Inflammation and Repair

Chapter 2: Inflammation and Repair

Overview of Inflammation

Definition of Inflammation

• What is Inflammation?

  • Definition: A response to tissue damage that can either be harmful or protective.

  • Goals: To eliminate the cause of injury.

  • Mechanisms involve:

  • Vascular reactions (mediated by plasma proteins and cytokines).

  • Cellular responses (mediated by leukocytes, cytokines, antibodies, and proteins).

  • Cardinal Signs of Inflammation:

  • Redness (rubor)

  • Swelling (tumor)

  • Heat (calor)

  • Pain (dolor)

  • Loss of function (functio laesa)

  • Nomenclature: “-itis” indicates inflammation in various tissues.

  • Quotation: “Without inflammation, infections would go unchecked, wounds would never heal, and injured tissues might remain permanent festering sores.”

Sequence of Inflammation (The 5 R's)

1. Recognition: Cellular mediators have receptors for pathogens and cell damage.

2. Recruitment: Of leukocytes and plasma proteins from the blood to the site of injury.

3. Removal: Phagocytosis by cellular mediators.

4. Regulation: Termination of the inflammatory response once pathogens are eliminated.

5. Repair: Regeneration or replacement of damaged cells and tissues.

Acute vs. Chronic Inflammation

Features Comparison

• Acute Inflammation:

  • Onset: Fast, within minutes to hours.

  • Cellular Infiltrate: Mainly neutrophils.

  • Tissue Injury: Usually mild and self-limited.

  • Fibrosis: None.

  • Local/Systemic Signs: Prominent.

• Chronic Inflammation:

  • Onset: Slow, taking days.

  • Cellular Infiltrate: Monocytes/macrophages and lymphocytes.

  • Tissue Injury: May be significant.

  • Fibrosis: May be severe and progressive.

  • Local/Systemic Signs: Variable, usually modest.

Causes of Inflammation

• Broad categories include:

1. Infections:

   • Inflammatory responses depend on the pathogen involved, aiding pathologists in diagnosis.

   • The goal is to eradicate the infection, outcome hinging on host-pathogen interactions.

2. Tissue Necrosis:

   • Necrosis leads to inflammation regardless of its cause.

   • Components from damaged cells stimulate ongoing inflammation.

   • Examples: Ischemia, trauma, burns, irradiation.

3. Foreign Bodies:

   • Both endogenous and exogenous materials can provoke inflammatory responses for their removal.

   • Exogenous examples: dirt, splinters.

   • Endogenous examples: gout, atherosclerosis.

4. Immune Reactions:

   • Inappropriate immune responses to self-antigens, primarily mediated by lymphocytes and antibodies.

   • Examples include allergies, rheumatoid arthritis, and systemic lupus erythematosus.

Recognition of Microbes or Cell Damage

• First step in the inflammatory process:

  • Receptors for Microbes (PAMPs):

  • Located on cell membranes, in the cytosol, or on endosomes.

  • Key types include Toll-like receptors and RIG-I-like receptors.

  • Sensors for Cell Damage (DAMPs):

  • NOD-like receptors detect substances released during cell breakdown.

  • Recognize components such as uric acid, ATP, DNA.

  • Activate the inflammasome pathway leading to production of IL-1.

  • Receptors for Antibody and Complement:

  • Antibody or complement coat microbes, facilitating recognition and phagocytosis by leukocytes.

Acute Inflammation Mechanism

• Three Major Components:

1. Dilation of blood vessels.

2. Increased permeability of blood vessels.

3. Emigration of leukocytes (neutrophils).

• Facilitates movement of inflammatory mediators out of circulation.

• Effusions are classified based on their content:

  • Exudate: High in protein, high in cells.

  • Modified Transudate: High in protein, low in cells.

  • Transudate: Low in protein, low in cells.

  • Chylous: High in lymphocytes and triglycerides.

• Inflammation usually results in an exudate.

Reactions of Blood Vessels in Inflammation

1. Vasodilation:

   • Increases blood flow to the site of inflammation.

   • Mediated by histamine and other cytokines acting on vascular smooth muscle.

   • Dilation causes slower blood flow, leading to congestion and stasis.

   • Facilitates leukocyte emigration.

2. Increased Vascular Permeability:

   • Caused by contraction of endothelial cells and/or endothelial damage.

   • Mediators involved: histamine, bradykinin, leukotrienes.

   • Occurs rapidly and is generally short-lived, though mild injuries (e.g., sunburn) may cause delayed vascular leakage for hours or days.

Mediators of Blood Vessel Changes in Inflammation

Lymphatic Vessel Reactions

• Lymphatic vessels are responsible for draining edema and fluid in response to inflammation:

  • They undergo dilation and proliferation.

