Inflammation KANG`OMBE C KAKENGE Inflammation • Protective host response to rid body of stimuli; damaged or necrotic tissues and foreign antigen • Occurs in vascularized tissue against stimuli leading to accumulation of fluid and leukocytes • Protective – rids body of injurious stimulus • Serves to destroy, dilute or wall off injurious agent and sets in motion process of repair • During repair injured tissue is replaced by regeneration of cells or fibrous tissue, or both • May be harmful in some situations - eg hypersensitivity reaction • Terminated when offending agent is eliminated 2 Types of inflammation • Acute – short duration, lasting minutes, hours or days - characterized by exudation of fluid and plasma proteins - emigration of leukocytes mainly neutrophils • Chronic – longer duration - associated with presence of lymphocytes & macrophages - proliferation of blood vessels, fibrosis and tissue necrosis 3 Cardinal signs of inflammation • Rubor – redness • Tumor – swelling • Calor – heat • Dolor – pain • Functio laesa – loss of function 4 Acute inflammation • Immediate and early response to injurious agents • Serves to deliver leukocytes and plasma proteins to sites of infection or tissue injury • Three major components: - alteration in vascular calibre blood flow - structural changes in microvasculature – plasma proteins and leukocytes leave circulation - emigration of leukocytes to focus of injury 5 Stimuli for acute inflammation Acute inflammatory reactions may be triggered by: • Infections and microbial toxins – most common cause of inflammation • Tissue necrosis from any cause – molecules released from necrotic cells elicit inflammation • Foreign bodies – cause traumatic tissue injury or carry microorganisms • Immune reactions – hypersensitivity reactions 6 Reactions of blood vessels • Undergo changes that facilitate movt of plasma proteins and leukocytes out of circulation • Escape of fluid, proteins and blood cells into interstitial tissue is called exudation • Exudate • Extracellular fluid with high protein content • Contains cellular debris • Has high specific gravity • Transudate • Low protein content • Little or no cellular material • Low specific gravity 7 Vascular changes • Changes in vascular flow and calibre occur early • Transient vasoconstriction then vasodilatation blood flow (heat and redness) • Slowing of circulation due to permeability exudation of fluid, blood viscosity and stasis • Peripheral orientation of leukocytes along endothelium (margination), followed by rolling and migration into interstitium • permeability exudation of protein-rich fluid into interstitium intravascular osmotic pressure oedema (swelling) 8 Cellular events • Movement of leukocytes to site of injury which then: - ingest offending agents - kill bacteria and other microorganisms - degrade necrotic tissue and foreign antigens - may prolong inflamm and induce tissue damage by release of enzymes, chem mediators • In an inflammatory lesion, neutrophils present in first 6 - 24 hours, monocytes in next 24 – 48 hours 9 Chemotaxis Movt of leukocytes along chemical gradient due to chemoattractants • Exogenous agents: - bacterial products • Endogenous products: - components of complement system eg C5a - products of lipooxygenase pathway – leukotrienes - cytokines eg IL-8 10 Phagocytosis Three steps in phagocytosis: • Recognition and attachment of particle • Opsonisation – particle is coated to phagocytosis • Engulfment –extension of cytoplasm (pseudopods) around object • Killing or degradation –superoxide is generated and converted to H2O2 • Granules of neutrophils contain enzymes • O2 independent mechanisms include bactericidal permeability increasing protein, lysozyme, lactoferrin, major basic protein 11 Chemical mediators of inflammation • Chemical compounds that modify or amplify inflammatory process • Originate from plasma or from cells • Bind to specific receptors on target cells • Can act on one or a few target cells • Most are short-lived once activated • Have potential to cause harmful effects 12 1. Vasoactive amines (histamine and serotonin) • Histamine derived from mast cells, basophils, platelets in preformed state • Causes dilatation of arterioles and permeability • Serotonin (5-hydroxytryptamine) present in platelets and enterochromaffin cells • Actions similar to histamine • Amines are released after platelets are stimulated upon contact with collagen, thrombin, ADP and Ab-Ag complexes 13 2. Plasma proteases • Complement system - after activation causes lysis by membrane attack complex. Gives out components: - C3a, C5a (anaphylatoxins) -permeability and vasodilation - C5a –chemotactic agent, C3a –opsonin • Kinin system - results in generation of bradykinin - permeability, causes contraction of smooth muscle, dilatation of vessels, pain when injected into skin - triggered by activation of FXII of intrinsic clotting pathway • Clotting