Monitoring mast cell activation by prostaglandin D2 in vivo
http://www.100md.com
《胸》
Experimental Asthma and Allergy Research, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Correspondence to:
Professor S-E Dahlén
Experimental Asthma and Allergy Research, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden; se.dahlen@imm.ki.se
Prostaglandin D2 is a useful in vivo marker of mast cell activation in humans
Keywords: asthma; mast cells; prostaglandin D2; plasma 9,11?-PGF2
While the pro-inflammatory role of eosinophilic granulocytes in asthma is currently under debate, an increasing body of evidence suggests that mast cells may indeed orchestrate many of the characteristic pathophysiological changes in asthma.1 There are also indications that the mast cell may be an effector cell in other lung diseases such as chronic obstructive pulmonary disease2–4 and lung fibrosis.5 Given the location of mast cells at multiple sites within the airways,1 they clearly have the potential to function as sensors of alterations in the microenvironment—be it to inhaled or bloodborne substances, microbes, or other insults that require a prompt host defence reaction. Their versatility is demonstrated by the great number of stimuli that trigger mast cell activation (fig 1). In addition to classical IgE dependent degranulation of mast cells, transduction pathways resulting in mast cell activation may be triggered by, for example, adenosine,6 hyperosmolarity,7 and lipopolysaccharide.8
Figure 1 Mast cells may produce a large number of mediators, enzymes, cytokines and other factors in response to allergic (IgE dependent) or non-allergic activation (adenosine, exercise, endotoxin, mannitol, non-steroidal anti-inflammatory drugs (NSAIDs) in NSAID intolerant subjects, etc). However, only tryptase and prostaglandin (PG) D2 (boxed) are specific markers of mast cell 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. LTC4 = leukotriene C4.
MAST CELL MARKERS
Although many mast cell mediators or products serve as useful markers of mast cell activation in vitro, it has been notoriously difficult conclusively to establish mast cell activation in human studies. For example, it is difficult to catch the short lived increase in plasma levels of histamine and its metabolites following allergen induced bronchoconstriction. Furthermore, circulating basophils may contribute significantly to plasma histamine9 and plasma values may be increased by non-specific challenges such as an ordinary exercise test. Measurements of urinary metabolites of histamine may sometimes be helpful to provide information regarding systemically released histamine over time10 but, due to extensive metabolism, only a small percentage of circulating histamine levels appear in the urine and the ambiguity with regard to the cellular source remains.
Tryptases, which are proteases secreted by degranulating human mast cells, have been reported to make up about 25% of total mast cell protein.11 This would seem to make tryptase an ideal marker of mast cell activation. Although tryptase measurements are very useful in experimental work with cells and tissues, this marker has not been particularly helpful in mechanistic studies addressing mast cell activation in humans. This may relate to limitations in the currently available methodology for measuring plasma or serum tryptase. Nevertheless, so far, the main uses of tryptase measurements are to provide evidence for the diagnosis of systemic mastocytosis or necropsy evidence of systemic anaphylaxis.12
Prostaglandins (PG) are ubiquitously biosynthesised and would therefore seem to be unlikely candidates as specific markers for any particular cell. However, in this issue of Thorax, Bochenek et al13 confirm and extend the accumulated evidence that measurement of PGD2 or its metabolites represents a sensitive and reliable strategy for assessment of mast cell activation in vivo. Specifically, they convincingly show, for the first time, increased levels of the primary PGD2 metabolite 911?-PGF2 in plasma during the early phase of allergen induced airway obstruction. This is achieved by applying gas chromatography-negative ion chemical ionisation-mass spectrometry (GC-NICI-MS) to samples collected at frequent intervals before and during allergen bronchoprovocation of subjects with atopic asthma. The methodology is very appropriate as GC-NICI-MS is the most specific measurement of this particular family of compounds, where the presence of numerous structurally related metabolites always complicates immunoassay measurements. Bochenek et al also deserve credit for their development of a protocol that improves the sensitivity of the GC-NICI-MS measurements.
