Inflammation I

Early events & terminology

PATH2220

Dr Sonia Fernandez

Inflammation – an overview

• The response of living tissues to injury

– The goal of the inflammatory reaction is to bring leukocytes and plasma proteins normally circulating in blood to the site of infection or tissue damage, eliminate the causative agent and initiate healing

• Is it harmful or beneficial?

– Generally beneficial - essential for survival

– If very severe or if unable to eradicate causative agent or if inappropriately directed (eg against host) inflammatory reaction may cause damage

Types of inflammation

• Classified as chronic or acute BUT some overlap exists

Feature Acute Chronic

Onset Fast: minutes or hours Slow: days, months or years

Cells involved Mainly neutrophils Monocytes/macrophages, lymphocytes

Tissue injury, fibrosis Mild, self limited Often severe, progressive

Local and systemic signs Prominent Less prominent

A common inflammatory condition

• Skin furuncle (boil) – inflammation of the skin caused by Staphylococcus

Cardinal signs of inflammation

Cardinal signs of inflammation

• 4 cardinal signs of Celsus (1st century AD)

– Rubor (redness)

• Increased blood flow

– Calor (heat)

• Increased blood flow

– Tumor (swelling)

• Leakage of cells and fluid into tissues

– Dolor (pain)

• Increased nerve sensitivity due to chemical mediators

• 5th sign added by Virchow (19th century)

– Function laesa (loss function)

Causes of inflammation

• Infective agents

– bacteria, viruses, parasites

• Foreign bodies

– dirt, splinters, suture material, implants

• Immune reactions

– allergic, hypersensitivity & autoimmune reactions

• Tissue necrosis (death)

– multiple causes

• Physical agents

– trauma, heat, cold, irradiation

• Chemical agents

– drugs, toxins

The inflammatory process

• Offending agent is recognized by host cells and molecules which then produce chemical mediators

• Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent is located

• Leukocytes and proteins are activated to destroy and eliminate the offending substance

• The reaction is controlled and terminated

• The damaged tissue is repaired

Inflammatory responses: two components

• Vascular changes that maximize movement of proteins and leukocytes from circulation to site of infection/injury

– Vasodilation - changes in calibre of vessels

– Changes in blood flow (increased at first, later slows)

– Changes in permeability (leakage of fluid and protein)

• Cellular events that recruit leukocytes to site of infection/injury and allow them to effect a response

– Leukocyte migration through endothelium (emigration)

– Migration of leukocytes to site of injury (chemotaxis)

– Recognition/removal of offending agent by phagocytes (phagocytosis)

– Other leukocyte responses – initiation of repair process

Vascular changes

• Vasodilation– action of mediators (eg histamine) on

vascular smooth muscle

– initial constriction (transient)

– arterioles dilate followed by capillary bed expansion

– increased blood flow → redness & heat

• Increased permeability– outpouring of protein rich fluid into the

extravascular tissues – EXUDATE

– swelling (edema)

• Cellular emigration occurs last

Normal

Inflamed

Vascular changes• Changes to permeability can

occur in two ways

1. Retraction of endothelial cells– Mediators cause endothelial cell

contraction

– Gaps appear between endothelial cells

2. Endothelial injury– Direct damage caused by burns,

microbial toxins

• End result is the same– Fluid and proteins escape

– small molecules first, fibrinogen last (cells later)

– ↑ osmotic pressure of tissue

– swelling

Chemical mediators of the vascular response

Mediator Principle Source Actions

Histamine Mast cells, platelets, basophils

Vasodilation, ↑ permeability, endothelial

activation

Seretonin Platelets Vasodilation, ↑ permeability

Prostaglandins Mast cells, leukocytes

Dilation (+ pain, fever)

Leukotrienes Mast cells, leukocytes

↑ permeability

Platelet-activating factor

Leukocytes, mast cells

Vasodilation, ↑ permeability

Cytokines TNF, IL-1 Macrophages, EC, mast cells

Endothelial activation (+ pain, fever, metabolic abnormalities)

Complement Plasma protein (liver)

Vasodilation

Kinins Plasma protein (liver)

Vasodilation, ↑ permeability

(+ pain)

Proteases activated during coagulation

Plasma proteins (liver)

Endothelial activation

Cellular events

• Leukocytes that are recruited to sites of inflammation perform the key function of eliminating the offending agents following their activation

• Most important leukocytes in typical inflammatory reactions are the ones capable of phagocytosis

• Neutrophils – rapidly recruited to sites of inflammation

– use cytoskeletal rearrangements & enzyme assembly to mount rapid, transient response

• Macrophages– slower responders

– ingest and destroy microbes, necrotic tissue and foreign substances

– produce growth factors that aid in repair

Cellular events – leukocyte emigration

• Infectious microbes that breach the epithelium are recognised by sub-epithelial dendritic cells and macrophages

• These cells respond by producing cytokines & chemokines

• Cytokines (TNF and IL-1) act on the endothelium of venules near the site of infection to initiate leukocyte emigration into tissues

