Disassociation of the Release of Histamine and Arachidonic Acid Metabolites from Osmotically Activated Basophils and Human Lung Mast Cells 1- 3

PEYTON A. EGGLESTON, ANNE KAGEY-SOBOTKA, DAVID PROUD, N. FRANKLIN ADKINSON, JR., and LAWRENCE M. LICHTENSTEIN4

Introduction

Arachidonic acid (AA) metabolism accelerates in the mast cell and basophil during activation by IgE-dependent (1, 2) and other (1, 3) stimuli, resulting in increased production of both lipoxygenase products such as leukotrienes and, in the case of the mast cell, cyclooxygenase products such as prostaglandin D, (pGDz) (1). In both basophils and mast cells (4, 5), these AA metabolites and the preformed mediator histamine appear simultaneously with most stimuli. Thus, it was quite surprising that in experiments with basophils stimulated by hyperosmolar solutions, Findlay and his colleagues (6) found that histamine was released without a simultaneous change in AA metabolism. These investigators assayed cell supernatants for SRS-A (slow-reacting substance of anaphylaxis, assayed at that time by guinea pig ileal contractions and now known to represent a mixture of LTC4 , LTD4 , and LTE 4 ) and found no increases despite significant elevations in histamine. Hyperosmolar activation of mast cells and basophils is a noncytotoxic process (6, 7) that differs from the Igli-dependent activation in terms of kinetics, Ca" requirements, temperature optima, and pharmacologic controls. It has been proposed that hyperosmolar activation has physiologic importance in anaphylactic responses to injected radiocontrast dyes (6, 8) and in the airway adaptation to respiratory water loss as occurs in hyperventilation with cold dry air (9). Because of the potential pathophysiologic importance of the selective secretion of mast cell and basophil products, we examined the effects of hyperosmolar environments on AA metabolism more closely. The results of these experiments form the basis of this report.

960

SUMMARY Upon activation by most stimuli, basophils and human lung mast cells simultaneously release histamine and arachidonic acid metabolites. Hyperosmolar activation was examined, and both cell types were shown to release histamine but little or no leukotriene C. or D. (LTC./D.) and, in the case ot mast cells, little or no prostaglandin O2 (PG02) . In addition, hyperosmolar buffers were capable of preventing the formation ot LTC./LTD. In basophils stimulated by anti·lgE when added simultaneously, or 2, 5, or 10 min atter, the addition ot anti.lgE. Catabolism ot PGD2 and LTC.lD. was not increased. Experiments with celilysates demonstrated that intracellular formation, rather than secretion, was arrested in hyperosmolar butfers. We conclude that this selective Inhibi· tion ot mediator production is a unique response ot mast cells and basophils to osmotic activation. Although the mechanism of this selective cellular response Is not clear, these in Ifitro observations have important therapeutic and pathophysiologic implications for the airway response to hyperos· AM REV RESPIR DIS 1990; 141:960-964 molar stimuli.

Methods Reagents The following Were purchased: PiperazineN;N-bis-(2-ethane sulfonic acid; PIPES), mannitol, arachidonic acid, deuterium oxide (D,O), pronase, chymopapain, elastase type II, collagenase and gelatin (Sigma Chemical Co., St. Louis, MO); EDTA and perchloric acid 60070 (Fisher Scientific Co., SilverSpring, MD); and dextran 70 (Cutter Laboratories, Berkeley, CA). Anti-IgE was an immunosorbent-purified rabbit antiserum to the Fc fragment of PS myeloma IgE in which the antibody was quantitated by comparative leukocyte histamine release dose response against a standardized goat anti-IgE kindly provided by Dr. K. Ishizaka. The following buffers were used: PAG, which contained 25 mM PIPES, 1I0 mM NaCI, 5 mM KCI, 0.003070 human serum albumin, and 0.1% glucose (pH 7.4, 280 mosmol/kg); and PAGCM, which also contained 1.0 mM caci, and 1.0 mM MgCI,.

