‘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.

• L-selectins.• V- CAM & I- CAM.• Integrins.• PECAM.

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.

Cellular migration - free flowing.

PMN

Vascular endothelium

Direction of blood flow

- selectin adhesion.

selectins

!

- integrin attachment, signalling.

integrins

!

- shape change.

!

- pseudopodia formation.

PECAM!

- extravasation..

!

- full migration.

!

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.