• Chemokines provide signals to leukocytes to help them traffic to the site of infection once they have migrated into tissues – this is known as chemotaxis

Cellular events – leukocyte emigration

Cellular events – leukocyte emigration• Loose attachment & rolling of leukocytes

– in response to cytokines, endothelial cells upregulate expression of adhesion molecules called selectins

– selectins bind to surface carbohydrates on leukocytes

– repetitive process of leukocytes becoming tethered to the endothelium, flowing blood disrupting binding and bonds reforming downstream

• Firm adhesion

– in response to chemokines, integrins expressed on leukocytes assume a high-affinity state

– endothelial cells upregulate expression of adhesion molecules ICAM-1 and VCAM-1 that bind to integrins expressed by leukocytes

– firm binding of integrins to their ligands arrests the rolling, cytoskeleton of leukocytes is reorganised such that they spread out on the endothelial surface

• Leukocyte migration

– chemokines stimulate the motility of leukocytes, as do bacterial products and products of complement activation

– leukocytes begin to migrate between endothelial cells, through the vessel wall and along the concentration gradient of these chemoattractants

Cellular events - chemotaxis

Cellular events - chemotaxis

• Movement of leukocytes after emigration towards an increasing concentration of a chemotactic agent (usually a protein or polypeptide)

• Both exogenous and endogenous substances can act as chemoattractants

– Bacterial products

– Chemokines

– Complement components (C5a)

Microscopic changes in early inflammation

Cellular events – leukocyte activation

• Leukocytes require activation in order to perform their many functions

• Both neutrophils and macrophages can become activated

• Activation is induced by a variety of chemical mediators

• Following activation, leukocytes are capable of:

– phagocytosis

– lysis/killing of injurious particles

– release of further chemical mediators

Cellular events - phagocytosis• The process by which neutrophils and

macrophages ingest debris / foreign particles

• 3 phases

1. Recognition and attachment by receptors on surface of macrophages– Mannose receptor binds to mannose, fructose on

bacteria

– Scavenger receptors

– Opsonins (IgG/C3/some lectins)

2. Engulfment– Pseudopods form around organism

– Foreign material incorporated within cell vacuole (phagosome)

– Fusion with lysosomes and release of lysosomal contents

3. Killing and degradation– Reactive oxygen species, nitric oxide, lysosomal enzymes

Cellular events - phagocytosis

• Macrophage (lives months-years)

• Successful kill may be accomplished

• If bacteria persist may remain at site or move via lymphatics to other areas

• All debris including dead polymorphs gradually removed

• Antigenic material presented to immune system

• Release of enzymes, oxidising agents into tissues can cause ongoing damage eg rheumatoid disease

Sequelae of phagocytosis

• Neutrophil (lives 1-2 days)

• Lysosomal enzymes discharged

into vacuole

• Oxidising agents may kill or digest

bacteria

• Neutrophil degranulates released

enzymes may cause injury

• Virulent bacteria may resist killing

• Bacteria liberated as cell dies and

can cause further damage

Chemical mediators of the cellular response

Mediator Principle Source Actions

Leukotrienes Mast cells, leukocytes Chemotaxis, leukocyte adhesion & activation

PAF Mast cells, leukocytes Leukocyte adhesion, chemotaxis, degranulation, oxidative burst

Cytokines MP, EC, Mast cells Endothelial activation (expression of adhesion molecules)

Nitric oxide Endothelium, MP Killing of microbes

Reactive O2 sp. Leukocytes Killing of microbes

Chemokines Leukocytes,active MP Chemotaxis, leukocyte activation

Complement Plasma (liver) Leukocyte chemotaxis & activation

Proteases Plasma (liver) Endothelial activation, WBC recruitment

MP – macrophages, EC – endothelial cells

Summary of vascular and cellular events

Outcomes of acute inflammation

• Ideal outcome: the harmful agent will be removed or killed and the damaged tissue will return to nomal = RESOLUTION

• Other outcomes are possible – next lecture

Resolution

• Restoration of tissue to a completely normal state after acute inflammation or other tissue damage or death

• Most likely to occur:

– when cell death and tissue damage is minimal

– when damaged cells are capable of regeneration

– when causative organism is rapidly eliminated

– where local conditions favour removal of exudate

The process of resolution

• Fibrin and other proteins dissolved by fibrinolysin and enzymes produced by neutrophils and macrophages

• Fluid removed in blood and lymphatic vessels

• Removal of all debris by phagocytes to lymph nodes

• Blood flow returns to normal

Classification of inflammation

1. Acute or chronic

– previously discussed

Classification of inflammation

1. Acute or chronic

2. According to site

Classification of inflammation

1. Acute or chronic

2. According to site

3. According to predominant component of exudate

Serous exudate

Fibrinous pericarditis

Classification of inflammation

1. Acute or chronic

2. According to site

3. According to predominant component of exudate

4. According to morphology – shape & anatomy

Gastric Ulcer