BIOSYNTHESIS OF PGD2 IN MAST CELLS
The release of PGD2 from isolated human mast cells was reported more than two decades ago,14 shortly followed by the demonstration of its release into human airways after local endotracheal instillation of allergen.15 However, the mechanistic significance of these reports was not generally appreciated. In humans, mast cells are an almost exclusive cellular source of PGD2.16 Although there is evidence of some PGD2 formation by platelets, macrophages and certain T lymphocytes,13 the reported amounts are 100–1000 times lower than those produced during IgE dependent activation of mast cells. More importantly, whereas the basophil and the mast cell both release histamine and leukotriene (LT) C4, it is only the mast cell that produces significant quantities of PGD2.16 There is, in fact, recent evidence to show that increased expression of the haematopoetic PGD2 synthase may be the functional response that is most specifically upregulated in activated mast cells.17
MEASUREMENT OF PGD2
The currently renewed interest in applications of PGD2 measurement would not have been possible without the comprehensive work of Roberts and colleagues at Vanderbilt who performed painstaking GC/MS identifications of PGD2 metabolites in blood and urine after injections of radiolabelled PGD2.18,19 More than 25 metabolites were identified but intact PGD2 was not found in the urine. The most abundant PGD2 metabolite identified was 9,11-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioc acid, commonly referred to as PGD-M. The earliest appearing urinary metabolite was 9,11?-PGF2, which was subsequently shown to be stereospecifically transformed from PGD2 by the NADPH dependent enzyme 11-ketoreductase20 in lung and liver. Interestingly, 9,11?-PGF2 retains biological activity. It has, for example, been found to contract bronchial smooth muscle21 and has vascular effects including contraction of coronary arteries.22 Metabolism of 9,11?-PGF2 by the 15-hydroxy prostaglandin dehydrogenase, followed by ?- and - oxidations, leads to PGD-M.
The Vanderbilt group thus used GC/MS measurements of PGD-M as a marker of systemic PGD2 production in different disease states. Markedly raised levels of PGD-M were discovered in systemic mastocytosis23 as well as during anaphylaxis. The GC/MS approach is, however, laborious and technologically demanding, which generally renders it less applicable to studies of populations and large numbers of samples. The more recent validation of an immunoassay method for the measurement of 9,11?-PGF2 in urine24,25 has therefore created new opportunities for using this PGD2 metabolite as a mast cell marker. Using this immunoassay methodology, increased excretion of metabolites of PGD2 into the urine has been observed after allergen induced bronchoconstriction10,24 and mast cell involvement in other indirect challenges has also been confirmed.24,26,27
As discussed by Bochenek et al,13 apart from weak indirect or anecdotal evidence, there has not previously been any investigation of 9,11?-PGF2 levels in plasma during allergen induced bronchoconstriction, which undoubtedly must be the gold standard for mast cell activation. Interestingly, the current demonstration of increased PGD2 release during allergen induced bronchoconstriction puts further weight behind a previous publication from the group in Krakow where increased plasma levels of 9,11?-PGF2 were found following aspirin induced bronchoconstriction.28 This adds to several other lines of evidence24 suggesting that the intolerance to aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) involves mast cell activation.
Bochenek et al confirmed the original observations by Liston et al18 that 9,11?-PGF2 was the first PGD2 metabolite to appear in urine, although they did not find the increase of this metabolite in the urine to be as great as that reported by O’Sullivan et al.10 These seemingly different findings are most probably explained by the demonstration25 that the immunoassay measures not only 9,11?-PGF2 but also at least two other metabolites that appear somewhat later. In other words, for detection of the sum of the initially excreted PGD2 metabolites in urine, the chemically less specific immunoassay will paradoxically have greater practical sensitivity as it measures several related PGD2 metabolites. However, as pointed out by Bochenek et al, for studies of the kinetics of 9,11?-PGF2 metabolism, the chemically more specific method is obviously preferable.
PERSPECTIVES
The method chosen to monitor mast cell activation by measurement of PGD2 metabolites will obviously depend on the questions asked and the resources available. Irrespective of the analytical method selected, measurements of 9,11?-PGF2 in plasma, urine, or other body fluids currently provide the most sensitive method for detection of mast cell activation in vivo. This was clearly shown in the paper by Bochenek et al, where there was no change in plasma tryptase despite the fivefold increase in plasma 9,11?-PGF2. Similarly, in previous work by O’Sullivan et al,10,26 there was consistently a much smaller or non-significant increase in urinary methyl histamine in contrast to consistent and prominent increases in urinary 911?-PGF2 metabolites. Thus, for investigations into the role of the mast cell in different pulmonary diseases, measurements of PGD2 metabolites in body fluids offer many new opportunities.
