Inflammation Overview and Types

Inflammation

• Inflammation is the reaction of vascularized living tissue to local injury.
• A protective response intended to eliminate the initial cause of cell injury and the necrotic cells and tissues arising from the injury.
• May be harmful.
• Intimately associated with the repair process.
• Inflammatory lesions designated by the suffix "(ITIS)".

Inflammation Purpose

• Localise 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 - minutes to days.
  • Immediate and early response to injury.
  • Characterized by fluid and protein.
  • Polymorphonuclear cells (neutrophils).
• Chronic - weeks to years.
  • 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).

Increased Vascular Permeability

• Increased hydrostatic pressure (increased "pushing pressure" inside blood vessels that forces fluid out).
• Decreased intravascular osmotic pressure (less "pulling power" inside the blood vessels to retain the fluid).
• Endothelial cell changes.
• Contraction.
• Junctional retraction.
• Injury.

Outcomes of Increased Vascular Permeability

• Transudate: Watery fluid with few proteins (imbalance in pushing and pulling pressures).
• Exudate: Thicker fluid rich in proteins and often with immune cells like neutrophils (during inflammation).

Cellular Response - Key Points

• 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 roll along and transiently adhere to the endothelial cells, mediated by selectin molecules (transiently bind to their receptors).
• Neutrophil activation: Mediated e.g., by IL-8.
• Firm adhesion (pavementing): Mediated by ICAM-1-LFA-1.
• Transmigration: mediated by PECAM-1…diapedesis (cells crawling).
• Chemotaxis: Movement toward the site of injury mediated by chemokines.

Functions of Neutrophils

• Primary granules: Myeloperoxidases (MPO) and others.
• Secondary granules: Collagenase and CHI3L1 (also known as chitinase 3-like 1).
• Tertiary granules: MMPs and others.
• Neutrophils express cell surface receptors that recognize pathogen-associated molecular patterns (PAMPs) produced by infectious agents and damage-associated molecular patterns (DAMPs) from injured and dead cells.

Antimocrobial Mechanisms of Neutrophils

• Phagocytosis: Ingestion of the microorganism into a phagocytic vacuole, fuses with lysosome to form phagolysosome. Microorganism is destroyed by oxidative burst with a sudden increase in oxygen consumption and glycogenolysis. Reactive oxygen species are released - superoxide ion O2-, hydrogen peroxide (H2O2), hypochlorous acid (HOCL), hydroxyl radical (OH), nitric oxide (NO).
• Degranulation: Release of granule contents to the environment (tissue damage).
• Neutrophil extracellular traps (NETs): Formed by DNA fibers, histones, etc.

Reactive Oxygen Species

• Elimination of bacteria
• Tissue damage.

Chemical Mediators of Inflammation

• Most bind to cell surface receptors, but some have direct enzymatic or toxic activity.
• All are tightly regulated.

Vasoactive Amines

• Histamine: Found in mast cells, basophils, and platelets. Promotes arteriolar dilation and venular endothelial contraction resulting in widening of inter-endothelial cell junctions with increased vascular permeability.
• Serotonin: Vasoactive effects similar to histamine. Found in platelets. Released when platelets aggregate.

Complement System

• 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)

• Punches a hole in the membrane.

Role in Inflammation (C3A and C5A)

• C3a & C5a are anaphylatoxins:
  • Induce degranulation of mast cells (release histamine).
  • Increase vascular permeability.
  • Attract leucocytes.
• C5a also:
  • Activates neutrophils, macrophages, and endothelial cells.
  • Can be chemotactic for neutrophils.
  • Increase phagocytosis.

Blood Coagulation System

• Factor XII is activated by inflammation.

Kallikrein-Bradykinin System

• Prekallikrein: Activates to kallikrein by exposure to negatively charged surfaces (e.g., collagen, activated platelets, bacterial cell walls).
• Kallikrein: Activated by Factor XII.
• Bradykinin: Increases vascular permeability. Induces pain.

Arachidonic Acid Pathway

• Cyclooxygenase (COX) pathway: Produces prostaglandins (PGI2, PGE2, TXA2). Involved in vasodilation, increased vascular permeability, pain, and fever.
• Lipoxygenase (LOX) pathway: Produces leukotrienes (LTB4, LTC4, LTD4, LTE4). Important in chemotaxis, vasoconstriction, bronchospasm, and increased vascular permeability.

Fever

• Beneficial effects of fever:
  • Oxygen-dissociation curve is shifted right.
  • More oxygen is available.
  • 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 agent.
  • Removal of tissue debris.
• Harmful:
  • Mechanical effect e.g., epiglottitis.
  • Impaired flow e.g., acute meningitis.
  • Impaired function.
  • Tissue destruction.

