Inflammation and Its Purposes

Inflammation

• A localized response to injury in vascularized living tissue.
• A protective response triggered by injury to eliminate the cause of injury and necrotic cells/tissues.
• Can be harmful.
• Intimately associated with repair processes.
• Inflammatory lesions are often indicated by the suffix, "itis."

Inflammation Purpose

• Localize and eliminate the causative agent.
• Limit tissue injury.
• Begin the process of healing.

Inflammation Causes

• Infectious agents (bacterial, viral, parasitic, fungal).
• Physical agents (trauma, burns, radiation, extreme temperatures).
• Chemical agents (acids, alkalis, toxins).
• Immune reactions (allergies, autoimmune diseases, hypersensitivity).
• Necrotic tissue.

Types of Inflammation

• Acute inflammation: Minutes to days. Characterized by fluid and protein, dominated by neutrophils.
• Chronic inflammation: Weeks to years. Characterized by mononuclear cells (macrophages, lymphocytes, plasma cells).

Five Classic Signs of Acute Inflammation

• Heat (Calor): Caused by increased blood flow.
• Redness (Rubor): Caused by increased blood flow.
• Swelling (Tumor): Caused by fluid accumulation.
• Pain (Dolor): Caused by chemical mediators, pressure from swelling.
• Loss of function (Functio laesa): Caused by swelling, pain, tissue destruction.

Two Major Events in Acute Inflammation

• Vascular response: Transient vasoconstriction followed by vasodilation, and increased vascular permeability.
• Cellular response: Extravasation of neutrophils.

Reasons for Increased Vascular Permeability

• Increased hydrostatic pressure: "Pushing pressure" forces fluid out of blood vessels.
• Decreased intravascular osmotic pressure: Less "pulling power" inside blood vessels retains fluid.
• Endothelial cell changes: Cells become leaky.

Outcomes of Increased Vascular Permeability

• Transudate: Watery fluid with low protein content. Forms due to imbalances in pressure.
• Exudate: Thicker fluid, rich in proteins and immune cells (neutrophils). Forms during inflammation.

Cellular Response - Key Points

• Margination: As blood slows, leukocytes move to the periphery of the vessel.
• Endothelial cell activation: Cytokines activate endothelium, causing selectins and other mediators to move to the surface.
• Rolling: Neutrophils roll and transiently adhere to endothelial cells, mediated by selectins.
• Neutrophil activation: Mediated by interleukin-8 (IL-8) and other chemokines.
• Firm adhesion (pavementing): Mediated by intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-1 (LFA-1).
• Transmigration (diapedesis): Mediated by platelet endothelial cell adhesion molecule-1 (PECAM-1). Cells crawl through vessel walls.
• Chemotaxis: Movement toward the site of injury mediated by chemokines (chemical attractants for cells ).

Neutrophil Functions

• Primary granules: Contain myeloperoxidase (MPO) and other enzymes.
• Secondary granules: Contain collagenase and chitinase 3-like 1 (CHI3L1).
• Tertiary granules: Contain matrix metalloproteinases (MMPs) and other enzymes.
• Neutrophils express receptors: Recognize pathogen-associated molecular patterns (PAMPs) from pathogens and damage-associated molecular patterns (DAMPs) from injured cells.

Antimicrobial Mechanisms of Neutrophils

• Phagocytosis: Ingestion of microorganisms into a phagocytotic vacuole, which fuses with lysosomes to destroy the microbe.
• Oxidative burst: Release of reactive oxygen species (ROS) such as superoxide ion (O2-), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), hydroxyl radical (OH), and nitric oxide (NO).
• Degranulation: Release of granule contents into the environment.
• Neutrophil extracellular traps (NETs): Form by releasing net like structures of DNA, histones, etc., to trap pathogens.

Reactive Oxygen Species

• Eliminate bacteria.
• Can damage tissues.

Chemical Mediators of Inflammation

• Most bind to cell surface receptors, while some act directly through enzymatic or toxic activity.
• Tightly regulated.

Vasoactive Amines:

• Histamine: Found in mast cells, basophils, and platelets. Promotes arteriolar dilation and venular endothelial contraction, increasing vascular permeability.
• Serotonin (5-HT): Similar vasoactive effects to histamine. Found in platelets, released during platelet aggregation.

Complement System

• Classical pathway: Antibody-dependent activation (antigen-antibody complex) to activate C1.
• Alternative pathway: Antibody-independent activation.

Membrane Attack Complex (MAC)

• Forms pores in cell membranes.

