Mast cell mediators: Prostaglandin D2 (PGD2)

Prostaglandin D2 (PGD2) is the predominant prostaglandin product released by mast cells. It is found prevalently in the central nervous system and peripheral tissues, where it performs both inflammatory and normal processes. In the brain, PGD2 helps to regulate sleep and pain perception. PGD2 can be further broken down into other prostaglandins, including PGF2a; 9a, 11b-PGF2a (a different shape of PGF2a), and forms of PGJ. 9a, 11b-PGF2a shares the same biological functions as PGD2. Both of these can be tested for in 24 hour urine test as markers of mast cell disease.

PGD2 is a strong bronchoconstrictor. It is 10.2x more potent in this capacity than histamine and 3.5x more potent than PGF2a. It has been associated with inflammatory and atopic conditions for many years. Presence of allergen activates PGD2 production in sensitized people. In asthmatics, bronchial samples can achieve over 150x the level of PGD2 compared to controls. Elevated PGD2 has been associated with chronic coughing.

PGD2 is a driver of inflammation in many settings. It acts on bronchial epithelium to cause production of chemokines and cytokines. It also brings lymphocytes and eosinophils to the airway, which induces airway inflammation and hyperreactivity in asthmatics. PGD2 may also inhibit eosinophil cell death, resulting in further inflammation.

An interesting facet of PGD2 is its role in nerve pain. It has been found that PGD2 is produced by microglia in the spine after a peripheral nerve injury. These cells make more COX-1, which then makes PGD2. Newer COX-2 inhibiting NSAIDs do not affect nerve pain in mouse models, but older NSAIDs that inhibit COX-1 and COX-2 reduce neuropathy.

PGD2 is found to inhibit inflammation in other settings. It can reduce eosinophilia in allergic inflammation in mouse models. Additionally, once the acute phase of inflammation is over and it is resolving, administering a COX-2 inhibitor actually makes the inflammation worse. This indicates that PGD2 may be important in resolving inflammation in some processes.

Aspirin is commonly used in mast cell patients to inhibit prostaglandin production. PGD2 is primarily manufactured by COX-2, but the pathway that evokes neuropathy uses COX-1. There are a number of COX-1 and COX-2 inhibitors available.

In mast cell patients, PGD2 is probably most well known for causing flushing. This happens due to dilation of blood vessels in the skin. Due to a well characterized response to aspirin, this is generally the first line medication choice. Some salicylate sensitive mast cell patients undergo aspirin desensitization to be able to use this medication.

 

References:

Emanuela Ricciotti, Garret A. FitzGerald. Prostaglandins and Inflammation. Arterioscler Thromb Vasc Biol. 2011; 31: 986-1000.

Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S. Prostaglandin D2 as a mediator of allergic asthma. Science. 2000;287: 2013–2017.

G Bochenek, E Nizankowska, A Gielicz, M Swierczynska, A Szczeklik. Plasma 9a,11b-PGF2, a PGD2 metabolite, as a sensitive marker of mast cell activation by allergen in bronchial asthma. Thorax 2004; 59: 459–464.

Victor Dishy, MD, Fang Liu, PhD, David L. Ebel, BS, RPh, George J. Atiee, MD, Jane Royalty, MD, Sandra Reilley, MD, John F. Paolini, MD, PhD, John A. Wagner, MD, PhD, and Eseng Lai, MD, PhD. Effects of Aspirin When Added to the Prostaglandin D2 Receptor Antagonist Laropiprant on Niacin-Induced Flushing Symptoms. Journal of Clinical Pharmacology, 2009; 49: 416-422