Outcomes of Acute Inflammation

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

Inflammation Definition

• A reaction of a vascularised living tissue to local injury.
• A protective response intending to eliminate the cause of injury and necrotic cells and tissues.
• May be harmful.
• Inflammation is closely linked to the repair process.
• Inflammatory lesions are usually indicated by the suffix "itis".
• The purpose of inflammation is to localise and eliminate the causative agent, limit tissue injury, and begin the process of healing.

Causes of Inflammation

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

Types of Inflammation

• Acute inflammation:
  • Occurs within minutes to days.
  • An immediate and early response to injury.
  • Characterized by fluid and protein.
  • Dominant cell type is the polymorphonuclear cell (neutrophil).
• Chronic inflammation:
  • Lasts for 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 of Acute Inflammation

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

Increased Vascular Permeability

• Increased hydrostatic pressure: Increased "pushing pressure" inside blood vessels, forcing fluid out.
• Decreased intravascular osmotic pressure: Reduced "pulling power" inside blood vessels to retain fluid.
• Endothelial cell changes: Vessel walls become leaky due to changes in endothelial cells.
• Contraction: Cells shrink, creating gaps.
• Junctional retraction: Connections between cells pull back, creating spaces.
• Injury: Damage to endothelial cells can lead to gaps.

Increased Vascular Permeability Outcomes

• Transudate: Watery fluid with few proteins. Forms when there's an imbalance in pushing and pulling pressures.
• Exudate: Thicker fluid, rich in proteins and immune cells (like neutrophils). Forms during inflammation.

Cellular Response: Key Points

• Margination: As blood slows down, leucocytes move from the center of the vessel towards the periphery.
• Endothelial cell activation: Cytokines activate the endothelium, causing selectins and other mediators to appear on the surface.
• Rolling: Neutrophils roll along and transiently adhere to endothelial cells, mediated by selectin molecules (transiently bind to their receptors).
• Neutrophil activation: Mediated by IL-8.
• Firm adhesion (pavementing): Mediated by ICAM-1-LFA-1.
• Transmigration: Mediated by PECAM-1 (diapedesis, cells crawling).
• Chemotaxis: Movement toward the site of injury mediated by chemokines.

Neutrophil Functions

• Primary granules: Myeloperoxidases (MPO) and other enzymes.
• Secondary granules: Collagenase and CHI3L1 (chitinase 3-like 1).
• Tertiary granules: MMPs and others.
• Neutrophils express cell surface receptors that recognize pathogen-associated molecular patterns (PAMPs) produced by infectious agents and damage-associated molecular patterns (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. The microorganism is destroyed by the oxidative burst, with a sudden increase in oxygen consumption and glycogenolysis; reactive oxygen species are released:
  • Superoxide ion (O2-)
  • Hydrogen peroxide (H2O2)
  • Hypochlorous acid (HOCL)
  • Hydroxyl radical (OH)
  • Nitric oxide (NO)
• Degranulation: Release of granule contents to the environment (tissue damage).
• Neutrophil extracellular traps (NETs): Formed by DNA fibers, histones, etc.

Reactive Oxygen Species

• Involved in the elimination of bacteria.
• Can cause tissue damage.

###Chemical Mediators of Inflammation

• Most bind to cell surface receptors, but some have direct enzymatic or toxic activity.
• All are tightly regulated.

Vasoactive Amines

• Histamine: Found in mast cells, basophils, and platelets. Promotes arteriolar dilation and venular endothelial contraction, resulting in a widening of inter-endothelial cell junctions with increased vascular permeability.
• Serotonin: Vasoactive effects similar to histamine; found in platelets; released when platelets aggregate.
• Complement system:
  • 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)

• Punches a hole in the membrane of target cells.

Role in Inflammation (C3A and C5A)

• C3A and C5A: Anaphylatoxins; induce mast cell degranulation, histamine release, and increased vascular permeability.

Blood Coagulation System

• Factor XII is activated by inflammation.

Kallikrein-Bradykinin System

• Bradykinin: Causes vasodilation; increases vascular permeability; induces pain.

Arachidonic Acid Pathway

• Involved in the production of prostaglandins, leukotrienes, and thromboxanes: Inflammatory mediators.

Fever (Beneficial Effects)

• Oxygen-dissociation curve is shifted right, making more oxygen available.
• Creates 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 effect (e.g., epiglottitis).
  • Impaired flow (e.g., acute meningitis).
  • Impaired function.
  • Tissue destruction.

