Effects of Platelet Activating Factor (PAF) in asthma and anaphylaxis

PAF is released by many different cells, including eosinophils, mast cells, neutrophils, monocytes, macrophages and endothelial cells. PAF receptors are expressed by platelets, monocytes, mast cells, neutrophils, and eosinophils. T and B cells do not express PAF receptors, but PAF can stimulate them to migration of these cells. PAF receptors are found to be increased in eosinophils of asthma patients. PAF receptors are also elevated in lungs of asthmatic patients. PAF can activate mast cells and basophils, causing histamine release. One study proposed the PAF activation of basophils may play a role in aspirin sensitivity in asthma patients.

PAF is most well known for its effects on the airway. It causes constriction of the airway and can affect the way oxygen is brought into the lungs. However, it also has many other effects in the body, many of which affect anaphylaxis and severity thereof.

PAF activates eosinophils and neutrophils to degranulate. It also causes leukotriene C4 production by activated eosinophils in asthma patients, but not in normal patients. A PAF inhibitor has been observed to prevent eosinophil migration and leukotriene C4. Another PAF inhibitor was able to inhibit eosinophil activation by PAF. In activated neutrophils in asthma patients, PAF causes an increase in secretion of leukotriene B4 and increased 5-lipoxygenase activity.

PAF is a powerful signal for eosinophils to migrate toward the cell releasing PAF, and may be involved in inflammation resulting in eosinophilic infiltration. PAF can cause eosinophilic movement across endothelium and into airway. This behavior is increased during asthma attacks and can be minimized with steroids.

PAF injected into the skin causes a biphasic reaction with immediate hiving, then a delayed redness and pain reaction that causes eosinophilic infiltration. PAF also increases IL-6 production by macrophages, activates IL-4 production by T cells, and enhances IL-6 production by mononuclear cells in peripheral blood.

PAF has been heavily linked to asthma. One study found higher levels of PAF as well as lower level of the enzyme that inactivates PAF in plasma of asthmatic adults both during attacks and the rest of the time. When exposed to allergens, PAF level in blood rapidly increases. The large increases in PAF level upon exposure were ameliorated upon successful allergen immunotherapy (also known in the US as “allergy shots”).

PAF induced bronchoconstriction does not affect histamine release and is not alleviated by H1 receptor antihistamines. Inhaling PAF does not change plasma histamine level in asthmatics. Leukotrienes may behave as secondary mediators of PAF action. Zileuton attenuated systemic and respiratory effects of PAF, including airway constriction and changes in neutrophil behavior.

PAF level, and the level of the enzyme that metabolizes it, PAF-acetylhydrolase, is directly correlated to severity of anaphylaxis. Patients with grade I anaphylaxis have 2.5x as much PAF as controls; grade II, 5x; and grade III, 10x. PAF blockers are being investigated for use in this context. Rupatadine is available in some countries, and has H1 antihistamine and PAF blocking activity.

The exact nature of PAF’s activity in anaphylaxis is unclear. It has been shown to cause mast cell degranulation and increased production and release of prostaglandin D2. It can also amplify the response to IgE, making the allergic reaction worse. However, these effects were not seen in skin mast cells for unknown reasons. The source of PAF that acts on mast cells in anaphylaxis is unknown, but is thought to be at least partially from mast cells themselves.

 

References:

Kasperska-Zajac, Z. Brzoza, and B. Rogala. Platelet Activating Factor as a Mediator and Therapeutic Approach in Bronchial Asthma. Inflammation, Vol. 31, No. 2, April 2008.

Peter Vadas, M.D., Ph.D., Milton Gold, M.D., Boris Perelman, Ph.D., Gary M. Liss, M.D., Gideon Lack, M.D., Thomas Blyth, M.D., F. Estelle R. Simons, M.D., Keith J. Simons, Ph.D., Dan Cass, M.D., and Jupiter Yeung, Ph.D. Platelet-Activating Factor, PAF Acetylhydrolase, and Severe Anaphylaxis. N Engl J Med 2008; 358:28-35.

Vadas P, Gold M, Liss G, Smith C, Yeung J, Perelman B. PAF acetylhydrolase predisposes to fatal anaphylaxis. J Allergy Clin Immunol 2003;111: S206-S206.

Kajiwara N, Sasaki T, Bradding P, Cruse G, Sagara H, Ohmori K, Saito H, Ra C, Okayama Y. Activation of human mast cells through the platelet-activating factor receptor. J Allergy Clin Immunol. 2010 May; 125(5): 1137-1145.

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