Histamine Release Assay Methods for studying mediator release from basophils in response to osmotic challenge have been described previously (7). Venous blood, obtained from adult volunteers who had given informed consent, was collected in a final concentration of 10mM EDTA, 20% vol/vol dextran 70, and 0.1% glucose, and the erythrocytes were sedimented for 60 to 90 min. The leukocyte-rich plasma was harvest-

ed and centrifuged at 180 x g for 8 min at 4 0 C, and the cell pellet was washed twice in PAG. The cells were resuspended in PAGCM for addition to test mixtures. In general, a 0.3ml cell suspension was brought to a final volume of I ml in 75 x 10mm polystyrene tubes (Sarstedt, Inc., Princeton, NJ). The osmolality of PAG and PAGCM was 280 mosmol/kg. Molar solutions of mannitol prepared in these buffers ranged from 0.2 to 2.0 M. In a reaction volume of 1 ml, 0.5 ml hyperosmolal mannitol was mixed with equal volumes of

(Received in original form January 26, 1989 and in revised form August 2, 1989) I From the Department of Pediatrics, Division of Immunology, and the Department of Medicine, Division of Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 2 Publication number 771 from the O'Neill Research Laboratories, Good Samaritan Hospital, Baltimore, Maryland. Supported by National Institutes of Health Grants AI-2I073, HL-30532, AI-07290, AI-08270, and HL-32272 and by the Hospital for Consumptions of Maryland (Eudowood Fund). 3 Correspondence and requests for reprints should be addressed to Peyton A. Eggleston, M.D., Department of Pediatrics, Division of Immunology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21205. • Recipient of a Pfizer Biomedical Research Award.

961

ARACHIDONIC ACID METABOLITES FOLLOWING OSMOTIC ACTIVATION

cell suspensions. The measured osmolality of these reaction mixtures ranged from 360 mosmollkg (0.1 M) to 1270 mosmollkg (1.0 M). When indicated, 0.2 ml of an appropriate concentration of anti-IgE, drug, or buffer control was included, and the volume of the cell suspension was reduced appropriately. After a 45-min incubation at 37° C, the suspensions were centrifuged and the supernatants assayed for histamine using the automated tluorometric method of Siraganian (10). Total cellular histamine was determined in cell samples lysed with 1.6070 perchloric acid, and release was expressed as a percentage of this total. Release in the absence of stimulus in isosmolar buffers was always less than 5070. In experiments with varying hyperosmolar solutes, the osmolality of each reaction mixture was determined by vapor point depression (model 5500; Wescor, Inc.).

Mast Cells Human lung mast cellswerestudied in singlecell suspensions (11). Normal human lung parenchyma obtained at surgery was minced into 5- to lO-mg fragments with scissors. Fragments were washed overnight in Tyrode's buffer, then resuspended in CaZ+-free Tyrode's, incubated twice in a mixture of pronase (2 mg/ml) and chymopapain (0.5 mg/ml), and then twice more in a mixture' of elastase type II (10 V/ml) and collagenase (1 mg/ml), For the last incubation and all washing, Tyrode's buffer with deoxyribonuclease type I (15 mg/L) and gelatin (I giL) was used. Digested cells were filtered through nytex cloth with 100 urn pore size (Tetko, Elmsford, NY), washed, and brought to 1 to 10070 purity as determined by Alcian blue staining (12). Preparations of greater purity (20 to 90070) could be obtained using countercurrent elutriation (11). Prior to use in the experiments described, cells were washed again and resuspended in PAOCM. The reaction volumes ranged from 400 to 600 III and contained 10' to 105 mast cells. After incu bation for 45 min at 37° C, supernatants were assayed as described previously. Leukotrienes (LTC,/D,) and prostaglandin D 2 (POD 2 ) were measured using radioimmunoassays. The specificity of these assays has been described previously (13, 14). Enzymes with arginine esterolytic activity weremeasured by their ability to liberate tritiated methanol from the synthetic substrate Nll-p-tosyl-L-arginine methyl ester (TAME) (IS). Statistical analysis was conducted using the Student's t test for paired samples or analysis of variance when multiple means were compared. Results