Outcomes of Acute Inflammation

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

Inflammation

• A reaction of a vascularized living tissue to local injury.
• A protective response to eliminate the cause of cell injury, necrotic cells and tissues.
• May be harmful.
• Intimately associated with the repair process.
• Inflammatory lesions are usually indicated by the suffix (ITIS).

Purpose 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: Minutes to days.
  • Immediate and early response to injury.
  • Characterized by fluid and protein.
  • Polymorphonuclear cells (neutrophils).
• Chronic: Weeks to years.
  • 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 of Acute Inflammation

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

Increased Vascular Permeability

• Increased hydrostatic pressure: Increased "pushing pressure" inside blood vessels that forces fluid out.
• Decreased intravascular osmotic pressure: Less "pulling power" inside the blood vessels to retain fluid.
• Endothelial cell changes: Make the vessel walls leaky.
• Contraction: Cells shrink, creating gaps.
• Junctional retraction: The connections between cells pull back, creating spaces.
• Injury: Damage to these cells can lead to gaps.

Outcomes of Increased Vascular Permeability

• Transudate: Watery fluid with few proteins. Forms when there is mainly an imbalance in pushing and pulling pressures.
• Exudate: Thicker fluid, rich in proteins and often with immune cells like neutrophils. Forms during inflammation.

Cellular Response: Key Points

• Margination: As blood slows, leukocytes 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 roll along and transiently adhere to endothelial cells, mediated by selectins molecules (transiently bind to their receptors).
• Neutrophil activation: Mediated by IL-8.
• Firm adhesion (pavementing): Mediated by ICAM-1-LFA-1.
• Transmigration: Mediated by PECAM-1…diapedesis (cells crawling).
• Chemotaxis: Movement toward the site of injury mediated by chemokines.

Functions of Neutrophils

• Primary granules: Myeloperoxidases (MPO), and others.
• Secondary granules: Collagenase and CHI3L1, also known as chitinase 3-like 1.
• Tertiary granules: MMPs and others.
• Neutrophils express cell surface receptors that recognize pathogen-associated molecular patterns (PAMPs) produced by infectious agents and damage-associated molecular patterns (DAMPs) from injured and dead cells.

Antimicrobial Mechanisms of Neutrophils

• Phagocytosis: Ingestion of the microorganism into a phagocytic vacuole, fuses with lysosome to form phagolysosome. Microorganism is destroyed by oxidative burst with a sudden increase in oxygen consumption and glycogenolysis reactive oxygen species are released - superoxide ion O2-, hydrogen peroxide (H2O2), hypochlorous acid (HOCL), hydroxyl radical (OH), nitric oxide (NO).
• Degranulation: Release of granule contents to the environment (tissue damage).
• Neutrophil extracellular traps (NETs): Formed by DNA fibres, histones, etc.

Reactive Oxygen Species

• Elimination of bacteria.
• Tissue damage.

Chemical Mediators of Inflammation

• Most bind to cell surface receptors, but some have direct enzymatic or toxic activity. All are tightly regulated.

Vasoactive Amines

• Histamine: Found in mast cells, basophils, and platelets. Promotes arteriolar dilation and venular endothelial contraction. Results in widening of inter-endothelial cell junctions with increased vascular permeability.
• Serotonin: Vasoactive effects similar to histamine. Found in platelets. Released when platelets aggregate.

Complement System

• 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

• Punches a hole in the membrane.

Role in Inflammation: C3a and C5a

• C3a and C5a: Increase vascular permeability and contraction of smooth muscle.

Blood Coagulation System

• Factor XII is activated by inflammation.

Kallikrein-Bradykinin System

• Kallikrein: Converts kininogen to bradykinin.
• Bradykinin: Increases vascular permeability, pain, and smooth muscle contraction.

Arachidonic Acid Pathway

• Cyclooxygenase (COX) pathway: Produces prostaglandins and thromboxanes.
• Lipoxygenase pathway: Produces leukotrienes and lipoxins.
• Prostaglandins: Vasodilation, pain, fever.
• Thromboxanes: Platelet aggregation and vasoconstriction.
• Leukotrienes: Bronchoconstriction, increased vascular permeability, chemotaxis.
• Lipoxins: Inhibit neutrophil chemotaxis and inflammation.

Fever

• Beneficial effects of fever:
  • Oxygen-dissociation curve is shifted right. More oxygen is available.
  • 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 agent.
  • Removal of tissue debris.
• Harmful:
  • Mechanical effect e.g., epiglottitis.
  • Impaired flow e.g., acute meningitis.
  • Impaired function.
  • Tissue destruction

Outcomes of Acute Inflammation

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