Finally, PGD2 is not only a marker of mast cell activation but also—together with its immediate metabolite 9,11?-PGF2—it is a potent mediator of bronchoconstriction, vasomotor tone, and cell recruitment.29 We hypothesise that PGD2 mediates the component of allergen induced bronchoconstriction that remains resistant to antihistamines and antileukotrienes.30 Experimental data are available to support such a role,29,31 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 receptors (TP, DP, and CRTH2) mediating the effects of PGD2 in the airways29 suggests that we may soon get improved opportunities to define more precisely the pulmonary role of this mast cell derived mediator.
REFERENCES
Brightling CE, Bradding P, Symon FA, et al. Mast cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002;346:1699–705.
Grashoff WF, Sont JK, Sterk PJ, et al. Chronic obstructive pulmonary disease: role of bronchioloar mast cells and macrophages. Am J Pathol 1997;151:1785–90.
Taube C, Holtz O, Mucke M, et al. Airway response to inhaled hypertonic saline in patients with moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1810–5.
Hattotuwa KL, Gizycki MJ, Ansari TW, et al. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo controlled biopsy study. Am J Respir Crit Care Med 2002;165:1592–6.
Inoue Y, King TE Jr, Tinkle SS, et al. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am J Pathol 1996;149:2037–54.
Bj?rck T, Gustafsson L-E, Dahlén S-E. Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of histamine and leukotrienes. Am Rev Respir Dis 1992;145:1087–95.
Eggleston PA, Kagey-Sobotka A, Schleimer R, et al. Interaction between hyperosmolar and IgE-mediated histamine release from basophils and mast cells. Am Rev Respir Dis 1984;130:86–91.
Marshall JS, McCurdy JD, Olynych T. Toll-like receptor operated activation of mast cells: implications for allergic disease? Int Arch Allergy Immunol 2003;132:87–97.
Howarth PH, Pao GJK, Church MK, et al. Exercise- and isocapnic hyperventilation-induced bronchoconstriction in asthma, relevance of circulating basophils to measurements of plasma histamine. J Allergy Clin Immunol 1984;73:391–9.
O’Sullivan S, Roquet A, Dahlén B, et al. Urinary excretion of inflammatory mediators during allergen-induced early and late phase asthmatic reactions. Clin Exp Allergy 1998;28:1332–9.
Schwartz LB, Irani A-M A, Roller K, et al. Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells. J Immunol 1987;138:2611–5.
Schwartz LB. Clinical utility of tryptase levels in systemic mastocytosis and associated hematologic disorders. Leuk Res 2001;25:553–62.
Bochenek G, Nizankowska E, Gielicz A, et al. Plasma 9,11?-PGF2, a PGD2 metabolite, as a sensitive marker of mast cell activation by allergen in bronchial asthma. Thorax 2004;59:459–64.
Lewis RA, Soter NA, Diamond PT, et al. Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE. J Immunol 1982;129:1627–31.
Murray JJ, Tonnel AB, Brash AR, et al. Release of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med 1986;315:800–4.
O’Sullivan S. On the role of PGD2 metabolites as markers of mast cell activation in asthma. Acta Physiol Scand Suppl 1999;644:1–74.
Li L, Yang Y, Stevens RL. Ras GRP4 regulates the expression of prostaglandin D2 in human and rat mast cell lines. J Biol Chem 2003;278:4725–9.
Liston TE, Roberts LJ II. Metabolic fate of radiolabelled prostaglandin D2 in a normal human male volunteer. J Biol Chem 1985;260:13172–80.
Liston TE, Roberts LJ II. Transformation of prostaglandin D2 to 9,11?-(15S)-trihydroxyprosta-(5Z,13E)-dien-1-oic acid (911?-PGF2): a unique biologically active prostaglandin produced enzymatically in vivo in humans. Proc Natl Acad Sci USA 1985;82:6030–4.
Pugliese G, Spokas EG, Marcinkiewicz E, et al. Hepatic transformation of prostaglandin D2 to a new prostanoid, 911?-PGF2, that inhibits platelet aggregation and constricts blood vessels. J Biol Chem 1985;260:14621–5.
