Monitoring Mast Cell Activation by Prostaglandin D2 in Vivo
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EDITORIAL 453 Mast cell activation by the demonstration of its release into ....................................................................................... human airways after local endotracheal Thorax: first published as 10.1136/thx.2003.016774 on 28 May 2004. Downloaded from instillation of allergen.15 However, the mechanistic significance of these reports Monitoring mast cell activation by was not generally appreciated. In humans, mast cells are an almost 16 prostaglandin D2 in vivo exclusive cellular source of PGD2. Although there is evidence of some S-E Dahle´n, M Kumlin PGD2 formation by platelets, macro- phages and certain T lymphocytes,13 ................................................................................... the reported amounts are 100–1000 times lower than those produced during Prostaglandin D2 is a useful in vivo marker of mast cell activation IgE dependent activation of mast cells. in humans More importantly, whereas the basophil and the mast cell both release histamine hile the pro-inflammatory role cells, have been reported to make up and leukotriene (LT) C4, it is only the of eosinophilic granulocytes in about 25% of total mast cell protein.11 mast cell that produces significant 16 asthma is currently under This would seem to make tryptase an quantities of PGD2. There is, in fact, W recent evidence to show that increased debate, an increasing body of evidence ideal marker of mast cell activation. suggests that mast cells may indeed Although tryptase measurements are expression of the haematopoetic PGD2 orchestrate many of the characteristic very useful in experimental work with synthase may be the functional response pathophysiological changes in asthma.1 cells and tissues, this marker has not that is most specifically upregulated in 17 There are also indications that the mast been particularly helpful in mechanistic activated mast cells. cell may be an effector cell in other lung studies addressing mast cell activation diseases such as chronic obstructive in humans. This may relate to limita- MEASUREMENT OF PGD2 pulmonary disease2–4 and lung fibrosis.5 tions in the currently available metho- The currently renewed interest in appli- Given the location of mast cells at dology for measuring plasma or serum cations of PGD2 measurement would multiple sites within the airways,1 they tryptase. Nevertheless, so far, the main not have been possible without the clearly have the potential to function as uses of tryptase measurements are to comprehensive work of Roberts and sensors of alterations in the microenvir- provide evidence for the diagnosis of colleagues at Vanderbilt who performed onment—be it to inhaled or bloodborne systemic mastocytosis or necropsy evi- painstaking GC/MS identifications of 12 substances, microbes, or other insults dence of systemic anaphylaxis. PGD2 metabolites in blood and urine that require a prompt host defence Prostaglandins (PG) are ubiquitously after injections of radiolabelled 18 19 reaction. Their versatility is demon- biosynthesised and would therefore PGD2. More than 25 metabolites strated by the great number of stimuli seem to be unlikely candidates as were identified but intact PGD2 was that trigger mast cell activation (fig 1). specific markers for any particular cell. not found in the urine. The most http://thorax.bmj.com/ In addition to classical IgE dependent However, in this issue of Thorax, abundant PGD2 metabolite identified degranulation of mast cells, transduc- Bochenek et al13 confirm and extend was 9,11-dihydroxy-15-oxo-2,3,18,19- tion pathways resulting in mast cell the accumulated evidence that measure- tetranorprost-5-ene-1,20-dioc acid, activation may be triggered by, for ment of PGD2 or its metabolites repre- commonly referred to as PGD-M. The example, adenosine,6 hyperosmolarity,7 sents a sensitive and reliable strategy for earliest appearing urinary metabolite 8 and lipopolysaccharide. assessment of mast cell activation in was 9a,11b-PGF2, which was subse- vivo. Specifically, they convincingly quently shown to be stereospecifically MAST CELL MARKERS show, for the first time, increased levels transformed from PGD2 by the NADPH Although many mast cell mediators or of the primary PGD2 metabolite 9a11b- dependent enzyme 11-ketoreductase20 in on September 28, 2021 by guest. Protected copyright. products serve as useful markers of mast PGF2 in plasma during the early phase lung and liver. Interestingly, 9a,11b- cell activation in vitro, it has been of allergen induced airway obstruction. PGF2 retains biological activity. It has, notoriously difficult conclusively to This is achieved by applying gas chro- for example, been found to contract establish mast cell