CHAPTER 4INFLAMMATION & WOUND

HEALING.BY

DR. UCHE AMAEFUNA-OBASI

•THERE ARE MORE TO LECTURES THAN LECTURE SLIDES

Definition of Inflammation.• It is a localized physical condition in which part

of the body becomes reddened, swollen, hot, and often painful, especially as a reaction to injury or infection.

The five classic signs of acute inflammation.• Redness.• Heat.• Swelling.• Pain.• Loss of function.

Rubor

Calor

Tumor

Dolor

5th (functio laesa)

HISTORICAL

HIGHLIGHTS(Egypt, 3000 BC)

Effects of Inflammation• Elimination of the cause of cell injury.• Elimination of the necrotic cells.• Paves the way for repair.• May lead to harmful results.

Nomenclature• -itis (after the name of a tissue) e.g.• Appendix Appendicitis• Dermis Dermatitis• Gallbladder Cholecystitis • Duodenum Duodenitis • Meninges Meningitis, etc.

Causes:• Microbial infections: bacteria, viruses, fungi,

parasites.• Immunologic: hypersensitivity (contact with

some substances), autoimmune reactions.• Physical agents: trauma, heat, cold, ionizing

radiation, etc. • Chemical agents: acids, alkali, bacterial toxins,

metals, etc.

• Foreign materials: sutures, dirt, etc• Tissue necrosis: ischemic necrosis.

The participants• 1. White blood cells and platelets:

Neutrophils, monocytes,lymphocytes, eosinophils,basophils.

• 2. Plasma proteins: Coagulation /fibrinolytic system, kinin system, complement system.

• 3. Endothelial cells and smooth muscles of vessels.

• 4. Extracellular matrix and stromal cells- Mast cells, fibroblasts, macrophages &

lymphocytes.- Structural fibrous proteins, adhesive

glycoproteins, proteoglycans, basement membrane.

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 2-3mm enucleate cells.

• 150-400,000/ml 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/ml 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 /ml 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/ml blood.

• Specialised for anti-parisitic defence.

• Granules contain enzymes and proteins with micro-biocidal properties.

• Important in asthma and allergies.

Lymphocytes.

• 1000-4000/ml blood; 30% total cells.

• Specialised for the production of antibodies and immune recognition.

• T- and B - cells.• NK cells.• Homing properties.

Basophils.

• 1-100/ml 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 (dorsal root ganglion) cells and elsewhere are up regulated 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.

Acute inflammation• Duration: minutes to days. • Predominance of neutrophils.• Fluid & plasma protein exudation.Chronic inflammation• Duration: days to years. • Predominance of lymphocytes and

macrphages. • Vascular proliferation and fibrosis.

Acute Inflammation• Early response of vascularized tissue toinjury.• Aim of acute inflammation:• Recruitment of neutrophils (1st 3days), and

monocytes (after 3days) to clear the cause of injury and remove necrotic cells.

• Deliver plasma proteins: antibodies, complement, others.

The two components of acute inflammation.

Vascular changes• Vasodilatation. • Increased vascular permeability. • Stasis.Cellular events• Emigration of cells from micro vessels. • Accumulation at sites of injury.The process is orchestrated by release of chemical

mediators.

Cellular Events

• Margination, rolling and adhesion.• Transmigration between endothelial cells.• Migration in the interstitium toward the site of

stimulus.• Phagocytosis and degranulation.• Release of leukocyte products.

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 (PolyMorphonuclear Neutrophil), 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 (b1 & b2) 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.

Causes of chronic inflammation •Persistent injury or infection –Ulcer, tuberculosis •Prolonged exposure to a toxic agent –Pulmonary silicosis (silica in the lung) •Autoimmune disease—self-perpetuating immune reaction that results in tissue damage and inflammation –Rheumatoid arthritis –Systemic lupus erythematosus–Multiple sclerosis