Beasley CR, Robinson C, Featherstone RL, et al. 9 alpha,11 beta-prostaglandin F2, a novel metabolite of prostaglandin D2 is a potent contractile agonist of human and guinea pig airways. J Clin Invest 1987;79:978–83.
Roberts LJ II, Seibert K, Liston TE, et al. Prostaglandin D2 is transformed by human coronary arteries to 911?-PGF2, which contracts human coronary artery rings. Adv Prostaglandin Thromboxane Leukot Res 1987;17A:427–9.
Roberts LJ II, Sweatman BJ, Lewis RA, et al. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med 1980;303:1400–4.
O’ Sullivan S, Dahlén B, Dahlén S-E, et al. Increased urinary excretion of the prostaglandin D2 metabolite9,11?-PGF2 after aspirin challenge supports mast cell activation in aspirin-induced airway obstruction. J Allergy Clin Immunol 1996;98:421–32.
O’Sullivan S, Mueller MJ, Dahlen SE, et al. Analyses of prostaglandin D2 metabolites in urine: comparison between enzyme immunoassay and negative ion chemical ionisation gas chromatography-mass spectrometry. Prostaglandins Other Lipid Mediat 1999;57:149–65.
O’Sullivan S, Roquet A, Dahlén B, et al. Evidence for mast cell activation during exercise-induced bronchoconstriction. Eur Respir J 1998;12:345–50.
Brannan JD, Gulliksson M, Anderson SD, et al. Evidence of mast cell activation and leukotriene release after mannitol inhalation. Eur Respir J 2003;22:491–6.
Bochenek G, Nagraba K, Nizankowska E, et al. A controlled study of 9alpha,11beta-PGF2 (a prostaglandin D2 metabolite) in plasma and urine of patients with bronchial asthma and healthy controls after aspirin challenge. J Allergy Clin Immunol 2003;111:743–9.
Matsuoka T, Hirata M, Tanaka H, et al. Prostaglandin D2 as a mediator of allergic asthma. Science 2000;287:2013–7.
Roquet A, Dahlén B, Kumlin M, et al. Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med 1997;155:1856–63.
Sundstr?m E, L?stbom L, Ryrfeldt ?, et al. Interactions among three classes of mediators explain antigen-induced bronchoconstriction in the isolated perfused and ventilated guinea pig lung. J Pharmacol Exp Ther 2003;307:408–18.
Naclerio RM, Proud D, Togias AG, et al. Inflammatory mediators in late antigen-induced rhinitis. N Engl J Med 1985;313:65–70.(S-E Dahlén and M Kumlin)
Correspondence to:
Professor S-E Dahlén
Experimental Asthma and Allergy Research, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden; se.dahlen@imm.ki.se
Prostaglandin D2 is a useful in vivo marker of mast cell activation in humans
Keywords: asthma; mast cells; prostaglandin D2; plasma 9,11?-PGF2
While the pro-inflammatory role of eosinophilic granulocytes in asthma is currently under debate, an increasing body of evidence suggests that mast cells may indeed orchestrate many of the characteristic pathophysiological changes in asthma.1 There are also indications that the mast cell may be an effector cell in other lung diseases such as chronic obstructive pulmonary disease2–4 and lung fibrosis.5 Given the location of mast cells at multiple sites within the airways,1 they clearly have the potential to function as sensors of alterations in the microenvironment—be it to inhaled or bloodborne substances, microbes, or other insults that require a prompt host defence reaction. Their versatility is demonstrated by the great number of stimuli that trigger mast cell activation (fig 1). In addition to classical IgE dependent degranulation of mast cells, transduction pathways resulting in mast cell activation may be triggered by, for example, adenosine,6 hyperosmolarity,7 and lipopolysaccharide.8
Figure 1 Mast cells may produce a large number of mediators, enzymes, cytokines and other factors in response to allergic (IgE dependent) or non-allergic activation (adenosine, exercise, endotoxin, mannitol, non-steroidal anti-inflammatory drugs (NSAIDs) in NSAID intolerant subjects, etc). However, only tryptase and prostaglandin (PG) D2 (boxed) are specific markers of mast cell 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. LTC4 = leukotriene C4.