The concentrations of histamine and LTC4/D4 in the supernatants of stimulated basophils in 15 experiments are shown in figure 1. Control cells in isosmolar buffers released 5 ± 1070 of total

HISTAMINE anti IgE 1030 mOsm/kg anti IgE &40 mOsm/kg

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Fig. 1. The results of stimulating suspensions of basophils with 0.1 ~ml of anti-lgE, hyperosmolar mannitol, or their combination. The upper panel represents the mean percentage release of total cellular histamine in 15experiments (± SEM). The hatched bars in the lower panel are the mean concentrations of immunoreactive LTC.JD.in supernatants from the same cell preparations.

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histamine and 8.0 ± 2.5 pg/O.1 ml LTC4/D4 • In responseto stimulation with anti-IgE (0.1 ug/ml), histamine release was significantly greater (46 ± 7%; p < 0.01), as was LTC4/D4 formation (93.6 ± 23.8 pg/O.1 ml; p < 0.01). Hyperosmolar buffers caused significant histamine release (43 ± 6% at 640 mosmol/kg; 72 ± 3% at 1030mosmol/kg), but LTC4/D4 concentrations (18.5 ± 7.0 pg/O.1 ml and 18.1 ± 6 pg/O.1 ml, respectively) were only slightly higher than those in control buffers (p > 0.05). As previously reported (16), IgE-dependent histamine release was augmented in hyperosmolar buffers. For instance, 72 ± 6% of total histamine was released with anti-IgE stimulation in 640 mosmol/kg compared to 46 ± 7% in isosmolar buffers (p < 0.01). In contrast, LTC4/D4 concentrations after anti-IgE stimulation in either 640 mosmol/kg buffers (8.~ ± 4.2 pg/O.1 ml) or 1030 mosmol/kg (18.4 ± 4.8 pg/O.1 ml) were no greater than in hyperosmolar buffers alone. Thus, hyperosmolar buffers increased IgE-dependent histamine release but diminished LTC4/D4 concentrations. The results of 12 similar experiments with human lung mast cells are shown in figure 2. Cells wereactivated to release histamine by exposure to 1 ug/ml of antiIgE (21 ± 4 versus 8 ± 1% in PAGCM control; p < 0.01) as well as by 770 mosmol/kg buffers (IS ± 3l1fo; p < 0.01). Release in 460 mosmol/kg buffers (10 ± 2l1fo) was not significantly above control. The expected synergy was seen when the two stimuli were combined [32 ± 4l1fo with anti-IgE in 460 mosmol/kg compared to 21 ± 4l1fo in isosmolar anti-IgE (p < 0.05) despite insignificant release in

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'81

460 mosmol/kg alone). Both LTC4/D4 and PGD 2 , the major lipoxygenase and cyclooxygenase products of mast cells (I), were significantly elevated in supernatants from anti-IgE-stimulated cells (7.5 ± 2.7 and 15.3 ± 2.7 ng/10 6 mast cells, respectively). However, levels of neither LTC4/D4 (0.14 ± 0.05 ng/10 6 mast cells) nor PGD2 (2.1 ± 0.6 ng/10 6 mast cells) were elevated following hyperosmolar challenge. Furthermore, when mast cells werestimulated with anti-IgE in 460 mosmol/kg buffers, concentrations of both LTC4/D4 (2.8 ± 1.4 ng/10 6 cells) and PGD 2 (6.6 ± 2.3 ng/10 6 cells) were significantly lower (p < 0.01)than with antiIgE alone. The possibility that mannitol interfered with the assays for the two AA metabolites was examined by comparing paired assays in buffers with and without mannitol. Supernatants containing leukotrienes were generated from basophils stimulated with isosmolar anti-IgE (0.1 ug/ml), and the concentration measured was similar when mannitol was added to one portion to make it 0.4 M (69 ± 28 pg/O.1 ml) to that measured in isotonic buffers (72 ± 34 pg/O.1 ml; n = 4, p > 0.1). In other experiments, when equal quantities of PGD 2 wereadded to PAGCM and to 0.5 M mannitol, the concentrations measured in the assay weresimilar; 64.5 ± 6 pg/O.1 ml and 71.0 ± 3 pg/O.1 ml, respectively (n = 4; p > 0.2). The initial experiments suggested that hyperosmolar buffers inhibited IgE-driven AA metabolism. To examine this notion more carefully, basophils were incubated at 37° C with PAGCM for 5 min before being mixed with 0.1 ug/ml of

