Lecture 2.1 - Acute inflammation

Inflammation

• Inflammation is a rapid response to injury of vascularized living tissue, delivering defensive materials (white blood cells and fluid containing plasma proteins) to the site of injury.
• It is a protective response, but can cause local and systemic complications.

Causes of Inflammation

• Foreign bodies (splinters, dirt, sutures)
• Immune reactions
• Infections (bacterial, viral, parasitic) and microbial toxins
• Trauma (blunt and penetrating)
• Physical and chemical agents (thermal injury, e.g., burns or frostbite, irradiation, environmental chemicals)

Clinical Signs

• Vasodilation of blood vessels (RUBOR)
• Loss of function (enforces rest and reduces the chance of further damage)

Vascular Changes

• Changes in blood flow
• Movement of fluid into tissue (vascular phase)
• Starling's law: fluid movement controlled by the balance between hydrostatic pressure and oncotic pressure
• Increased capillary hydrostatic pressure = increased fluid flow out of vessel
• Increased interstitial oncotic pressure = increased fluid flow out of vessel

Acute Inflammation

• Vasodilation = increased capillary hydrostatic pressure
• Increased vessel permeability = loss of plasma proteins into interstitium (increased interstitial oncotic pressure)
• Net flow of fluid OUT of vessel INTO interstitium
• Oedema (swelling, TUMOUR)

Types of Interstitial Fluid

• Exudate:
  • Occurs in inflammation
  • Increased vascular permeability
  • Protein-rich (delivering proteins to area of injury)
• Transudate:
  • Fluid loss due to increased capillary hydrostatic pressure or reduced capillary oncotic pressure
  • No change of vascular permeability - therefore less protein present
  • Occurs in heart failure, hepatic failure, renal failure - systemic problems

Mechanisms of Increased Vascular Permeability

• Endothelial contraction (gaps between endothelial cells)
  • Histamine, leukotrienes
• Endothelial cytoskeleton reorganization (change of shape increases gaps between them)
  • Cytokines IL-1 beta, TNF alpha
• Direct injury:
  • Chemical, toxic burns
• Leucocyte-dependent injury:
  • Enzymes and toxic oxygen species from leucocytes

Neutrophils

• The primary white blood cell involved in acute inflammation
• Trilobed nucleus
• A granulocyte
• Chemotaxis and neutrophil infiltration:
  • Stasis causes neutrophils to line up at the edge of blood vessels along the endothelium (MARGINATION)
  • Neutrophils then roll along endothelium, sticking to it intermittently (ROLLING)
  • Then stick more avidly - use of adhesion molecules (ADHESION)
  • Followed by EMIGRATION of neutrophils through blood vessel wall

Adhesion Molecules

• Selectins:
  • On endothelial cell surface
  • Upregulated by chemical mediators
• Integrins:
  • On neutrophil surface
  • Bind to receptors on endothelial surface

Inflammatory Infiltrate

• How do neutrophils move through the interstitium?
  • Chemotaxis:
    • Movement along a chemical gradient of chemoattractants
    • Rearrangement of neutrophil cytoskeleton
    • Pseudopod formation

What Do Neutrophils Do?

• Phagocytosis:
  • Phagosomes fuse with lysosomes
  • Produce secondary phagolysosomes

How Do Inflammatory Cells Limit Damage?

• Removal of toxins and pathogenic organisms
• Removal of necrotic tissue
• Release of chemical mediators stimulates and regulates further inflammation
• Stimulates pain (encourages rest and limits risk of further damage)

Why Is Acute Inflammation Effective?

• Vascular phase:
  • Exudation of fluid into interstitium (oedema)
  • Dilute toxin effect
• Cellular phase:
  • Infiltration of neutrophils
  • Kills pathogens

How Does Oedema Limit Damage?

• Dilutes toxins
• Delivers plasma proteins to area of injury
• Fibrin (mesh limits spread of toxin)
• Inflammatory mediators - stimulates and regulates further inflammation
• Immunoglobulins - regulates the process
• Increased lymphatic draining from area of injury

Chemical Mediators

• A vast array of chemicals that contribute to the inflammatory process
• Overlapping functions
• Varying chemical structures
• Some circulate in an inactive state in blood
• Released by:
  • Activated inflammatory cells
  • Platelets
  • Endothelial cells

Chemical Mediators at Each Step

• Vasodilation:
  • Histamine, serotonin, prostaglandins, nitric oxide
• Increased vascular permeability:
  • Histamine, bradykinins, leukotrienes, C3a, and C5a
• Chemotaxis:
  • C5a, LTB4, TNF-alpha, IL-1 beta, IL8, bacterial peptides
• Fever:
  • Prostaglandins, IL-1 beta, TNF-alpha, IL-6
• Pain:
  • Bradykinin, substance P, prostaglandins

Local Complications

• Swelling:
  • Blockage of nearby tubes and ducts (bile duct/intestines)
• Exudate:
  • Compression of organs
  • E.g. complete resolution, abscess, chronic inflammation, and fibrous repair

Complete Resolution

• All changes gradually reverse:
  • Resolution is absolutely vital
  • Neutrophils no longer marginate
  • Vascular permeability returns to normal
  • Vessel calibre
• Therefore:
  • Exudate drains away via lymphatics
  • Fibrin is degraded
  • Neutrophils die, break up, and get phagocytosed
  • Damaged tissue may be able to regenerate, if architecture is preserved
  • Mediators are diluted/inactivated/degraded

Clinical Examples

• Appendicitis:
  • Blocked lumen (commonly faecolith)
  • Accumulation of bacteria, increased pressure, reduced blood flow
• Pneumonia:
  • Many causative organisms
  • Signs and symptoms: shortness of breath, fever, cough, sputum production, chest pain
  • Risk factors: smoking, pre-existing lung condition (COPD, asthma, malignancy)
• Bacterial meningitis:
  • Inflammation of the meninges
  • Caused by a variety of pathogens
  • Clinical signs: neck stiffness, fever, photophobia, altered mental state
  • Rapidly fatal

Abscess

• An accumulation of dead and dying neutrophils
• With associated liquefactive necrosis
• Causes compression of surrounding structures and nerves:
  • Pain, blockage of ducts

Inflammation of Serous Cavities

• Variety of causes:
  • Exudate pours into serous cavity:
    • Ascites - abdominal distension
    • Pleural effusion - shortness of breath
    • Pericardial effusion - cardiac impairment

Disorders of Acute Inflammation

• Rare disorders
• Illustrate the complex mechanisms of acute inflammation
• Hereditary angio-oedema:
  • Autosomal dominant condition
  • Inherited deficiency of C1-esterase inhibitor
  • Patients have attacks of non-itchy cutaneous angio-oedema
  • Recurrent abdominal pain due to intestinal oedema
  • Family history of sudden death due to laryngeal involvement
• Alpha-1 antitrypsin deficiency:
  • Autosomal recessive disorder
  • Varying levels of severity
  • Low levels of alpha-1 antitrypsin
  • Patients develop emphysema
  • Liver disease also occurs
• Chronic granulomatous disease:
  • Genetic condition
  • Phagocytes are unable to generate the free radical superoxide
  • Bacteria are phagocytosed but phagocytes cannot kill them
  • Results in many chronic infections in the first year of life