MAST CELL MARKERS
Although many mast cell mediators or products serve as useful markers of mast cell activation in vitro, it has been notoriously difficult conclusively to establish mast cell activation in human studies. For example, it is difficult to catch the short lived increase in plasma levels of histamine and its metabolites following allergen induced bronchoconstriction. Furthermore, circulating basophils may contribute significantly to plasma histamine9 and plasma values may be increased by non-specific challenges such as an ordinary exercise test. Measurements of urinary metabolites of histamine may sometimes be helpful to provide information regarding systemically released histamine over time10 but, due to extensive metabolism, only a small percentage of circulating histamine levels appear in the urine and the ambiguity with regard to the cellular source remains.
Tryptases, which are proteases secreted by degranulating human mast cells, have been reported to make up about 25% of total mast cell protein.11 This would seem to make tryptase an ideal marker of mast cell activation. Although tryptase measurements are very useful in experimental work with cells and tissues, this marker has not been particularly helpful in mechanistic studies addressing mast cell activation in humans. This may relate to limitations in the currently available methodology for measuring plasma or serum tryptase. Nevertheless, so far, the main uses of tryptase measurements are to provide evidence for the diagnosis of systemic mastocytosis or necropsy evidence of systemic anaphylaxis.12
Prostaglandins (PG) are ubiquitously biosynthesised and would therefore seem to be unlikely candidates as specific markers for any particular cell. However, in this issue of Thorax, Bochenek et al13 confirm and extend the accumulated evidence that measurement of PGD2 or its metabolites represents a sensitive and reliable strategy for assessment of mast cell activation in vivo. Specifically, they convincingly show, for the first time, increased levels of the primary PGD2 metabolite 911?-PGF2 in plasma during the early phase of allergen induced airway obstruction. This is achieved by applying gas chromatography-negative ion chemical ionisation-mass spectrometry (GC-NICI-MS) to samples collected at frequent intervals before and during allergen bronchoprovocation of subjects with atopic asthma. The methodology is very appropriate as GC-NICI-MS is the most specific measurement of this particular family of compounds, where the presence of numerous structurally related metabolites always complicates immunoassay measurements. Bochenek et al also deserve credit for their development of a protocol that improves the sensitivity of the GC-NICI-MS measurements.
BIOSYNTHESIS OF PGD2 IN MAST CELLS
The release of PGD2 from isolated human mast cells was reported more than two decades ago,14 shortly followed by the demonstration of its release into human airways after local endotracheal instillation of allergen.15 However, the mechanistic significance of these reports was not generally appreciated. In humans, mast cells are an almost exclusive cellular source of PGD2.16 Although there is evidence of some PGD2 formation by platelets, macrophages and certain T lymphocytes,13 the reported amounts are 100–1000 times lower than those produced during IgE dependent activation of mast cells. More importantly, whereas the basophil and the mast cell both release histamine and leukotriene (LT) C4, it is only the mast cell that produces significant quantities of PGD2.16 There is, in fact, recent evidence to show that increased expression of the haematopoetic PGD2 synthase may be the functional response that is most specifically upregulated in activated mast cells.17
MEASUREMENT OF PGD2
The currently renewed interest in applications of PGD2 measurement would not have been possible without the comprehensive work of Roberts and colleagues at Vanderbilt who performed painstaking GC/MS identifications of PGD2 metabolites in blood and urine after injections of radiolabelled PGD2.18,19 More than 25 metabolites were identified but intact PGD2 was not found in the urine. The most abundant PGD2 metabolite identified was 9,11-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioc acid, commonly referred to as PGD-M. The earliest appearing urinary metabolite was 9,11?-PGF2, which was subsequently shown to be stereospecifically transformed from PGD2 by the NADPH dependent enzyme 11-ketoreductase20 in lung and liver. Interestingly, 9,11?-PGF2 retains biological activity. It has, for example, been found to contract bronchial smooth muscle21 and has vascular effects including contraction of coronary arteries.22 Metabolism of 9,11?-PGF2 by the 15-hydroxy prostaglandin dehydrogenase, followed by ?- and - oxidations, leads to PGD-M.
