Inflammation

Introduction to Inflammation

• Inflammation is a complex response to tissue injury and infection, marked by redness, heat, swelling, pain, and loss of function.
• The immune system, including cells and soluble factors (like antibodies and complement proteins), mediates this response.
• Inflammatory cells and factors aim to eliminate the initial stimulus and initiate an immunological response.

Objectives of the Presentation

• Briefly review the inflammatory process.
• Examine pharmacologic strategies for managing inflammation.
• Explain how anti-inflammatory agents work, particularly on eicosanoids and histamine.
• Detail features of some anti-inflammatory agents.

Triggers of Inflammation

• Inflammation is triggered by various stimuli, such as:
  • Trauma
  • Exposure to foreign substances
  • Infectious agents
  • Ischemia
  • Immune reactions

Benefits of Inflammation

• Combats foreign invaders.
• Removes inciting stimuli and resolves tissue damage.

Chronic Inflammation

• Sometimes, inflammation can persist for too long, leading to chronic damage.
• This persistence can be due to a sustained inappropriate response (e.g., allergies) or failure to remove the offending agent (e.g., chronic infection).

Mediators of Inflammation

• An initial insult triggers a cascade of cytokines (like interleukins and tumor necrosis factor).
• These cytokines stimulate enzymes (like COX-2 and LOX).
• The enzymes promote the production of pro-inflammatory mediators (e.g., prostaglandins and leukotrienes).
• The inflammatory mediators attract inflammatory cells.

Arachidonic Acid Pathways - Overview

• Arachidonic acid is a precursor to most eicosanoids.
• It’s derived from essential fatty acid linoleic acid.
• Alpha-linolenic acid, EPA, and DHA are omega-3 fatty acids.

Arachidonic Acid - Cellular Level

• In the cell, arachidonic acid is stored in membrane phospholipids.
• The enzyme phospholipase A2 releases arachidonic acid.
• This is the rate-limiting step in forming eicosanoids.

Products of the COX pathway

• PGE2: Acts on mast cells and macrophages; responsible for pain responses, vasodilation, bronchoconstriction, fever, and inflammatory cell activation; contributes to mucus production.
• PGF2alpha: Affects bronchial smooth, uterine, and blood vessel smooth muscle; roles in vascular tone, bronchoconstriction and abortion.
• PGD2: Influences neurons and mast cells; involved in bronchoconstriction (asthma), sleep control, and Alzheimer's disease.
• PG12: Affects endothelial cells; inhibits platelet aggregation and causes vasodilation.
• TXA2: Acts on platelets and causes vasoconstriction and platelet activation.

Products of the LOX Pathway

• LTB4: Activating neutrophils, and thus, their migration, degranulation , superoxide generation, and eicosanoid synthesis. Also promotes natural killer cell activity.
• LTC4, LTD4: Bind to CysLT1 receptors; responsible for vasoconstriction, bronchospasm, and increased vascular permeability.

Lipoxins

• Lipoxins are products of LOX pathway; have anti-inflammatory and pro-resolving roles that counter the action of leukotrienes.
• LXA4 and LXB4 are two of the lipoxins.

Some Inflammatory Diseases

• Includes Asthma, Rheumatoid arthritis, Inflammatory bowel disease, Glomerulonephritis, cardiovascular and cancerous conditions

Pharmacologic Anti-inflammatory Strategies

• Two main approaches exist, These include targeting inflammation and immune system components, and altering the root cause.

Pharmacologic Classes of Anti-inflammatory Agents

• Glucocorticoids
• COX inhibitors
• Leukotriene inhibitors
• Thromboxane antagonists
• Cytokine inhibitors
• Lipoxins/protectins/maresins

Glucocorticoids

• Lower and inhibit lymphocytes and macrophages.
• Indirectly inhibit phospholipase A2 by raising lipocortin levels, and thereby block the release of arachidonic acid (a precursor of prostaglandins and leukotrienes).
• Reduce COX-2 synthesis.
• Interfere with mast cell degranulation which lowers histamine release.

NSAIDs (Nonsteroidal Anti-Inflammatory Drugs)

• Inhibit cyclooxygenase enzymes, crucial for prostaglandin production.
• COX-1 and COX-2 contribute to prostaglandin production.
• Most NSAIDs are reversible and competitive inhibitors.
• Aspirin is an exception, with irreversible effects.

Leukotriene Inhibitors (CysLT1 antagonists)

• Montelukast and Zafirlukast are two CysLT1 antagonists
• They block CysLT1 receptors, thereby opposing leukotriene effects.
• Zileuton inhibits 5-lipoxygenase.

Leukotriene Inhibitors (5-LOX inhibitor)

• Zileuton inhibits 5-lipoxygenase.
• A less common approach to combating leukotrienes.

Cytokine Inhibitors (Targeting TNF-α)

• Infliximab: A humanized mouse monoclonal antibody directed at TNF-α; used for rheumatoid arthritis, inflammatory bowel disease, and autoimmune conditions.
• Adalimumab is another TNF-α blocking agent.

Cytokine Inhibitors (Targeting IL-1)

• Anakinra is the IL-1 receptor antagonist.
• Applicable for use in patients with rheumatoid arthritis.

Interplay of Inflammatory Cells and Mediators

• The complexity of inflammation stems from the numerous mediators at play
• Successful management necessitates targeting the various components and mechanisms.

Drugs used in Rheumatoid Arthritis

• NSAIDs
• Glucocorticoids
• Disease-modifying antirheumatic drugs (DMARDs )
  • Examples: Methotrexate, azathioprine, cyclosporine
• Biologics
  • Examples: abatacept, rituximab, tocilizumab, adalimumab, infliximab

Histamine

• Histamine is an autocoid, a crucial mediator in immune, allergic, and inflammatory processes.
• Histamine plays a part in gastric acid regulation, neurotransmission, and immune modulation.

Histamine and Anaphylaxis

• Systemic mast cell degranulation can trigger anaphylaxis, a life-threatening condition.
• Triggers often include hypersensitivity to insect bites, antibiotics like penicillin, or food allergens, such as peanuts.

Histamine Receptors

• H1 receptors - Predominantly on vascular endothelial and smooth muscle cells. Influence inflammatory and allergic events, causing edema and bronchoconstriction, and activating primary afferent nerves.

Strategies of Histamine Inhibition

• Administering antihistamines.
• Stopping the degranulation of mast cells.
• Counteracting histamine effects directly.

Antihistamines

• Are inverse agonists for H1 receptors.
• Bind to the inactive state of the receptor, shifting the equilibrium towards a non-active state.
  • Types of antihistamines include first and second generations.
    • First generation antihistamines (e.g., diphenhydramine, promethazine): are less selective, can cross the blood-brain barrier, have more side effects (e.g., drowsiness, dry mouth). They're beneficial in cases of nausea and motion sickness.
    • Second-generation antihistamines (e.g., loratadine, fexofenadine, olopatadine): are more specific for H1, have fewer CNS side effects, and are useful in allergic conditions.

Clinical Uses of H1-antihistamines

• Allergy relief (e.g., rhinitis, conjunctivitis, urticaria, and pruritus) particularly for prophylactic use.
• Treatment of generalized itching.
• Nausea and motion sickness.
• Insomnia.

Limitations of Antihistamines

• Not a monotherapy choice for conditions where leukotrienes have significant impact (i.e., asthma).
• Ineffective for anaphylaxis.

This quiz delves into the characteristics of the inflammatory response, its triggers, and the role of eicosanoids. It also explores H1-antihistamines and their clinical uses. Test your understanding of inflammation and its resolution mechanisms with a set of targeted questions.