activation in human matography-negative ion chemical ioni- bronchial smooth muscle21 and has studies. For example, it is difficult to sation-mass spectrometry (GC-NICI- vascular effects including contraction catch the short lived increase in plasma MS) to samples collected at frequent of coronary arteries.22 Metabolism of levels of histamine and its metabolites intervals before and during allergen 9a,11b-PGF2 by the 15-hydroxy prosta- following allergen induced bronchocon- bronchoprovocation of subjects with glandin dehydrogenase, followed by b- striction. Furthermore, circulating baso- atopic asthma. The methodology is very and v- oxidations, leads to PGD-M. phils may contribute significantly to appropriate as GC-NICI-MS is the most The Vanderbilt group thus used GC/ plasma histamine9 and plasma values specific measurement of this particular MS measurements of PGD-M as a family of compounds, where the pre- may be increased by non-specific chal- marker of systemic PGD2 production in lenges such as an ordinary exercise test. sence of numerous structurally related different disease states. Markedly raised Measurements of urinary metabolites of metabolites always complicates immu- levels of PGD-M were discovered in histamine may sometimes be helpful to noassay measurements. Bochenek et al systemic mastocytosis23 as well as dur- provide information regarding systemi- also deserve credit for their development ing anaphylaxis. The GC/MS approach cally released histamine over time10 but, of a protocol that improves the sensitiv- is, however, laborious and technologi- due to extensive metabolism, only a ity of the GC-NICI-MS measurements. cally demanding, which generally ren- small percentage of circulating hista- ders it less applicable to studies of mine levels appear in the urine and the BIOSYNTHESIS OF PGD2 IN MAST populations and large numbers of sam- ambiguity with regard to the cellular CELLS ples. The more recent validation of an source remains. The release of PGD2 from isolated immunoassay method for the measure- 24 25 Tryptases, which are proteases human mast cells was reported more ment of 9a,11b-PGF2 in urine has secreted by degranulating human mast than two decades ago,14 shortly followed therefore created new opportunities for www.thoraxjnl.com 454 EDITORIAL induced bronchoconstriction that Allergen Non-allergic triggers remains resistant to antihistamines Thorax: first published as 10.1136/thx.2003.016774 on 28 May 2004. Downloaded from and antileukotrienes.30 Experimental data are available to support such a 29 31 role, and a role for PGD2 in rhinitic responses in humans has also been implicated.32 The recent awareness that there are at least three different recep- tors (TP, DP, and CRTH2) mediating the Heparin 29 effects of PGD2 in the airways suggests that we may soon get improved oppor- tunities to define more precisely the LTC 4 Cytokines, pulmonary role of this mast cell derived Growth factors mediator. Thorax 2004;59:453–455. Histamine doi: 10.1136/thx.2004.026641 PGD 2 TRYPTASE ...................... Authors’ affiliations Figure 1 Mast cells may produce a large number of mediators, enzymes, cytokines and other S-E Dahle´n, M Kumlin, Experimental Asthma factors in response to allergic (IgE dependent) or non-allergic activation (adenosine, exercise, and Allergy Research, The National Institute of endotoxin, mannitol, non-steroidal anti-inflammatory drugs (NSAIDs) in NSAID intolerant subjects, Environmental Medicine, Karolinska Institutet, etc). However, only tryptase and prostaglandin (PG) D2 (boxed) are specific markers of mast cell Stockholm, Sweden activation. As reported by Bochenek et al in this issue, measurement of PGD2 and its metabolites is currently the most sensitive strategy to monitor mast cell activation in human subjects. Correspondence to: Professor S-E Dahle´n, LTC4 = leukotriene C4. Experimental Asthma and Allergy Research, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm using this PGD2 metabolite as a mast metabolites in urine, the chemically SE-171 77, Sweden; [email protected] cell marker. Using this immunoassay less specific immunoassay will para- methodology, increased excretion of doxically have greater practical sensi- metabolites of PGD2 into the urine has tivity as it measures several related REFERENCES been observed after allergen induced PGD2 metabolites. However, as pointed 1 Brightling CE, Bradding P, Symon FA, et al. Mast bronchoconstriction10 24 and mast cell out by Bochenek et al, for studies of cell infiltration of airway smooth muscle in the kinetics of 9a,11b-PGF metabo- asthma. N Engl J Med 2002;346:1699–705. involvement in other indirect challenges 2 2 Grashoff WF, Sont JK, Sterk PJ, et al. Chronic 24 26 27 has also been confirmed. lism, the chemically more specific obstructive pulmonary disease: role