962

EGGLESTON, KAGEY·SOBOTKA, PROUD, ADKINSON, AND LICHTENSTEIN

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Fig. 2. The results of activating suspensions of human lung mast cells (2 to 75% pure) with 1 !1g/ml of anti·lgE, hyperosmolar mannitol, or their combination. The top panel represents the mean percentage release of total cejular histamine in 12 experiments (± SEM). The middle panel represents the mean concentrations of PGD 2 in supernatants from the same experiments, and the bottom panel represents mean concentrations of immunoreactive LTC 21D. in the supernatants. Both concentrations have been normalized by expressing them as ng/l0· mast cells.

anti-IgE in PAGCM (280 mosmol/kg). Aliquots werewithdrawn immediately after mixing and then at 2,5, and 10 min. These aliquots weremixed with PAGCM/ mannitol to raise the osmolality to 640 mosmol/kg. One aliquot was centrifuged immediately at 10,000 x g for 3 sand the supernatants were assayed for histamine and LTC4/LTD4 • The other aliquot was incubated at 37° C for a total incubation time of 45 min, then centrifuged and the supernatant assayed for histamine and LTC4/LTD4 • As controls, other cell aliquots were incubated for 45 min at 37° C in PAGCM, isosmolar anti-IgE, or hyperosmolar anti-IgE. As can be seen in the 10 experiments shown in figure 3, 60 ± 6% histamine release occurred during 45 min exposure to anti-IgE. Release occurred rapidly, reaching 83070 of maximum by 10 min. Increasing the osmolality to 640 mosmol/kg at any time after exposure to antiIgE increased histamine release to levels that were not significantly different from those from cells that had been exposed to hyperosmolar anti-IgE for 45 min at 37° C (p > 0.5; analysis of variance). In contrast, IgE-mediated LTC4/D4 production was inhibited when hyperosmolar mannitol was added to the cellsus-

pensions. In isosmolar anti-IgE, supernatants from control cells incubated at 37° C for 45 min contained 301 + 72 pg LTC4/D4 per 0.1 ml but supernatants from control cells suspended for 45 min in hyperosmolar anti-IgE werenot different from unstimulated controls (8 ± 3 versus 10 ± 6 pg LTC4/D4 per 0.1 ml; p > 0.1). Cells made hyperosmolar after stimulation with anti-IgE stopped producing LTC4/D4 • For instance, stimulated cells produced LTC4/D 4 concentrations of 198 ± 79 pg/O.1 ml by 5 min; when incubated for an additional 40 min in hyperosmolar anti-IgE, concentrations were only 228 ± 78 pg/O.1 ml, which was not significantly greater than control cells with anti-IgE (p > 0.1). Thus it would appear that AA metabolism or secretion stops when cells are placed in a hyperosmolar environment. It was possible that hyperosmolar buffers interfered with the release of AA metabolites rather than with their formation. It was further possible that catabolism by other cells in the leukocyte preparations or in the suspensions of human lung mast cells was accelerated in hyperosmolar buffers. Decreased secretion of metabolites was examined in stimulated mast cells by simultaneously

