3.1-Inflammation

Elie Metchnikoff

Concluded that the job of inflammation is to bring phagocytic cells to the injured area to engulf invading bacteria

Paul Ehrlich

Humoral immunity, specific antibodies, and non-specific phagocytes at 20th century

Sir Thomas Lewis

Demonstrated that inflammation is brought about by chemical mediators

Histamines produce the triple response of Lewis: red scratch, flare, and wheal

Inflammation

A protective response to eliminate the cause of cell injury and dead cells/tissues, goal is restoring normal tissue function

Fundamentals of inflammation

Components of response

Mediators

Local/systemic

Acute/Chronic

Harmful consequences

Inflammation reaction sequence

Recognition, Recruitment, Removal, Regulate, Repair

Recognition step of inflammation

Offending agent is recognized by host cells/molecules in extravascular tissues

Recruitment step of inflammation

Leukocytes and plasma proteins are recruited from circulation

Removal step of infllammation

Leukocytes and proteins are activated to destroy/eliminate the offender

Regulation step of inflammation

Reaction is controlled/terminated

Repair step of inflammation

Tissue damage is repaired

How does recognition of microbes/damaged cells work?

Initiated by DAMPs and PAMPs, activates inflammasome and IL-1 production

Cellular receptors for recognition

TLRs (pattern recognition)

NLRs (damage sensors)

Fc receptors

Complement

Circulating proteins

Main inflammatory cells

Neutrophils

Endothelial Cells

Monocytes/Macrophages

Neutrophils

Primary cell of acute inflammation

Endothelial Cells

Regulate vascular dilation/contraction, mediate leukocyte recruitment

Monocytes/Macrophages

Phagocytosis and regulation of acute/chronic inflammation

Neutrophil mediators

ROS, PAMP and DAMP receptors, NETs, lysosomal granules (e.g., myeloperoxidase, bactericidal proteins, plasminogen activator)

Endothelial mediators

Nitric Oxide

Monocyte/Macrophage mediators

Cytokines (IL-1, IL-6, TNFα), chemokines, ROS

Acute Inflammation

Fast onset, neutrophilic infiltrate, mild/limited tissue injury, prominent signs

Chronic Inflammation

Slow onset, monocyte/macrophage infiltrate, severe/progressive tissue injury, less obvious signs

Cardinal signs of inflammation

Pain, Heat, Redness, Swelling, Loss of Function

Pain mediators

Bradykinin, PGE2

Heat and Redness mediators

Histamine, Bradykinin, Prostaglandins

Swelling mediator

Histamine

Common causes of inflammation

Infections (PAMPs)

• Most common

Tissue necrosis (DAMPs)

Foreign bodies

Immune reactions (hypersensitivity)

Three components of acute inflammation

Vasodilation

Increased permeability

Leukocyte emigration

Vasodilation in Acute Inflammatoin

Caused by histamine; increases blood flow; causes heat/redness

Increased vascular permeability in Acute Inflammation

Causes edema; via endothelial contraction or injury

Leukocyte emigration in Acute Inflammation

Leukocytes accumulate at injury site and are activated

Exudation

Escape of fluid, proteins, and blood cells into tissues/cavities

Happens in acute inflammation

Increased vascular permeability cause

Endothelial cell contraction (main), endothelial injury (secondary)

Mediators: histamines, bradykinin, NO, PGs

Exudate

High-protein fluid with cells/debris; implies inflammation and increased vascular permeability

Transudate

Low-protein fluid; caused by osmotic/hydrostatic imbalance; non-inflammatory

Causes of transudate

CHF (pitting edema), Cirrhosis (ascites fluid)

Outcome of exudate

Fibrinous Pericarditis—pericardial friction rub and adhesions

Lymphatic role in inflammation

Can become inflamed (lymphangitis), lymph nodes enlarge (lymphadenitis)

Signs of lymphangitis

Red streaks near wound, painful enlarged lymph nodes

Leukocyte movement

Controlled by adhesion molecules and chemokines

Leukocyte margination and rolling

Along the periphery of vessels

E-selectin and P-selectin

Transmigration mediator

PECAM-1

Integrins role

Enable strong adhesion to endothelial molecules

Initial rolling mediator

Selectins

Firm adhesion mediators

Integrins

Transmigration (Diapedesis)

Migration of leukocytes across endothelium

Chemotaxis

Leukocytes move toward injury guided by chemoattractants

Chemoattractants Examples

C5a (from complement)

Leukotriene B4

fMLF (from bacteria)

Inflammatory cell timeline

Neutrophils first, then monocytes/macrophages

Exceptions to neutrophil-first response in inflammation (and what they’re replaced with)

Pseudomonas (persistent neutrophils)

Viruses (lymphocytes)

Hypersensitivity (lymphocytes/macrophages/plasma cells)

Helminths/allergies (eosinophils)

Function of chemokines

Chemoattractants that cause leukocyte chemotaxis

Major phagocytes in inflammation

Neutrophils and Macrophages

Neutrophil characteristics

Bone marrow origin, short-lived, rapid, ROS use, NETs, lysosomes

Macrophage characteristics

Longer-lived, prolonged response, cytokine production, less ROS

Leukocyte activation

Microbe/dead cell recognition triggers leukocyte response (e.g., Dohl bodies-RNA in activated cell)

Phagocytosis steps

1. Recognition/attachment to leukocyte

2. Engulfment into leukocyte

3. Killing/degradation

Killing of microbe mechanism

ROS and RNS, lysosomal enzymes for phagocytosed material

When is the efficiency of phagocytosis better?

When microbes are coated with opsonins

• C3b

• Plasma lectins like mannose-binding-lectin

• Immunoglobulin (IgG) reacting with microbe

Chronic Granulomatous Disease

Inherited deficiency of NADPH oxidase

Increases susceptibility of body to infections caused by fungi and catalase producing bacteria, resulting in granuloma formation.

Chediak-Higashi Syndrome

Impaired phagocytosis; infections, neutropenia, giant granules, albinism

Myeloperoxidase Deficiency

Reduced killing; severe Candida if diabetic

Neutrophil Extracellular Traps (NETs)

Extracellular DNA networks trap/kill microbes

NETosis is activated to cause this!

Leukocyte-mediated injury Mechanisms (3)

Collateral damage to host tissues (ex. TB)

Autoimmunity

Hypersensitivity

How leukocytes damage tissues

Use same mechanisms as in defense (ROS, enzymes)

Inflammation resolution mechanisms

Short half-life mediators

Neutrophil apoptosis

Anti-inflammatory cytokines (IL-10, TGF-β)

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