  • Can become inflamed themselves (“lymphangitis”).

  • Draining lymph nodes may become hyperplastic and inflamed due to inflammation.

Leukocyte Recruitment Steps

• Vascular changes facilitate the emigration of leukocytes:

1. Margination: Redistribution of WBCs along vessel walls due to vascular dilation and congestion.

2. Rolling: Inflammatory cytokines increase adhesion molecule expression on WBCs and endothelial cells.

3. Adhesion: Firm attachment mediated by integrins and their receptors.

4. Transmigration (Diapedesis): Movement through the endothelium at postcapillary venules.

5. Migration: Movement towards the site of inflammation (chemotaxis).

Specific Mechanisms of Leukocyte Recruitment

• Margination:

  • Occurs with vascular dilation and congestion, allowing WBCs to adhere to vessel walls.

  • Increased expression of adhesion molecules such as selectins and integrins leads to strong adherence.

  • Selectin types include L-selectin (on leukocytes), E-selectin (on activated endothelium), and P-selectin (on platelets).

  • Integrins:

  • Examples include VLA-4 and LFA-1 which mediate the firm adhesion of leukocytes to endothelium.

Chemotaxis in Leukocyte Recruitment

• Leukocytes migrate towards infection sites attracted by:

  • Exogenous substances: Bacterial products (amino acids, lipids).

  • Endogenous substances: Cytokines, complement proteins, and arachidonic acid metabolites.

  • Binding to G-protein coupled receptors leads to cytoskeletal reorganization in leukocytes, enabling movement towards infection sites.

Neutrophils vs. Macrophages

Phagocytosis Process

• Involves a series of sequential steps:

1. Recognition: Phagocyte receptors bind to pathogens.

2. Engulfment: Cytoplasm extends around the particle forming a vesicle (phagosome).

3. Killing: Fusion of phagosome with lysosome releases enzymes for microbial destruction.

Mechanisms of Destruction

• Reactive Oxygen Species (ROS):

  • Generated during respiratory burst in neutrophils through NADPH oxidase activity, leading to superoxide production.

  • Combine with granule contents (e.g., myeloperoxidase) to produce additional antimicrobial agents like H2O2 and HOCl.

• Nitric Oxide (NO):

  • Produced by various nitric oxide synthases (NOS) like iNOS in macrophages during microbial killing.

  • NO may combine with superoxide to form peroxynitrite (ONOO-).

• Lysosomal Enzymes:

  • Various enzymes contained in neutrophil granules (e.g., myeloperoxidase, elastase, acid proteases) aid in microbial destruction.

  • Neutrophil extracellular traps (NETs) can entrap microbes and contain antimicrobial peptides.

Leukocyte-Mediated Injury

• Leukocytes can cause damage to normal tissues during the process of infection clearance:

  • Bystander effect: Damage inflicted on normal cells while targeting pathogens.

  • Can cause autoimmune diseases due to inappropriate immune reactions to benign substances.

Resolution of Acute Inflammation

• Inflammation resolves partly through the apoptosis of activated leukocytes.

• Transition from pro-inflammatory to anti-inflammatory processes via cytokines such as:

  • Lipoxins (from leukotrienes).

  • TNFα, IL-1β, IL-18 transitioning to IL-10 and TGF-β.

Mediators of Inflammation

• 
  

• Substances initiating and regulating inflammatory responses:
  

  Mediator	Source	Action
  Histamine	Mast cells, basophils, platelets	Vasodilation, increased vascular permeability
  Prostaglandins	Mast cells, leukocytes	Vasodilation, pain, fever
  Leukotrienes	Mast cells, leukocytes	Increased vascular permeability, chemotaxis
  Cytokines (TNF, IL-1, IL-6)	Macrophages, endothelial cells	Local: endothelial activation, Systemic: fever, metabolic changes
  Chemokines	Leukocytes, activated macrophages	Chemotaxis and activation of leukocytes
  Vasoactive Amines

  • Histamine:

    • Primarily released from mast cells in response to trauma, IgE, and complement activation.

    • Causes vascular dilation and increased permeability in venules, and smooth muscle contraction.

  • Serotonin (5-hydroxytryptamine):

    • Primarily stored in platelets and neuroendocrine cells.

    • Functions include vasoconstriction and increasing peristalsis in the gut.

  Arachidonic Acid Metabolites

  • Eicosanoids: Prostaglandins and leukotrienes derived from arachidonic acid in membrane phospholipids through phospholipase A2.

  • Synthesized by:

    • Cyclooxygenases (COX-1 and COX-2) to form prostaglandins.

    • Lipoxygenases to produce leukotrienes and lipoxins.

