Key Inflammatory Mediators

Why This Matters

Inflammation is the body's frontline defense—and understanding its chemical messengers is essential for recognizing clinical presentations, predicting disease progression, and selecting appropriate interventions. You're being tested on more than just knowing that histamine causes hives; you need to understand why certain mediators produce vasodilation while others trigger bronchoconstriction, and how these mechanisms explain the symptoms you'll assess at the bedside.

These mediators work through distinct pathways: vasoactive amines, lipid-derived signals, protein cascades, and neuropeptides. Each category has unique sources, targets, and clinical implications. When you encounter an NCLEX question about anaphylaxis or a patient presenting with sepsis, you'll need to connect symptoms to the underlying mediators driving them. Don't just memorize names—know what each mediator does, where it comes from, and what happens when it's dysregulated.

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Vasoactive Amines: The Rapid Responders

These mediators are stored preformed in cells and released immediately upon activation, making them responsible for the earliest signs of inflammation. Their rapid release explains why allergic reactions can escalate within minutes.

Histamine

• Released from mast cells and basophils—the primary mediator of immediate (Type I) hypersensitivity reactions
• Causes vasodilation and increased vascular permeability through $H_1$ receptor activation, producing the classic triad of redness, warmth, and swelling
• Clinical relevance: antihistamines block $H_1$ receptors to manage urticaria, allergic rhinitis, and mild allergic reactions

Serotonin

• Released by activated platelets during clotting and tissue injury, contributing to early vascular changes
• Functions as both neurotransmitter and inflammatory mediator—explains the connection between inflammation and altered pain perception
• Dual vascular effects: can cause vasoconstriction or vasodilation depending on receptor type and tissue location

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Lipid-Derived Mediators: The Arachidonic Acid Pathway

These mediators are synthesized on demand from membrane phospholipids, specifically arachidonic acid. Understanding this pathway explains why NSAIDs and corticosteroids work—and why they have different effects.

Prostaglandins

• Derived from arachidonic acid via the cyclooxygenase (COX) pathway—the target of NSAIDs like ibuprofen and aspirin
• Mediate pain, fever, and vasodilation by sensitizing pain receptors and acting on the hypothalamus's thermoregulatory center
• Protective functions too: prostaglandins maintain gastric mucosa and renal blood flow, explaining NSAID side effects

Leukotrienes

• Produced via the lipoxygenase pathway from arachidonic acid, primarily by leukocytes and mast cells
• Potent bronchoconstrictors—major players in asthma pathophysiology, causing airway narrowing and mucus secretion
• Attract immune cells to inflammation sites through chemotaxis; leukotriene receptor antagonists (montelukast) are used in asthma management

Platelet-Activating Factor (PAF)

• A phospholipid mediator that promotes platelet aggregation, bronchoconstriction, and leukocyte activation simultaneously
• Key player in anaphylaxis—contributes to cardiovascular collapse through profound vasodilation and increased permeability
• Amplifies inflammation by stimulating release of other mediators, creating a positive feedback loop

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Cytokines and Proteins: The Systemic Communicators

These protein mediators coordinate the inflammatory response across tissues and organ systems. They're responsible for systemic symptoms like fever, fatigue, and the acute phase response.

Cytokines (IL-1, IL-6, TNF-α)

• Signaling proteins produced by macrophages and other immune cells that orchestrate local and systemic inflammation
• TNF-α and IL-1 are "alarm" cytokines—they induce fever, activate endothelium, and trigger the acute phase response in the liver
• IL-6 drives the acute phase response and stimulates production of C-reactive protein (CRP), a key clinical marker of inflammation

Complement Proteins

• A cascade of plasma proteins that amplify immune responses through sequential activation (classical, alternative, and lectin pathways)
• Three main functions: opsonization ($C3b$), inflammation promotion ($C3a$, $C5a$ as anaphylatoxins), and direct pathogen lysis via membrane attack complex (MAC)
• Clinical significance: complement deficiencies increase susceptibility to bacterial infections, especially encapsulated organisms

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Vasoactive Peptides: Pain and Permeability

These peptide mediators link the vascular, nervous, and immune systems. They explain why inflammation hurts and why neural input can modulate immune responses.

Bradykinin

• Generated from plasma kininogens during tissue injury and inflammation via the kinin-kallikrein system
• Potent pain inducer—sensitizes nociceptors and is one of the most powerful endogenous pain-producing substances
• ACE inhibitor connection: ACE degrades bradykinin, so ACE inhibitors can cause bradykinin accumulation, leading to cough and angioedema

Substance P

• A neuropeptide released from sensory nerve endings that bridges the nervous and immune systems
• Amplifies pain signals and contributes to neurogenic inflammation—inflammation triggered by nerve activation rather than immune cells
• Promotes "flare response"—the spreading redness around an injury site due to axon reflex and local vasodilation

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Gaseous Mediators: The Unconventional Signal

Nitric oxide represents a unique class of mediator—a gas that acts locally and cannot be stored. Its dual nature makes it both protective and potentially harmful.

Nitric Oxide

• Produced by nitric oxide synthase (NOS) in endothelial cells, macrophages, and neurons from the amino acid L-arginine
• Causes vasodilation by relaxing vascular smooth muscle—the mechanism behind nitroglycerin's therapeutic effect in angina
• Dual inflammatory role: low levels are protective and anti-inflammatory; high levels (from inducible NOS during sepsis) contribute to pathological vasodilation and shock

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Quick Reference Table

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Self-Check Questions

1. Which two mediators are derived from arachidonic acid but cause opposite respiratory effects—and what enzyme pathways distinguish them?

2. A patient on an ACE inhibitor develops angioedema. Which inflammatory mediator is accumulating, and why does this medication cause this effect?

3. Compare and contrast the roles of histamine and leukotrienes in an acute asthma exacerbation. Why might antihistamines alone be insufficient?

4. Which cytokines would you expect to be elevated in a patient presenting with fever, elevated CRP, and signs of systemic inflammation? What cells produce them?

5. A patient in septic shock has profound vasodilation unresponsive to fluids. Which gaseous mediator is likely overproduced, and what enzyme form is responsible for its excessive synthesis?