Chronic Inflammation PDF

Chronic Inflammation  SUMMARY OF MAIN POINTS OF ACUTE INFLAMMATION Mechanisms of Disease. Rapid response of living tissue to any injury. Naked eye (Macroscopic): Redness, swelling, heat, pain & loss offunction. Microscopic: Vascular dilatation, exudate leaks into tissues,neutrophils em...

Chronic Inflammation  SUMMARY OF MAIN POINTS OF ACUTE INFLAMMATION Mechanisms of Disease. Rapid response of living tissue to any injury. Naked eye (Macroscopic): Redness, swelling, heat, pain & loss offunction. Microscopic: Vascular dilatation, exudate leaks into tissues,neutrophils emigrate. Changes controlled by many short-lived chemical mediators. Some can be manipulated by drugs. Neutrophils: Fast acting, short-lived phagocytes, engulf & degrade bacteria, dead tissue etc. Phagocytosis enhanced by opsonisation of particles, e.g. antibody or complement on surface. Bacterial killing largely oxygen dependent. Defects in the system lead to severe susceptibility to infection.  CHRONIC INFLAMMATION 1. May ‘take over’ from acute inflammation. …if damage is too severe to be resolved within a few days 2. May arise de novo– some autoimmune conditions (e.g. RA) – some chronic infections (e.g. viral hepatitis) – “chronic low-level irritation” 3. May develop alongside acute inflammation…in severe persistent or repeated irritation.  CHRONIC INFLAMMATION What is chronic inflammation? Characterised by the microscopic appearances. Most important characteristic is the type of cell present. Macrophages  Derived from blood monocytes. Accumulate in chronic inflammation due to: 1. Recruitment from blood 2. Mitotic division 3. Immobilisation by cytokines (macrophage inhibitory factor)  May undergo activation once extravasated. Interferon gamma (IFN-γ) secreted by sensitised T-cells , bacterial endotoxins Others  Macrophage Function 1. Phagocytosis of debris & bacteria A-Recognition e.g opsonisation by Igs,complement B- Engulfment into a phagosome C- Formation of phagolysosome and killing(oxygen dependent/ independent mechanisms) 2. Control of other cells by cytokinerelease: TNF-α and IL-1 – Other leukocytes - promote cytokine secretion, reciprocal relationship with lymphocytes – Endothelial cells – promote leukocyte adherence – Fibroblasts – proliferation and collagen synthesis 3. Synthesis: not only cytokines also complement components, blood clotting factors, growth factors and proteases. 4. Processing and presentation of antigen to immune system. T-cell activation Lymphocytes Sometimes called ‘chronic inflammatory cells’ (but note they are a normal component of some tissues) Functions: – Complex, mainly immunological. – B lymphocytes differentiate to produce antibodies. – T lymphocytes involved in control & some cytotoxic functions.  Other cells involved in chronic inflammation Plasma cells:– Differentiated antibody-producing B lymphocytes. Implies considerable chronicity. Eosinophils: – Allergic reactions, parasite infestations, some tumours. Fibroblasts / Myofibroblasts: – Recruited by macrophages; make collagen. ‘Giant’ Cells Multinucleate cells made by fusion of macrophages. Several types recognised. Langhans type giant cell - Tuberculosis Foreign body type giant cells Cell types in chronic inflammation Morphology of most chronic inflammatory reactions is non-specific, BUT proportions of each cell type may vary in different conditions. For example: – Rheumatoid arthritis: Mainly plasma cells. – Chronic gastritis: Mainly lymphocytes. – Leishmaniasis (a protozoal infection): Mainly macrophages. – Giant cell type may be a help to diagnosis  EFFECTS OF CHRONIC INFLAMMATION Fibrosis e.g. gall bladder (chronic cholecystitis), chronic ulcers. Impaired