Role of C3a and C5a in Inflammation

• C3a and C5a: Anaphylatoxins that cause mast cell degranulation, smooth muscle contraction, and increased vascular permeability.

Blood Coagulation System

• Factor XII (Hageman factor): Activated during inflammation, triggering the coagulation cascade.

Kallikrein-Bradykinin System

• Bradykinin: A potent vasodilator and pain mediator.

Arachidonic Acid Pathway

• Arachidonic acid: A fatty acid released from cell membranes during inflammation.
• Cyclooxygenase (COX) pathway: Leads to the production of prostaglandins and thromboxane A2.
• Lipoxygenase pathway: Leads to the production of leukotrienes and lipoxins.

Fever

• Beneficial effects:
  • Shifts the oxygen-dissociation curve to the right, increasing oxygen availability for cells.
  • Provides a hostile environment for bacterial and viral reproduction.

Effects of Inflammation

• Beneficial:
  • Dilution of toxins.
  • Stimulation of adaptive immunity, arrival of antibodies.
  • Delivery of nutrients and oxygen, drug transport.
  • Formation of fibrin (delays bacterial spread).
  • Destruction of microbial agents.
  • Removal of tissue debris.
• Harmful:
  • Mechanical effects (e.g., epiglottitis).
  • Impaired flow (e.g., acute meningitis).
  • Impaired function.
  • Tissue destruction.

Outcomes of Acute Inflammation

• Resolution: Healing and repair.
• Abscess formation: Walled-off collection of pus.
• Progression to chronic inflammation.

Inflammation Definition

• Inflammation is a localised reaction to injury in vascularised living tissues
• It is a protective response that aims to eliminate the cause of the injury and its byproducts (necrotic cells and tissues)
• Inflammation can be beneficial in the short term
• Inflammation is closely linked to the repair process
• Many inflammatory lesions are identified by the suffix "-itis"

Inflammation Purpose

• Localise and eliminate the causative agent
• Limit tissue injury
• Initiate the healing process

Inflammation Causes

• Infectious agents
• Physical agents
• Chemical agents
• Immune reactions
• Necrotic tissue

Types of Inflammation

• Acute inflammation occurs within minutes to days
  • Characterized by fluid and protein exudation
  • Polymorphonuclear cells (neutrophils) are the primary inflammatory cells
• Chronic inflammation persists for weeks to years
  • Dominated by mononuclear cells (macrophages, lymphocytes, and plasma cells)

Classic Signs of Acute Inflammation

• Heat: Calor
• Redness: Rubor
• Swelling: Tumor
• Pain: Dolor
• Loss of function: Function laesa

Major Events in Acute Inflammation

• Vascular response:
  • Transient vasoconstriction, followed by vasodilatation
  • Increased vascular permeability
• Cellular response:
  • Extravasation of neutrophils (polymorphonuclear leukocytes)

Increased Vascular Permeability Mechanisms

• Increased hydrostatic pressure: Increased pressure inside blood vessels forces fluid out
• Decreased intravascular osmotic pressure: Lower pressure inside vessels reduces fluid retention
• Endothelial cell changes: Damaged or altered endothelial cells allow fluid leakage
• Contraction: Cells shrink, creating gaps between them
• Junctional retraction: Connections between cells loosen, forming spaces
• Injury: Direct damage to endothelial cells leads to gaps

Outcomes of Increased Vascular Permeability

• Transudate: Watery fluid with few proteins, primarily due to pressure imbalances
• Exudate: Thick fluid rich in proteins and inflammatory cells like neutrophils, characteristic of inflammation

Cellular Response Key Points

• Margination: As blood flow slows, leukocytes move to the periphery of blood vessels.
• Endothelial cell activation: Cytokines activate endothelial cells, causing selectins and other mediators to surface.
• Rolling: Neutrophils transiently adhere to endothelial cells, facilitated by selectins.
• Neutrophil activation: Triggered by chemokines, like IL-8, preparing neutrophils for firm adhesion.
• Firm adhesion (pavementing): Through ICAM-1-LFA-1 binding neutrophils firmly adhere to endothelium.
• Transmigration: Mediated by PECAM-1, neutrophils crawl through endothelial gaps (diapedesis).
• Chemotaxis: Movement towards the injury site guided by chemokines.

