Chapter 35: Anti-Inflammatory Agents

DEFINING INFLAMMATION

Inflammation, from the Latin word inflammatio (to set on fire), is a dynamic vascular and cellular reflexive response of the living tissue to injury; such injury may present in the form of infection, chemical damage (e.g., toxins, irritants), physical damage (e.g., heat, cold, radiation, mechanical trauma), and the binding of antibodies to antigens within the body.¹ Inflammation is therefore a protective mechanism of the organism intended to remove such injurious stimuli as well as to initiate the healing process of the damaged tissue.

Localized vasodilation, increased vascular permeability, extravasation of plasmatic proteins, and migration of leukocytes into the affected tissue produce what Cornelius Celsius defined in the first century as the “cardinal signs” of acute inflammation: calor (heat), dolor (pain), rubor (redness), and tumor (swelling).² Functio laesa (loss of function) was later added to the definition of inflammation by Rudolf Virchow in the 19th century.³

A basic sequence of events characterizes virtually all types of inflammatory responses regardless of the provocative stimuli.⁴ The initial reaction is vasodilation followed by transient vasoconstriction. The microvascular endothelium then becomes more permeable to plasma proteins, which leak out into the extravascular compartment thus establishing an inflammatory exudate. Inflammatory mediators released in the area induce the expression of selectin-type adhesion molecules on the endothelial cells. Recruited leukocytes then interact with such adhesion molecules, bind to the inflamed endothelium, and extravasate into the tissue where they respond to the insult through phagocytosis and degranulation. Finally, the inflammatory response must be actively terminated when no longer essential to prevent unnecessary damage to tissue.

The process of inflammation, both vascular and cellular, is orchestrated by a large array of inflammatory mediators, which will be reviewed below. These mediators include the following: (1) cellular-derived products, such as vasoactive amines (e.g., histamine), cytokines, eicosanoids (e.g., prostaglandins, thromboxanes, and leukotrienes), enzymes, and oxygen radicals and (2) plasma-derived mediators, which include complement cascade components, kinins, and fibrinopeptides.

CELL-DERIVED INFLAMMATORY MEDIATORS AND THEIR ROLES IN THE INFLAMMATORY PROCESS

Role of Eicosanoids

In reaction to inflammatory stimuli, molecular signaling, or cell destruction, phospholipids contained in the cellular membrane are hydrolyzed by phospholipase A2 (PLA2) thus releasing free arachidonic acid (AA). This fatty acid is the primary precursor of eicosanoids (Fig. 35-1)—important inflammatory mediators that include prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs) among others⁵ (Fig. 35-2). Eicosanoids are not stored. Once formed, they act locally at the site of synthesis to regulate autocrine and paracrine functions.⁶ Different cell types have particular sets of enzymes for eicosanoid synthesis, which determine their eicosanoid profile. Similarly, different stimuli also influence the eicosanoid profile produced by the cell.⁶ There are two different pathways in the synthesis of eicosanoids from AA: