Open Mind, Open Airways
Broadening the Paradigm of Prostaglandins and Allergic Airway Inflammation

Marc Peters-Golden, M.D.

Division of Pulmonary and Critical Care Medicine, University of Michigan Health System,Ann Arbor, Michigan

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Prostaglandins (PGs) are proinflammatory, and pharmacologic agents that inhibit cyclooxygenase (COX)-catalyzed synthesis of PGs from arachidonic acid are antiinflammatory.

What self-respecting medical student does not recognize this statement as the epitome of medical dogma? Dogma provides a comfortable framework for the things we know. Yet one of the important functions of research is to question whether the constraints of dogma may have blinded us to unexpected findings that warrant a reformulation of the paradigm. Indeed, a number of observations over the last decade suggest that the "PGs are proinflammatory" axiom tells only part of the story. The article in this issue of the AJRCCM (pp. 1154-1160) by Peebles and colleagues (1) provides some thought-provoking insights into the role of PGs in allergic airway inflammation that will be surprising to many readers.

In allergic asthma, it is thought that airway hyperresponsiveness is the eventual consequence of a so-called T helper 2 (Th2)-type of inflammation, in which lymphocytes producing cytokines such as interleukins (IL)-4, -5, and -13 drive an eosinophilic inflammatory process. There is abundant evidence that the COX product PGD₂ can promote Th2 responses and airway hyperresponsiveness (2). It is less well appreciated that PGE₂ can have salutary effects on these processes. Peebles and coworkers (1) focus our attention on the role of PGs, most likely PGE₂, in Th2 immune responses.

These authors tested the effects of administration of COX inhibitors throughout the entire duration of ovalbumin sensitization and airway challenge in mice. One of the inhibitors utilized was indomethacin, a widely used agent that inhibits both the so-called constitutive (COX-1) and inducible (COX-2) isoforms of COX. To probe the specific roles of each of the enzyme isoforms, they also administered selective inhibitors of either COX-1 or COX-2. Their key findings were that in allergen sensitized and challenged mice, indomethacin as well as both of the isoform-selective COX inhibitors (1) increased lung expression of the Th2 cytokines IL-5 and -13; (2) increased mRNA for the chemokine receptors CCR1-5; and (3) increased airway hyperresponsiveness.

The classical mechanism-based actions of COX inhibitors reflect the consequences of inhibiting the metabolism of arachidonate to bioactive PGs. Alternatively, these agents can divert arachidonic acid to other metabolic products, such as the proinflammatory leukotrienes; however, Peebles and coworkers found only a modest but nonsignificant increase in lung leukotriene levels in the COX inhibitor-treated mice. COX inhibitors can also act at molecular targets other than COX (3), but the fact that three structurally unrelated inhibitors had similar effects argues against this possibility. Thus, it seems likely that the observed effects reflect inhibition of an anti- allergic PG, most likely PGE₂. This conclusion will ultimately require more definitive experimental approaches that specifically target PGE₂ or its receptors.

One of the most important but least appreciated actions of arachidonate metabolites is their capacity to modulate the generation of other mediators of inflammation. The observation by Peebles and coworkers that COX inhibitors enhanced the pulmonary expression of the Th2 cytokines IL-5 and -13 suggests that PGE₂ (or a functionally similar PG) must exert a downregulatory effect on these cytokines. Such an action is consistent with a sizable body of evidence indicating that PGE₂ can inhibit the gene expression or synthesis of a variety of proinflammatory molecules (4). These include tumor necrosis factor, IL-8, monocyte chemoattractant protein-1, adhesion molecules, endothelin, superoxide, and leukotrienes. A novel finding in this paper was the increased pulmonary expression of mRNA encoding the chemokine receptors CCR1-5 after the administration of the COX-2 inhibitor. This indicates that PGE₂ can downregulate inflammation by inhibiting the expression of both inflammatory mediators as well as their receptors.

The suggestion that PGE₂ inhibits the generation of Th2 cytokines in vivo in this model of allergic asthma appears to contradict the commonly held view that PGE₂ favors a Th2 cytokine profile. This latter perception is based on in vitro studies demonstrating that it selectively inhibits lymphocyte synthesis of Th1 cytokines such as IL-2 and interferon-, while either not affecting or actually increasing Th2 cytokine synthesis (5). The explanation for this discrepancy may simply reflect the fact that in vivo, cells other than lymphocytes (e.g., antigen-presenting dendritic cells) participate in immune responses. Alternatively, it may relate to the existence of four different types of PGE₂ receptors, each coupled to different signal transduction pathways (4). Which of the pleiotropic effects of PGE₂ are manifest therefore depends on the profile of PGE₂ receptors expressed, and it is possible that T lymphocyte PGE₂ receptor profiles differ in vitro and in the allergen-challenged lung in vivo.

A number of important questions raised by this paper remain unanswered, but I will highlight only two of them. First, it is not clear whether the inhibitory effects of a suppressive PG (presumably PGE₂) on airway hyperresponsiveness in this study reflect its actions on the afferent or the efferent limbs of the immune response. Both are possible because PGE₂ has been shown to inhibit dendritic cell function (6), cytokine formation, eosinophil recruitment, and airway smooth muscle contractility (7). It was recently reported that COX-2 inhibitors, initiated after the period of allergen sensitization, abrogated airway inflammation, presumably by inhibiting the synthesis of proinflammatory PGD₂ (8). This would suggest that the pro-allergic effects of COX inhibitors observed by Peebles and coworkers (1) reflect an interruption of the actions of a suppressive PG on the afferent immune response.

Second, what are the clinical implications of these findings? It is important to recognize that the mere presence of COX-2 at sites of inflammation does not necessarily indict it as a perpetratorthe police officer at the scene of a crime analogy. In fact, a growing body of literature suggests that the capacity to induce COX-2 and to upregulate PGE₂ synthesis can serve an important protective role (9, 10). The fact that COX inhibitors abrogate the synthesis of both pro- and anti-allergic PGs may explain why, in most patients, their use has no apparent effect on airway responses. However, there may well be patients in whom, for genetic or acquired reasons, airway synthesis or actions of PGD₂ versus PGE₂ may predominate, or may be more susceptible to inhibition; in this scenario, a COX inhibitor could either reduce or promote susceptibility to allergic airway disease. The fact that these agents are so widely used and that their use is so often not even reported to physicians makes it hazardous to dismiss such possibilities out of hand.

Pharmacologic agents that selectively inhibit the synthesis or actions of PGD₂ are currently under development and certainly hold promise. However, we should not ignore the therapeutic potential of complementary strategies designed to increase either the levels of PGE₂ or the anti-allergic and anti-asthmatic responses to this prostanoid.

	References

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