‘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 2-3  m enucleate cells ,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 ) /  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 /  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; /  l blood. Specialised for anti-parisitic defence. Granules contain enzymes and proteins with micro- biocidal properties. Important in asthma and allergies.

Lymphocytes /  l blood; 30% total cells. Specialised for the production of antibodies and immune recognition. T- and B - cells. NK cells. Homing properties.

Basophils /  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, PGI 2.

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 Addison first induced the phenomenon experimentally in 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.