Inflammation: An Overview

• RA1 week 5 is about inflammation
• Experiment

Historical Context - Inflammation

• Celsus (ca 30 BC - ca 45): Defined characteristics of inflammation.
  • Rubor: Redness
  • Tumor: Swelling
  • Calor: Warmth
  • Dolor: Pain
• Virchow (1821-1902): Added functio laesa.
  • Functio Laesa: Disturbed function

Inflammation Overview

• Local reaction to damage.
• Occurs in vascularized tissue.
• Objective of inflammation: Neutralize, clean up, and restore.
• Requires good regulation.

Naming Inflammation

• Inflammation naming convention: [Organ/tissue]-itis.

Components of Acute Inflammation

• Vascular component: Local increase in blood flow.
• Exudative component: Leakage of protein-rich fluid from vessels.
• Cellular component: Migration and activation of leukocytes, mainly neutrophils in the acute phase.
• Proliferative component: Tissue regeneration, granulation tissue, healing.

Circulation

• Blood moves in a continuous circuit throughout the body
• Oxygenated blood is pumped from the lungs and throughout the body
• Deoxygenated blood is returned to the lungs

Blood Flow Velocity

• Blood flow velocity is affected by the total vascular cross-sectional area
• Arterial flow has a higher velocity relative to venous flow

Normal Arterioles

• In a normal scenario, arterioles feed a network of capillaries
• This network has a preferred channel, with an outgoing venue

Acute Inflammation Arterioles

• During inflammation, arterioles are extremely dilated
• This is due to a reduced smooth muscle contraction of the arteriole walls
• Capillaries are strongly suffused with blood
• Venue is relatively less dilated, thus reducing flow and causing blockage

Passive Hyperemia

• Passive Hyperemia leads to blockage, congestion
• Can lead to liver damage

Fluid Output during Inflammation

• Hydrostatic pressure is normally equal to Colloid osmotic pressure
• Healthy: there is no net fluid or protein leakage
• Exudate: High protein content, containing white and red blood cells occurs locally
• Transudate: Low protein content leaks systemically. May be caused by venous outflow obstruction

Exudation

• Occurs primarily from post-capillary venules

Endothelial Damage

• Endothelial damage can lead to bleeding and hemorrhage

Blood Composition

• Plasma: Liquid phase after centrifuging uncoagulated blood.
• Serum: Liquid phase after centrifuging coagulated blood.

Exudative Component Composition

• Normal: Mostly water and small molecules.
• Transudate: More than normal, little proteins, and no cells.
• Exudate: Depends on the size of endothelial openings.
  • Small: Serous exudate, mainly with transudate and much protein.
  • Large: Fibrinous exudate, serous exudate plus large proteins, including fibrinogen leading to fibrin.
• Edema: Volume increase in tissue due to transudate or exudate.
• Pus: Purulent exudate, rich in leukocytes, cell debris, often microorganisms.

Fibrin-Mediated Adhesions

• Can cause complications

Circulation Changes During Marginating

• Normal: Laminar, axial flow in blood vessels.
• Acute Inflammation: Fluid exits post-capillary venules causing stasis.
  • Lower Stream Speed increases viscosity, and increases fibrinogen causing turbulent movement
• Margination: Neutrophils marginate.

Rouleaux Formation

• Rouleaux: A stack of red blood cells which form because of the unique discoid shape of the cells in vertebrate blood

Rouleaux and margination

Additional components of acute inflammation listed again:

• Vascular component: Local increase in blood flow.
• Exudative component: Leakage of protein-rich fluid from vessels.
• Cellular component: Migration and activation of leukocytes(esp. neutrophils in acute phase).
• Proliferative component: Tissue regeneration, granulation tissue, healing.

Cellular Component

• Occurs at the myocardium infarct

Neutrophil Granulocyte Migration

• Neutrophils migrate via Integrin activation of chemokines

Rolling, Adhesion, Diapedesis

• Rolling, adhesion, diapedesis steps of a leukocyte

Emigration/Transmigration/Diapedesis

Exudation and Emigration Differences

• In post-capillary venules, but not through the same openings (different processes).
• Exudation is caused by vaso-active inflammatory mediators.
• Emigration requires activation of both endothelium and leukocytes.

Adhesion Interactions Regulated

• Redistribution: Stored molecules in Weibel-Palade bodies (e.g., P-selectin) are moved to the endothelial cell surface due to inflammatory mediators.
• Induction: Synthesis and surface expression of adhesion molecules (e.g., E-selectin) on endothelium.
• Increased Binding Avidity: Integrins become more active (LFA-1, Mac-1, VLA-4) on leukocyte surface.

Integrin Signalling Activation

• Integrin signalling activates binding

Leukocyte Adhesion Deficiency

• Impaired leukocyte adhesion, leading to recurrent bacterial infections.
• LAD type I: CD18 mutations result in no or non-functional expression of LFA-1 and Mac-1 integrins.
• LAD type II: Defect in fucose metabolism, causing no expression of sialyl-Lewis X.

Removing, killing, and Breaking Down

Additional Notes on Killing and Degradation

• Can also effect own surrounded tissue --> causes extra necrosis

Neutrophil Extracellular Traps (NETs)

• They trap bacteria via extracellular neutrophil

Cytoskeleton Polarization

• Occurs during Chemotaxis