The Vanderbilt group thus used GC/MS measurements of PGD-M as a marker of systemic PGD2 production in different disease states. Markedly raised levels of PGD-M were discovered in systemic mastocytosis23 as well as during anaphylaxis. The GC/MS approach is, however, laborious and technologically demanding, which generally renders it less applicable to studies of populations and large numbers of samples. The more recent validation of an immunoassay method for the measurement of 9,11?-PGF2 in urine24,25 has therefore created new opportunities for using this PGD2 metabolite as a mast cell marker. Using this immunoassay methodology, increased excretion of metabolites of PGD2 into the urine has been observed after allergen induced bronchoconstriction10,24 and mast cell involvement in other indirect challenges has also been confirmed.24,26,27
As discussed by Bochenek et al,13 apart from weak indirect or anecdotal evidence, there has not previously been any investigation of 9,11?-PGF2 levels in plasma during allergen induced bronchoconstriction, which undoubtedly must be the gold standard for mast cell activation. Interestingly, the current demonstration of increased PGD2 release during allergen induced bronchoconstriction puts further weight behind a previous publication from the group in Krakow where increased plasma levels of 9,11?-PGF2 were found following aspirin induced bronchoconstriction.28 This adds to several other lines of evidence24 suggesting that the intolerance to aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) involves mast cell activation.
Bochenek et al confirmed the original observations by Liston et al18 that 9,11?-PGF2 was the first PGD2 metabolite to appear in urine, although they did not find the increase of this metabolite in the urine to be as great as that reported by O’Sullivan et al.10 These seemingly different findings are most probably explained by the demonstration25 that the immunoassay measures not only 9,11?-PGF2 but also at least two other metabolites that appear somewhat later. In other words, for detection of the sum of the initially excreted PGD2 metabolites in urine, the chemically less specific immunoassay will paradoxically have greater practical sensitivity as it measures several related PGD2 metabolites. However, as pointed out by Bochenek et al, for studies of the kinetics of 9,11?-PGF2 metabolism, the chemically more specific method is obviously preferable.
PERSPECTIVES
The method chosen to monitor mast cell activation by measurement of PGD2 metabolites will obviously depend on the questions asked and the resources available. Irrespective of the analytical method selected, measurements of 9,11?-PGF2 in plasma, urine, or other body fluids currently provide the most sensitive method for detection of mast cell activation in vivo. This was clearly shown in the paper by Bochenek et al, where there was no change in plasma tryptase despite the fivefold increase in plasma 9,11?-PGF2. Similarly, in previous work by O’Sullivan et al,10,26 there was consistently a much smaller or non-significant increase in urinary methyl histamine in contrast to consistent and prominent increases in urinary 911?-PGF2 metabolites. Thus, for investigations into the role of the mast cell in different pulmonary diseases, measurements of PGD2 metabolites in body fluids offer many new opportunities.
Finally, PGD2 is not only a marker of mast cell activation but also—together with its immediate metabolite 9,11?-PGF2—it is a potent mediator of bronchoconstriction, vasomotor tone, and cell recruitment.29 We hypothesise that PGD2 mediates the component of allergen induced bronchoconstriction that remains resistant to antihistamines and antileukotrienes.30 Experimental data are available to support such a role,29,31 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 receptors (TP, DP, and CRTH2) mediating the effects of PGD2 in the airways29 suggests that we may soon get improved opportunities to define more precisely the pulmonary role of this mast cell derived mediator.
REFERENCES
Brightling CE, Bradding P, Symon FA, et al. Mast cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002;346:1699–705.
Grashoff WF, Sont JK, Sterk PJ, et al. Chronic obstructive pulmonary disease: role of bronchioloar mast cells and macrophages. Am J Pathol 1997;151:1785–90.
Taube C, Holtz O, Mucke M, et al. Airway response to inhaled hypertonic saline in patients with moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1810–5.
Hattotuwa KL, Gizycki MJ, Ansari TW, et al. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo controlled biopsy study. Am J Respir Crit Care Med 2002;165:1592–6.
Inoue Y, King TE Jr, Tinkle SS, et al. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am J Pathol 1996;149:2037–54.
Bj?rck T, Gustafsson L-E, Dahlén S-E. Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of histamine and leukotrienes. Am Rev Respir Dis 1992;145:1087–95.
Eggleston PA, Kagey-Sobotka A, Schleimer R, et al. Interaction between hyperosmolar and IgE-mediated histamine release from basophils and mast cells. Am Rev Respir Dis 1984;130:86–91.
Marshall JS, McCurdy JD, Olynych T. Toll-like receptor operated activation of mast cells: implications for allergic disease? Int Arch Allergy Immunol 2003;132:87–97.