system – activation results in formation of fibrinopeptides which permeability 14 3. Arachdonic acid (AA) metabolites • AA derived from diet or by conversion from linoleic acid of cell membrane phospholipids • AA by cycloxygenase pathway produces prostaglandins (PG): - thromboxane (TXA2) –vasoconstrictor and PLT aggregating factor - prostacyclin (PGI2) –vasodilator, inhibits PLT aggregation - PGD2, PGE2, PGF2 -cause vasodilation, potentiate oedema 15 • Lipoxygenase pathway generates 5-HETE leukotrines (LTs) - 5-HETE –chemotactic agent - LTB4 –chemotactic agent - LTC4, LTD4, LTE4 –vasoconstriction, bronchospasm, permeability • Lipoxins - inhibitors of inflammation - inhibit leukocyte recruitment 16 4. Platelet-activating factor (PAF) • Derived from phospholipids in a number of cells - causes PLT activation - vasoconstriction and bronchoconstriction - increases leukocyte adhesion to endothelium 5. Cytokines –substances that modulate function of other cells - include monokines, lymphokines, colony stim factors, interleukins, chemokines, growth factors - IL-1, TNF –fever, sleep, PGI synthesis - chemokines – activate specific leukocytes and are chemoattractants 17 6. Nitric oxide (NO) • Produced by endothelial cells, macrophages, neurones • Acts in a paracrine manner through cGMP • Potent vasodilator • Causes smooth muscle relaxation • Reduces PLT aggregation and adhesion 18 Outcomes of acute inflammation • Complete resolution • Abscess formation – infection by pyogenic organisms • Healing by connective tissue replacement (fibrosis) • Progression to chronic inflammation 19 Chronic inflammation • Inflammation of long duration • There is active inflammation, tissue destruction and attempts at repair at same time • May follow acute inflammation • Or may begin insidiously as a slow-grade smoldering response without an acute phase • Most disabling chronic inflammatory conditions such as rheumatoid arthritis start as such • Causes tissue damage and disability in some cases 20 Causes of chronic inflammation May arise under the following conditions: • Persistent infection by organisms that are difficult to eradicate eg mycobacteria • They elicit a delayed type hypersensitivity reaction • Persistent exposure to toxic or non-degradable agents eg silica • Immune mediated inflammatory diseases • Autoimmune diseases • Allergic diseases 21 Histologic features Chronic inflammation characterised by: • Infiltration by chronic inflammatory cells – macrophages, lymphocytes, plasma cells • Tissue destruction by offending agent or by inflammatory cells • Healing by connective tissue replacement of damaged tissue with fibrosis 22 Cells in chronic inflammation Macrophages –derived from blood monocytes • Dominant cells in chronic inflammation • Present in many tissues • Also found in organs - liver (Kupffer cells), spleen+LNs (sinus histiocytes), lungs (alveolar macrophages) • Are activated by different stimuli • Activated macrophages: – Eliminate injurious agent – Causes tissue injury • Macrophage accumulation persists by continuous recruitment from circulation or local proliferation 23 Lymphocytes • Interact with macrophages in chronic inflammation • When activated produce cytokines, some of which activate macrophages eg IFN-γ Plasma cells – derived from activated B lymphocytes • Produce antibodies against specific antigens Mast cells –present in connective tissue • Anaphylactic reactions and parasitic infections • Present in many chronic inflammatory reactions Eosinophils – produce major basic protein which is toxic to parasites • Also causes lysis of epithelial cells 24 Granulomatous inflammation • Characterized by formation of granulomas • A granuloma consists of macrophages that are transformed into epithelial-like cells surrounded by a collar of lymphocytes and occasionally plasma cells • Epithelioid cells may fuse to form giant cells with multiple nuclei. Types of giant cells: - Langhan’s type –nuclei arranged in a horse-shoe. Seen in tuberculous infections - Foreign body type – nuclei haphazardly arranged - Warthin-Finkeldey type –have cytoplasm and nuclear inclusion bodies. Seen in measles infection 25 Granulomatous inflammation • Distinctive pattern of chronic inflammation seen in a limited number of conditions • Mycobacterium tuberculosis granulomas are called tubercles • May display central caseous necrosis which if present is characteristic of tuberculosis • Other conditions in which granulomas may be formed: - leprosy - fungal infections - parasitic infections - syphilis - cat-scratch disease – caused by Afipia felis organisms - sarcoidosis 26 - Crohn disease Systemic effects of inflammation • Systemic changes associated with acute inflammation called acute phase response • Due to reactions to cytokines • Fever • Acute phase proteins – C-reactive proteins, fibrinogen, serum amyloid A • Leukocytosis • Others – ↑pulse, BP, rigors, chills, anorexia, malaise 27