Neutrophil Functions

• Primary granules: Contain myeloperoxidase (MPO) and other enzymes.
• Secondary granules: Include collagenase and CHI3L1 (chitinase 3-like 1).
• Tertiary granules: Contain MMPs and other enzymes.
• Cell surface receptors: Recognize pathogen-associated molecular patterns (PAMPs) from pathogens and damage-associated molecular patterns (DAMPs) from damaged cells.

Neutrophil Antimicrobial Mechanisms

• Phagocytosis: Engulfing microorganisms into a phagosome that fuses with a lysosome to form a phagolysosome for degradation.
• Microorganism destruction: Reactive oxygen species (ROS) are produced, including superoxide ion (O2-), hydrogen peroxide (H2O2), hypochlorous acid (HOCL), hydroxyl radical (OH), and nitric oxide (NO).
• Degranulation: Release of granule contents into the environment, potentially leading to tissue damage.
• Neutrophil extracellular traps (NETs): DNA fibers, histones, and other components form traps to capture pathogens.

Reactive Oxygen Species (ROS)

• Eliminate bacteria
• Cause tissue damage

Chemical Mediators of Inflammation

• Bind to cell surface receptors, although some have direct enzymatic or toxic activity.
• All mediators are tightly regulated.

Vasoactive Amines

• Histamine:
  • Found in mast cells, basophils, and platelets.
  • Causes arteriolar dilation and venular endothelial contraction, increasing vascular permeability.
• Serotonin:
  • Vasoactive effects similar to histamine.
  • Found in platelets.
  • Released during platelet aggregation.

Complement System

• Classical pathway: Requires antibodies for activation (Ag-Ab complex)
  • C1 binds to IgG or IgM bound to antigens
• Alternative pathway: Does not require antibodies for activation

Membrane Attack Complex (MAC)

• Complements system component that forms pores in cell membranes, leading to cell lysis.

Complement Role in Inflammation

• C3a and C5a: Act as anaphylatoxins, triggering mast cell degranulation, histamine release, and other inflammatory responses.

Blood Coagulation System

• Factor XII: Activated by inflammation, initiating the coagulation cascade.

Kallikrein-Bradykinin System

• Bradykinin:
  • Causes vasodilation, increased vascular permeability, and pain.
  • Plays a role in the inflammatory response.

Arachidonic Acid Pathway

• Cyclooxygenase (COX) pathway: Produces prostaglandins, thromboxanes, and prostacyclins.
• Lipoxygenase pathway: Generates leukotrienes and lipoxins.
• Prostaglandins: Involved in vasodilation, pain, and fever.
• Leukotrienes: Attract neutrophils and cause bronchoconstriction.
• Lipoxins: Anti-inflammatory mediators.

Fever

• Beneficial effects:
  • Shifts the oxygen-dissociation curve to the right, increasing oxygen availability.
  • Creates an unfavorable environment for bacterial and viral reproduction.

Effects of Inflammation

• Beneficial:
  • Dilution of toxins
  • Stimulation of adaptive immunity, antibody delivery
  • Nutrient and oxygen supply, drug transport
  • Fibrin formation, delaying bacterial spread
  • Destruction of microbial agents
  • Removal of tissue debris
• Harmful:
  • Mechanical effects (e.g., epiglottitis)
  • Impaired flow (e.g., acute meningitis)
  • Impaired function
  • Tissue destruction

Outcomes of Acute Inflammation

• Resolution: Healing and repair
• Abscess formation: Walled-off collection of pus
• ** Progression to chronic inflammation:** Persistent inflammation with a shift in cell types.

Inflammation

• A reaction of a vascularized living tissue to injury
• Protective response to eliminate the source of injury and infected cells
• Plays a role in tissue repair
• Inflammatory lesions often indicated by the suffix "itis"

Aims of inflammation

• Localize and eliminate the causative agent
• Limit tissue injury
• Begin the process of healing

Causes of inflammation

• Infectious agents
• Physical agents
• Chemical agents
• Immune reactions
• Necrotic tissue

Types of Inflammation

• Acute
  • Immediate and early response to injury
  • Characterized by fluid and protein
  • Predominantly involves Polymorphonuclear cells (neutrophils)
• Chronic
  • Onset takes weeks to years
  • Characterized by Mononuclear cells (macrophages, lymphocytes and plasma cells)

Five classic signs of acute inflammation

• Heat (Calor)
• Redness (Rubor)
• Swelling (Tumor)
• Pain (Dolor)
• Loss of function (Function laesa)

Two major events in acute inflammation

• Vascular response
  • Transient vasoconstriction, followed by vasodilatation
  • Increased vascular permeability
• Cellular response
  • Extravasation of neutrophils (polymorphonuclear leucocytes)