function e.g. chronic inflammatory bowel disease – Rarely increased function e.g. mucus secretion,thyrotoxicosis in Graves disease Atrophy – gastric mucosa, adrenal glands - Stimulation of immune response Macrophage - lymphocyte interactions Fibrosis: Chronic Cholecystitis. Repeated obstruction by gall stones. Repeated acute inflammation leads to chronic inflammation. Fibrosis of gall bladder wall. Fibrosis: Gastric Ulceration. Acute gastritis (alcohol, drugs). Chronic gastritis (Helicobacter pylori) Ulceration occurs because of: Imbalance of acid production and mucosal defence. Impaired Function: Inflammatory Bowel Disease Ulcerative colitis is superficial – Diarrhoea, bleeding Crohn’s disease is transmural – Strictures, fistulae Impaired Function:Rheumatoid arthritis Autoimmune disease. Localised and systemic immune response. Localised chronic inflammation of synovium leads to joint destruction. Systemic immune response can affect blood vessels, skin, lung Chronic Inflammation and Immune Response. Chronic inflammation and immune responses overlap:– Immune diseases cause pathology by chronic inflammation e.g. rheumatoidarthritis – Chronic inflammatory processes can stimulate immune responses e.g.macrophage induced T cell activation  GRANULOMATOUS INFLAMMATION = chronic inflammation with granulomas What is a granuloma? Tuberculous granuloma in lung Granulomas arise with: Persistent, low-grade antigenic stimulation Hypersensitivity :inappropriate reaction to a stimulus by the immune system Main causes of granulomatous inflammation: Mildly irritant ‘foreign’material. Mycobacteria: Tuberculosis, leprosy Syphilis Other rare infections e.g. some fungi Unknown causes: Sarcoid Wegener’s granulomatosis Crohn’s disease Foreign material from breakdown of artificial joint  TUBERCULOSIS Caused by Mycobacteria – especially M. tuberculosis. Difficult & slow toculture. Nature of organism: see microbiologists – n.b. wall lipids (Mycosides). Produces no toxins or lytic enzymes. Causes disease by persistence and induction of cell-mediated immunity. Destruction of tissues by caseating granulomas. Patterns of disease: Primary: Non-sensitized individual. Secondary: Previously exposed individual PRIMARY TUBERCULOSIS Initial infection,mid-zones of lung: GHON FOCUS. Spread to hilar lymph nodes:GHONCOMPLEX.  Outcome: Usually heals with some scarring &persistent bacteria in lung. Other possibility:– Progressive primary tuberculosis. 1) Massive hilar lymph nodes 2) 2) Tuberculous bronchopneumonia 3) 3) ‘Miliary’ tuberculosis :Outcomes.SECONDARY TUBERCULOSIS ?Re-activation or re-infection PATTERN OF DISEASE IMMENSELY.VARIABLE.Usually starts in apex of lung.Arrest, fibrosis, scaring.1.Erosion into bronchus.2 bronchopneumonia Tuberculous empyema.3 Erosion into blood stream.4 Many bugs: MILIARY TUBERCULOSIS Few bugs: SINGLE ORGAN TUBERCULOSIS Kidneys, GIT, bone marrow OTHER GRANULOMATOUS INFECTIONS Leprosy Syphilis Chronic fungal infections ‘Cat-scratch’ disease Xanthogranulomatous pyelonephritis &malakoplakia many more GRANULOMATOUS DISEASES OF UNKNOWN CAUSE Sarcoidosis – Variable clinical manifestations Young adult women Non-caseating granulomas, giant cells Involves lymph nodes, lungs… Crohn’s Disease – ‘Regional enteritis’: patchy full-thickness inflammation throughout bowel. Wegener’s granulomatosis. many others Sarcoid granulomas in a lymph node  Summary How does it happen? 1. Severe acute inflammation 2. De Novo Chronic inflammation 3. Repeated attacks of acute inflammation  CHRONIC INFLAMMATION Why it is important? 1. Fibrosis 2. Impaired function and atrophy 3. Stimulation of Immune response Next week: How to make it better or Healing, Regeneration and Repair