‘The Holy Grail’ -mediators of inflammation. Lecture 3 Rod Flower, WHRI, London.
‘Laudable pus’ - the cells of inflammation. Lecture 2 Rod Flower, WHRI, London.
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Transcript of ‘Laudable pus’ - the cells of inflammation. Lecture 2 Rod Flower, WHRI, London.
The components of inflammation.
• Cells..- Fixed cells such as vascular cells.- Migratory cells such as PMNs.
• Mediators..- many chemicals released into the
body.• Immune system..
-Innate.-Acquired.
Migratory cells.
• Platelets.
• Polymorphonuclear leukocytes.
• Macrophage/monocytes.
• Lymphocytes.
• Eosinophils.
• Basophils.
• Dendritic cells.
Platelets.
• Small 2-3m enucleate cells.
• 150-400,000/l blood.
• Derived from megakaryocytes.
• Vital to haemostasis.
• Contain or generate mediators such as amines and eicosanoids.
Polymorphonuclear (PMN) cells.
• Most abundant (>50% total ) 2500-7500/l blood.
• ‘Shock troops’ of the system.• Early involvement in the
response.• Contain many microbiocidal
weapons and enzymes.• Phagocytic.• Short lived.• Crucial to host defence.
Macrophage/monocytes.
• 100-800 /l blood. 6-7% total.
• Blood borne monocytes mature to macrophages in tissues.
• Crucial to antigen presentation.
• Secrete many important mediators and enzymes.
• Phagocytic.• Long lived.
Eosinophils.
• Relatively small population 2.5% total; 50-400/l blood.
• Specialised for anti-parisitic defence.
• Granules contain enzymes and proteins with micro-biocidal properties.
• Important in asthma and allergies.
Lymphocytes.
• 1000-4000/l blood; 30% total cells.
• Specialised for the production of antibodies and immune recognition.
• T- and B - cells.• NK cells.• Homing properties.
Basophils.
• 1-100/l blood; 0.5% total cells.
• Circulate in blood and ‘home' into tissues.
• Precursors of mast cells.
Dendritic cells.
• Macrophage – like cells.
• Distributed in blood and tissues.
• Long cytoplasmic processes.
• Intimate contact with lymphocytes.
• Play a key role in early host defence.
Fixed cells.
• Vascular endothelial cells.
• Liver cells.
• Airway cells.
• Nervous tissue.
• Many other cell types.
Vascular endothelial cells.
• Have a barrier function but can undergo fenestration.
• Contain adhesion molecules crucial for cell transmigration.
• Can elaborate mediators such as NO, PGI2.
Liver cells.
• Liver cells especially Kupffer cells are involved in phagocytic functions.
• The liver elaborates ‘acute phase’ proteins.
Airway cells.
• Airway epithelial, and other, cells play a crucial role in host defence and elaborate mucus and micro-biocidal enzymes.
• Especially important in asthma and allergies.
Nervous tissue.
• Obviously important in pain transmission.
• Many receptors and enzymes in DRG cells and elsewhere are upregulated during inflammation.
• Cranial nerves and CNS structures are also important.
Many other cells and tissues.
• Inflammation can affect virtually any structure in the body!
• Follows physical trauma, injury or infection.
Two ‘types’ of inflammation.
• Acute…- short lived- doesn’t always involve the immune system.- healing usually occurs.- little systemic disease.
• Chronic…- long lived.- often inappropriate.- healing poor or absent.- tends to be the most usual indication for therapy.- often severe systemic effects including bone and cartilage breakdown.
The healing response.
• The ultimate objective of inflammation, it involves…- angiogenesis.- remodelling of damaged tissues.- the correct hormonal and cytokine milieu.- sometimes migrating cells also play a role (e.g.platelets).
What goes on at the tissue level in inflammation?
• Vascular ‘fenestration’ and plasma leakage.
• Cellular degranulation.
• Leukocyte migration.
• Liver acute phase response.
Vascular changes.
• Post-capillary venules most important site.
• Extravasation of plasma proteins e.g. immunoglobulins.
• Role of PMNs in this process.
• Promotes access of protective proteins to invading organisms.
Cellular degranulation.
• Principally by PMN, monocytes, eosinophils, platelets and mast cells.
• The latter release enzymes, histamine and eicosanoids.
• Very important in allergic reactions and asthma.
Leukocyte emigration.
• Dutrochet first reported leukocyte emigration in 1824.
• Addison first induced the phenomenon experimentally in 1843.
• Multi-step paradigm for emigration developed from 1970s-1990s by several groups.
• Leukocyte emigration important in many pathologies (Epstein, 1989).
Leukocyte emigration.
• Mainly PMN, monocytes and eosinophils.
• Mediated by adhesion molecules.
• Brings cells into contact with microorganisms.
• Crucial to host defence.
Adhesion molecules.
• Reversible interaction with L-selectin responsible for rolling phenomena.
• More stable adhesion mediated through increases in ICAM-1 and VCAM-1.
• Integrins (1 & 2) mediate a stable adhesion and have important signalling properties.
• Most of these adhesion molecules are up-regulated during inflammation in response to cytokines etc.
Acute phase response.
• A diverse collection of proteins and factors including, protease and other enzyme inhibitors.
• Released in from the liver in response to many forms of inflammatory response.
• Often accompanied by a fall in albumin synthesis.
• Clinically useful marker.
Summary of lecture 2.
• Many cells participate in the development of the inflammatory response.
• Migrating cells are particularly crucial.
• Fixed tissues such as the liver secrete factors which help co-ordinate the response.
Picture credits.
• Life Art.• Austrian Rheumatology Teaching slides.• ‘Mediators of Inflammation’, GP Lewis .• ‘Cellular and Molecular Immunology’, Abbas et al.• N Goulding.• St Barts Hospital Medical Illustration service.• A du Vivier.• Leo & Astra.• ‘Atlas of Clinical Endocrinology’, Besser et al.