  Prostaglandin Functions

  • Generated by COX-1 & COX-2; with COX-1 being constitutively expressed and COX-2 induced by inflammation.

  • Major mediators include:

    • Prostaglandin E2 (PGE2): Causes vasodilation and increased permeability, involved in fever.

    • Thromboxane A2 (TXA2): Potent vasoconstrictor promoting platelet aggregation.

  Leukotriene Roles

  • Produced by leukocytes via lipoxygenases; example, LTB4 is a potent neutrophil chemotactic agent.

  • Other leukotrienes cause vasoconstriction and increased vascular permeability, while lipoxins play a role in resolving inflammation.

  Pharmacologic Inhibitors of Inflammation

  • COX Inhibitors:

    • Aspirin and NSAIDs inhibit both COX-1 and COX-2 (Aspirin irreversibly).

    • May cause toxicity through ischemia due to the inhibition of vasodilation.

  • Lipoxygenase Inhibitors: Used in asthma management to prevent bronchoconstriction.

  • Corticosteroids: Broad-spectrum anti-inflammatory effects, suppress gene transcription of pro-inflammatory signals including COX-2 and cytokines.

  Cytokines and Chemokines

  • Primary Inflammatory Cytokines:

    • TNFα, IL-1, IL-6, and IL-17.

    • TNFα and IL-1 enact endothelial activation and leukocyte activation, contributing to systemic acute phase response leading to fever.

    • TNFα antagonists are used in treating rheumatoid arthritis and various autoimmune diseases, but increase infection susceptibility.

  Chemokine Functions

  • Act primarily as chemoattractants for leukocytes and classified into four groups based on cysteine arrangement:

    • C-X-C chemokines (e.g., IL-8) attract neutrophils.

    • C-C chemokines (e.g., MCP-1) attract various leukocytes.

    • CX3C chemokines, e.g. Fractalkine promotes adhesion and attraction of monocytes and T-cells.

  Complement System

  • Plasma proteins involved in defense and inflammation numbered C1 through C9.

  • Activation leads to cleavage into subcomponents involved in promoting inflammation (C3a, C5a) and opsonization (C3b).

  • Three main activation pathways:

    • Classical Pathway: Activated by antibody binding to C1.

    • Alternative Pathway: Triggered by microbial LPS.

    • Lectin Pathway: Activated via mannose-binding lectin.

  Systemic Effects of Inflammation

  • Inflammatory cytokines lead to systemic effects known as the “acute-phase response,” including:

    • Fever

    • Increased acute phase proteins

    • Leukocytosis

    • Possible septic shock from high levels of TNF and IL-1, which can lead to disseminated intravascular coagulation (DIC), hypotensive shock, and insulin resistance.

  Tissue Repair Mechanisms

  • Involves restoration of tissue architecture/function and can occur via:

    • Regeneration: Occurs primarily in epithelial tissues (skin, intestines) that have stem cells.

    • Connective Tissue Deposition (Scarring): For tissues incapable of regeneration post-injury (e.g., heart, lung).

  Cell and Tissue Regeneration

  • Process of regeneration depends on maintaining an intact basement membrane and involves different cell types:

    • Labile Tissues: Continuously divide (e.g., hematopoietic cells, skin epithelium).

    • Stable Tissues: Minimal normal proliferation but can increase (e.g., liver, kidney).

    • Permanent Tissues: No proliferation after injury (e.g., neurons, cardiac muscle).

  Repair via Connective Tissue Deposition

  • Requires structurally intact residual tissue for normal structure restoration.

  • Steps include:

    1. Inflammation

    2. Cell proliferation

    3. Granulation tissue formation

    4. Deposition of connective tissue via signaling factors (PDGF, FGF, TGF-β).

  Factors Influencing Repair Quality

  • Influences on healing include:

    • Infections

    • Diabetes

    • Nutritional deficiencies

    • Mechanical factors

    • Blood perfusion

    • Substance presence leading to chronic inflammation

    • Severity and location of injury

  Examples of Tissue Repair and Fibrosis

  • First Intention Healing:

    • Surgical incisions; healing proceeds smoothly with minimal scarring.

    • Healing phases include immediate clot formation, neutrophil infiltration, epithelial proliferation, and remodeling.

  • Second Intention Healing:

    • Large tissue defects; involves larger clot formation and more fibrous tissue leading to delayed healing.

    • Myofibroblasts assist in wound contraction.

  Abnormalities in Tissue Repair

  • Defects in Healing:

    • Chronic wounds (e.g. venous leg ulcers, arterial ulcers, diabetic ulcers).

    • Excessive scarring phenomena (e.g. hypertrophic scars, keloids).

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