Howarth PH, Pao GJK, Church MK, et al. Exercise- and isocapnic hyperventilation-induced bronchoconstriction in asthma, relevance of circulating basophils to measurements of plasma histamine. J Allergy Clin Immunol 1984;73:391–9.
O’Sullivan S, Roquet A, Dahlén B, et al. Urinary excretion of inflammatory mediators during allergen-induced early and late phase asthmatic reactions. Clin Exp Allergy 1998;28:1332–9.
Schwartz LB, Irani A-M A, Roller K, et al. Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells. J Immunol 1987;138:2611–5.
Schwartz LB. Clinical utility of tryptase levels in systemic mastocytosis and associated hematologic disorders. Leuk Res 2001;25:553–62.
Bochenek G, Nizankowska E, Gielicz A, et al. Plasma 9,11?-PGF2, a PGD2 metabolite, as a sensitive marker of mast cell activation by allergen in bronchial asthma. Thorax 2004;59:459–64.
Lewis RA, Soter NA, Diamond PT, et al. Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE. J Immunol 1982;129:1627–31.
Murray JJ, Tonnel AB, Brash AR, et al. Release of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med 1986;315:800–4.
O’Sullivan S. On the role of PGD2 metabolites as markers of mast cell activation in asthma. Acta Physiol Scand Suppl 1999;644:1–74.
Li L, Yang Y, Stevens RL. Ras GRP4 regulates the expression of prostaglandin D2 in human and rat mast cell lines. J Biol Chem 2003;278:4725–9.
Liston TE, Roberts LJ II. Metabolic fate of radiolabelled prostaglandin D2 in a normal human male volunteer. J Biol Chem 1985;260:13172–80.
Liston TE, Roberts LJ II. Transformation of prostaglandin D2 to 9,11?-(15S)-trihydroxyprosta-(5Z,13E)-dien-1-oic acid (911?-PGF2): a unique biologically active prostaglandin produced enzymatically in vivo in humans. Proc Natl Acad Sci USA 1985;82:6030–4.
Pugliese G, Spokas EG, Marcinkiewicz E, et al. Hepatic transformation of prostaglandin D2 to a new prostanoid, 911?-PGF2, that inhibits platelet aggregation and constricts blood vessels. J Biol Chem 1985;260:14621–5.
Beasley CR, Robinson C, Featherstone RL, et al. 9 alpha,11 beta-prostaglandin F2, a novel metabolite of prostaglandin D2 is a potent contractile agonist of human and guinea pig airways. J Clin Invest 1987;79:978–83.
Roberts LJ II, Seibert K, Liston TE, et al. Prostaglandin D2 is transformed by human coronary arteries to 911?-PGF2, which contracts human coronary artery rings. Adv Prostaglandin Thromboxane Leukot Res 1987;17A:427–9.
Roberts LJ II, Sweatman BJ, Lewis RA, et al. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med 1980;303:1400–4.
O’ Sullivan S, Dahlén B, Dahlén S-E, et al. Increased urinary excretion of the prostaglandin D2 metabolite9,11?-PGF2 after aspirin challenge supports mast cell activation in aspirin-induced airway obstruction. J Allergy Clin Immunol 1996;98:421–32.
O’Sullivan S, Mueller MJ, Dahlen SE, et al. Analyses of prostaglandin D2 metabolites in urine: comparison between enzyme immunoassay and negative ion chemical ionisation gas chromatography-mass spectrometry. Prostaglandins Other Lipid Mediat 1999;57:149–65.
O’Sullivan S, Roquet A, Dahlén B, et al. Evidence for mast cell activation during exercise-induced bronchoconstriction. Eur Respir J 1998;12:345–50.
Brannan JD, Gulliksson M, Anderson SD, et al. Evidence of mast cell activation and leukotriene release after mannitol inhalation. Eur Respir J 2003;22:491–6.
Bochenek G, Nagraba K, Nizankowska E, et al. A controlled study of 9alpha,11beta-PGF2 (a prostaglandin D2 metabolite) in plasma and urine of patients with bronchial asthma and healthy controls after aspirin challenge. J Allergy Clin Immunol 2003;111:743–9.
Matsuoka T, Hirata M, Tanaka H, et al. Prostaglandin D2 as a mediator of allergic asthma. Science 2000;287:2013–7.
Roquet A, Dahlén B, Kumlin M, et al. Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med 1997;155:1856–63.
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