Arachidonic acid (AA) is an omega-6 polyunsaturated fatty acid found within the membranes of nearly every cell. It serves as the direct precursor for a group of signaling molecules called eicosanoids. The arachidonic acid pathway is the metabolic route AA takes when a cell experiences stress, injury, or infection. This cascade rapidly produces local mediators that initiate inflammation, including pain, fever, and swelling, ensuring the body can quickly rally its defenses and begin tissue repair.
Releasing Arachidonic Acid from Cell Membranes
The initiation of the arachidonic acid pathway relies entirely on the successful liberation of AA from its stored position within the cell membrane phospholipids. AA is typically esterified, or chemically bound, to the sn-2 position of cell membrane phospholipids. The “gatekeeper” enzyme responsible for snipping AA free from the membrane structure is Phospholipase A2 (PLA2).
When a cell is stimulated by mechanical damage, chemical irritants, or inflammatory signals, PLA2 becomes activated and moves to the cell membrane. This enzyme hydrolyzes the sn-2 ester bond, releasing the free AA molecule into the cell’s interior. The release of AA is the mandatory first step, as the downstream enzymes responsible for creating inflammatory mediators can only act upon the free fatty acid.
There are multiple isoforms of PLA2, with cytosolic PLA2 (cPLA2) being particularly important in mobilizing AA for eicosanoid production. By cleaving the membrane phospholipid, PLA2 also generates lysophospholipid, which can be converted into other inflammatory mediators. The action of PLA2 is the trigger that determines whether the pro-inflammatory cascade will begin.
The Role of Cyclooxygenase in Inflammation
Once arachidonic acid is released, it can enter the Cyclooxygenase (COX) pathway, which represents the first major branch of the cascade. The COX enzymes, specifically COX-1 and COX-2, convert the free AA into a class of molecules known as prostanoids, which include prostaglandins and thromboxanes. This branch is directly responsible for most of the acute symptoms associated with localized inflammation.
Cyclooxygenase-1 (COX-1) is termed a constitutive enzyme, meaning it is expressed continuously in most tissues and performs necessary “housekeeping” functions. COX-1 activity generates prostaglandins that protect the stomach lining, regulate kidney blood flow, and produce thromboxane A2 (TxA2) to promote blood clotting in platelets.
Cyclooxygenase-2 (COX-2), conversely, is largely an inducible enzyme, meaning its expression is dramatically increased at sites of injury or inflammation by pro-inflammatory signals. The prostaglandins generated by COX-2 activity are the primary mediators of pain, fever, and the localized swelling and redness characteristic of inflammation. Specifically, these prostaglandins cause vasodilation, increasing blood flow to the injured area, and sensitize nerve endings to pain.
Thromboxanes, primarily TxA2, are synthesized mainly by COX-1 in platelets. They act as vasoconstrictors and promote platelet aggregation, which is necessary for forming a plug to stop bleeding. Prostaglandins, such as PGE2, are involved in virtually all aspects of the inflammatory response, including regulating the body’s temperature set-point in the hypothalamus to induce fever.
Leukotrienes and Immune Signaling
The second major branch of the arachidonic acid pathway involves the Lipoxygenase (LOX) enzymes, which convert the liberated AA into leukotrienes. Leukotrienes are lipid mediators that contrast with prostaglandins by focusing primarily on immune cell recruitment and allergic responses. This pathway is most active in specific immune cells, such as neutrophils, mast cells, and eosinophils.
The enzyme 5-Lipoxygenase (5-LOX) is responsible for initiating this branch, transforming AA into intermediate products that are then rapidly converted into various leukotrienes. One primary product, leukotriene B4 (LTB4), functions as a chemoattractant, signaling neutrophils to migrate rapidly to the site of injury or infection. This process is a fundamental part of the acute immune response.
Another important group, the cysteinyl leukotrienes (LTC4, LTD4, and LTE4), are the primary mediators in allergic and respiratory conditions like asthma. These molecules induce sustained contraction of the smooth muscle lining the airways, leading to bronchoconstriction and increased mucus secretion. The excessive production of these specific leukotrienes is what drives the severe symptoms associated with asthmatic attacks and anaphylaxis.
Therapeutic Regulation of the Pathway
Understanding the enzyme-driven steps of the pathway has allowed for the development of targeted therapies to manage inflammation and pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, work by inhibiting the COX enzymes, thereby blocking the synthesis of pro-inflammatory prostaglandins and thromboxanes. These are considered non-selective because they inhibit both the constitutive COX-1 and the inducible COX-2 isoforms.
The inhibition of COX-1, while providing pain relief, can unfortunately lead to gastrointestinal side effects, as it reduces the protective prostaglandins that maintain the stomach lining. To mitigate this risk, scientists developed selective COX-2 inhibitors, often called coxibs, like celecoxib. These drugs primarily target the COX-2 enzyme at the site of inflammation, aiming to reduce pain with less impact on the protective functions of COX-1.
Corticosteroids, a different class of anti-inflammatory drugs, work higher up in the cascade, providing broader suppression of the pathway. Their mechanism involves inhibiting Phospholipase A2 (PLA2), the initial enzyme responsible for releasing AA from the cell membrane. By blocking this first step, corticosteroids prevent the formation of both prostaglandins and leukotrienes.
The LOX pathway can also be targeted with specific medications to treat conditions like asthma. Leukotriene receptor antagonists, such as montelukast, do not inhibit the enzyme itself but rather block the receptors on cells that leukotrienes would normally bind to. This prevents the cysteinyl leukotrienes from causing bronchoconstriction and inflammation, offering a focused treatment for respiratory allergies.