tissue mast cells, Basophils, Polymorphonuclear Leucocytes (neutrophils), Endothelial cells, Monocytes and macrophages and injured cells themselves

36. Mediators of Increased Vascular Permeability Plasma derived factors are mostly precursor proteins or zymogens, activated by proteolytic enzymes. Once activated they generally have a short half life. They are rapidly inactivated in tissues by a variety of systems.

37. Cellular Mediators The mediators of increased vascular permeability released by cells are either preformed and stored within the cell as cytoplasmic granules, e.g. HISTAMINE, SERATONIN, LYSOSOMAL HYDROLASES or are derived from the metabolism of phospholipids and arachidonic acid e.g. PROSTAGLANDINS, PLATELET ACTIVATING FACTOR (PAF), LEUKOTRIENES and THROMBOXANES

38. Outcomes of Acute Inflammation Foreign and/or infectious agents removed and debris Damaged area regrows and trauma resolved Scar (collagenous) formed Formation of abscess Chronic inflammation

39. Time for a break…….

40. Glossary Post capillary venule: Arteries bringing blood from heart divide into smaller arterioles which then divide into capillaries when they enter tissue. Capillaries exchange substances with tissue then reunite into small veins – venules zymogen (or proenzyme): The inactive or nearly inactive precursor of an enzyme, converted into an active enzyme by proteolysis

41. http://www.whfreeman.com/kuby/content/anm/kb01 an01.htm