Acute Inflammation 2 PDF 2023-2024

Acute inflammation-2 Prof. Dr. Hadi Al-mousawi Session 4 2023-2024 objectives Chemical mediators (overview) – More detail mechanism of fluid loss – More detail neutrophil emigration Action of neutrophils-phagocytosis Local complications and systemic effects Seq...

Acute inflammation-2 Prof. Dr. Hadi Al-mousawi Session 4 2023-2024 objectives Chemical mediators (overview) – More detail mechanism of fluid loss – More detail neutrophil emigration Action of neutrophils-phagocytosis Local complications and systemic effects Sequelae Clinical examples Chemical mediators of acute inflammation Proteases (plasma proteins, produced in liver) – Kinins (Bradykinin and Kallikrein) – Complement system C3a, C5a – Coagulation / fibrinolytic system Prostaglandins / Leukotrienes – Metabolites of arachidonic acid – Synthesis blocked by NSAIDs, e.g. aspirin Cytokines / chemokines (produced by WBC) – Many and varied! Interleukins, PAF, TNF alpha, PDGF, TGF beta.... Other inflammatory mediators: From platelets: 5-HT, Histamine, ADP From neutrophils: Lysosomal constituents Products released on neutrophil death From endothelium: Prostacyclin, Nitric oxide Plasminogen activators / inhibitors Oxygen derived free radicals – Endothelial damage, inactivation of antiproteases, injury to other cells Vascular changes CHEMICAL MEDIATORS Vascular dilatation – Histamine, prostaglandins, nitric oxide Increase in vascular permeability – Transient - Histamine – Bradykinin, leukotrienes C4, D4, E4 Emigration of neutrophils – C5a, leukotriene B4, bacterial products Mechanisms of vascular leakage Endothelial contraction -->gaps – histamine, leukotrienes Cytoskeletal reorganization --> gaps – Cytokines IL-1 and TNF. Direct injury - toxic burns, chemicals Leukocyte dependent injury – toxic oxygen species and enzymes from leucocytes (pulmonary and glomerular capillaries). Increased transcytosis - channels across endothelial cytoplasm – VEGF Mechanisms of neutrophil migration Neutrophil adhesion and emigration due to binding of complementary adhesion molecules on endothelial and neutrophil surfaces Chemical mediators change surface expression or avidity of adhesion molecules – Selectins – Immunoglobulins – Integrins How do neutrophils escape from vessels? Relaxation of inter-endothelial cell junctions Digestion of vascular basement membrane Movement :Diapedesis and Emigration; Chemotaxis.  Chemotaxis = movement along concentration gradients of chemo-attractants Receptor-ligand binding Rearrangement of cytoskeleton Production of pseudopod  Phagocytosis Contact, Recognition, Internalization. Cytoskeletal changes (as with chemotaxis) Microbial killing Recognition is facilitated by opsonins e.g. C3b receptors on phagocyte will recognize organisms coated with immuno- globulin or complement Phagosomes fuse with lysosomes to produce secondary lysosomes. Killing mechanisms O2 dependent – produces superoxide and hydrogen peroxide. – H2O2-Myeloperoxidase-halide system - produces HOCl. – Myeloperoxidase independent killing is less efficient. O2 independent – Lysozyme & hydrolases – Bactericidal Permeability Increasing Protein (BPI) – Cationic proteins (‘Defensins’) – Major Basic Protein (MBP; Eosinophils) Complications of Acute Inflammation Local (rubor, calor, dolor, tumor). Systemic Local complications of acute inflammation Swelling: – Blockage of tubes, e.g. bile duct, intestine Exudate: – Compression e.g. cardiac tamponade – Serositis Loss of fluid e.g. burns Pain & loss of function - especially if prolonged Systemic Effects of Acute Inflammation Acute phase response – Decreased appetite, altered sleep patterns and raised heart rate changes in plasma concentrations ofAcute phase proteins: – C-reactive protein (CRP) (Clinically useful) – 1 antitrypsin – Haptoglobin – Fibrinogen – Serum amyloid A protein Systemic Effects of Acute Inflammation Acute phase response – Spread of micro-organisms and toxins –SHOCK a clinical syndrome of circulatory failure. Systemic Effects of Acute Inflammation Fever – ‘Endogenous pyrogens’ produced: IL1 and TNF – Prostaglandins, aspirin etc reduce fever Leukocytosis IL1 and TNF produce an accelerated release from marrow Macrophages, T lymphocytes produce colony- stimulating factors Bacterial infections - neutrophils, viral - lymphocytes Clinically useful ACUTE INFLAMMATION: sequelae 1) Complete resolution. 2) Continued acute inflammation with chronic inflammation; chronic suppuration (abscess). 3) Chronic inflammation and fibrous repair, probably with tissue regeneration. 4) Death.  Resolution All mediators of acute inflammation have short half-lives and may be inactivated by degradation, dilution in exudate or inhibition. Gradually all of the changes of acute inflammation reverse, and the vascular changes stop. Neutrophils no longer marginate, and the vessel permeability and calibre returns tot normal. Resolution Therefore, the exudate drains via the lymphatics, fibrin is degraded by plasmin/other proteases and the neutrophils die. Damaged tissue may then be able to regenerate, but if tissue architecture has been destroyed, complete resolution is not possib Clinical Examples LOBAR PNEUMONIA – Causative organism Streptococcus pneumoniae (‘Pneumococcus’) – Population at risk Young adults in confined conditions, alcoholics.... – Clinical course Worsening fever, prostration, hypoxaemia over a few days. Dry cough. Fairly sudden improvement (‘resolution by crisis’) when antibodies appear. Skin blister Causes: heat, sunlight, chemical Predominant features: PAIN EXUDATE – Collection of fluid strips off overlying epithelium – more pain, more tissue damage. – Inflammatory cells relatively few, therefore exudate clear UNLESS bacterial infection develops. Abscess Solid tissues Inflammatory exudate forces tissue apart Liquefactive necrosis in center May cause high pressure therefore PAIN May cause tissue damage and squash adjacent structures Hepatic abscess Acute inflammation in serous cavities Exudate pours into cavity ascites, pleural or pericardial effusion respiratory or cardiac impairment Localized fibrin deposition in pericarditis Pericardium becomes inflamed and increases pressure on the heart Pericarditis Disorders of Acute Inflammation Hereditary Angio-Oedema It characterized by recurrent episodes of sever swelling affecting the limbs, face intestinal tract & airways. Hereditary Angio-Oedema is caused by a deficiency of C1 inhibtor. C1 is a complement protein that cleaves C2 and C4 to form C3. C1 inhibitor does not only inhibit C1, but Bradykinin too. Uninhibited Bradykinin vastly increases the permeability of endothelia, causing Oedema. Hereditary Angio-Oedema is treated with C1 inhibitor infusion or fresh frozen plasma. α1-antitrpysin Deficiency α1-antitrpysin inhibits Elastase. Without this inhibition elastase breaks down lung/liver tissue Causes emphysema and Liver Sclerosis. Chronic Granulomatous Disease Recessive sex linked Immune phagocytes doesn’t work properly.. Granulomas formed in an attempt to contain the bacteria. People with disease may develop infections in their lungs, skin, lymph nodes, liver & intestine.