Reasons for increased vascular permeability

• Increased hydrostatic pressure (pushing fluid out of blood vessels)
• Decreased intravascular osmotic pressure (less pulling power inside blood vessels)
• Endothelial cell changes (vessel walls become leaky)
• Contraction (cells shrink, creating gaps)
• Junctional retraction (connections between cells pull back)
• Injury (damage to cells creates gaps)

Outcomes of increased vascular permeability

• Transudate
  • Watery fluid with few proteins
  • Occurs due to imbalances in pushing and pulling pressures
• Exudate
  • Thicker fluid, rich in proteins and often with immune cells (neutrophils)
  • Forms during inflammation

Key points of cellular response

• Margination: As blood slows, leucocytes move from the center of the vessel towards the periphery
• Endothelial cell activation: Cytokines activate the endothelium causing selectins and other mediators to move to the surface
• Rolling: Neutrophils transiently adhere to endothelial cells, facilitated by selectins molecules
• Neutrophil activation: Mediated by chemokines, for example IL-8
• Firm adhesion (pavementing): Mediated by ICAM-1-LFA-1 (integrin molecules)
• Transmigration: Mediated by PECAM-1 ... diapedesis (cells crawling through endothelial gaps)
• Chemotaxis: Movement towards the site of injury, mediated by chemokines

Functions of neutrophils

• Primary granules: contain myeloperoxidases (MPO) and other enzymes
• Secondary granules: contain collagenase and CHI3L1 (chitinase 3-like 1)
• Tertiary granules: contain MMPs (matrix metalloproteinases) and other enzymes
• Neutrophils express cell surface receptors that recognize PAMPs (produced by infectious agents) and DAMPs (from injured and dead cells)

Antimicrobial mechanisms of neutrophils

• Phagocytosis: Ingestion of microorganisms into a phagocytic vacuole, which fuses with a lysosome to form a phagolysosome. Microorganisms are destroyed by oxidative burst, with oxygen consumption and glycogenolysis
• Degranulation: Release of granule contents to the environment (which can damage tissue)
• Neutrophil extracellular traps (NETs): Formed by DNA fibres, histones, etc.

Reactive oxygen species (ROS)

• Generated by neutrophils
• Eliminate bacteria
• Contribute to tissue damage

Chemical mediators of inflammation

• Most bind to cell surface receptors, some have direct enzymatic or toxic activity
• Tightly regulated

Vasoactive Amines

• Histamine
  • Found in mast cells, basophils and platelets
  • Promotes arteriolar dilation and venular endothelial contraction, increasing vascular permeability
• Serotonin
  • Vasoactive effects similar to histamine
  • Found in platelets
  • Released when platelets aggregate

Complement system

• Essential part of innate immunity
• Classical Pathway: Requires antibodies to activate (Ag-Ab complex) C1 binds to IgG or IgM that is bound to antigen)
• Alternative Pathway: Does not require antibody to activate

Membrane attack complex (MAC)

• Forms pores in cell membranes, leading to cell lysis

Role of C3a and C5a in inflammation

• Act as anaphylatoxins by inducing mast cell degranulation and histamine release
• C5a also acts as a chemoattractant for neutrophils

Blood coagulation system

• Plays a role in inflammation via factor XII activation

Kallikrein-Bradykinin system

• Activated by Factor XII
• Bradykinin causes vasodilation, increased vascular permeability and pain

Arachidonic Acid pathway

• Produces inflammatory mediators:
  • Prostaglandins: Vasodilation, pain, fever
  • Leukotrienes: Vasoconstriction, bronchospasm, increased vascular permeability
  • Lipoxins: Anti-inflammatory effects

Fever

• Beneficial effects:
  • Shifts oxygen-dissociation curve right, increasing oxygen availability
  • Creates a hostile environment for bacterial and viral reproduction

Effects of inflammation

• Beneficial:
  • Dilution of toxins
  • Stimulation of adaptive immunity
  • Delivery of nutrients and oxygen
  • Formation of fibrin (delays bacterial spread)
  • Destruction of microbial agents
  • Removal of tissue debris
• Harmful:
  • Mechanical effects (e.g., epiglottitis)
  • Impaired flow (e.g., acute meningitis)
  • Impaired function
  • Tissue destruction

Outcomes of acute inflammation

• Resolution: Healing and repair
• Abscess formation: Walled-off collection of pus
• Progression to chronic inflammation