20

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30

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Fig. 3. The effect of adding hyperosmolar mannitol to basophil suspensions during incubation with 0.1 !1g/ml of anli-lgE at -yo C in 10 replicate experiments. Immediately after mixing and at 2, 5, and 10 min afterward, aliquots were withdrawn for analysis or warm hyperosmolar mannitol in PAGCM was added to increase osmolality to 640 mosmol/kg and the incubation was continued to 45 min. The upper panel represents the mean percentage of total cellular histamine released, and the lower panel the concentrations of LTCiD•. The open circles (0) represent levels after incubation with anti-lgE alone, and the solid circles (.) connected by dotted lines are the levels after further incubation with anti-lgE and mannitol. The solid squares (.) are control aliquots incubated with the same concentrations of anti-lgE and mannitol for the entire 45 min (± SEM).

measuring concentrations of PGD 2 and LTC4/D4 in the supernatants and lysates (freeze-thaw) of stimulated and control cells. In the five experiments shown in table 1, PGD 2 and LTC4/D 4 concentrations in lysates from stimulated cells did not differ from those of control cells in PAGCM. Intracellular concentrations were also similar in cells stimulated with anti-IgE in isosmolar buffers. At the same time, supernatants from these cells showed the expected pattern of mediators. Anti-IgE stimulated cells released significantly more PGD 2 and LTC4/D4 into supernatants than did control cells or either hyperosmolar aliquot. Thus hyperosmolar buffers interfered with the appearance of metabolites into the supernatants without increasing intracellular concentrations. Accelerated catabolism is unlikely since similar results were obtained in experiments with mast cell preparations containing various numbers of other cells; the 12 experiments summarized in figure 2 were conducted with preparations containing from 2 to 75070 mast cells: Furthermore, in basophil prepara-

ARACHIDONIC ACID METABOLITES FOLLOWING OSMOTIC ACTIVATION

TABLE 1

963

IgE-dependent and hyperosmolar stimuli act synergistically to induce histamine release (16). The present experiments describe another important functional difAnti-lgE Anti-lgE (111g1ml), (1119/ml), ference in that the AA metabolites, char280 mosmollkg 770 mosmollkg 460 mosmol/kg PAGCM acteristic of IgE-dependent activation, do not appear following osmotic activation. PGD" nglml 0.8 ± 0.2 Supernatant 11.8 ± 2.1' 0.8 ± 0.3 5.0 ± 1.4' Furthermore, hyperosmolar conditions, 2.8 ± 1.3 2.4 ± 1.0 2.9 ± 1.8 2.1 ± 0.8 Celis instead of enhancing IgE-dependent AA LTC,ID., ng/ml metabolism, actually diminish extracel0.1 ± 0.02 0.9 ± 0.4' Supernatant 0.1 ± 0.07 3.2 ± 1.4' of both cyclooxylular concentrations 0.1 ± 0.07 0.2 ± 0.1 0.01 ± 0.05 0.06 ± 0.05 Celis genase and lipoxygenase products. , Different from PAGCM, p < 0.05; n = 5. Although this disassociation of AA metabolism and histamine release following activation is unusual, other examples of tions, concentrations of LTC4 / 04 did not in 460 mosmol/kg buffers (5.7 ± 1.7% partial disassociation have been reported. decrease significantly during up to 40 min release); however, hyperosmolar buffers For instance, human skin mast cellsrelease exposure to hyperosmolar buffers. Final- significantly enhanced IgE-dependent re- histamine and P00 2 but not LTC4 / 04 (18), and human basophils do not form ly, in three experiments, when exogenous lease (34 ± 6.1% release; p < 0.05). P002 (2). At least one other stimulus, C5 P00 2 was added to a suspension of mast peptide (19), activates basophils to release cells in 770 mosmol/kg buffers, to inDiscussion histamine but not LTC4 / 04 • The most crease the concentration to 59 ± 6 pg/O.1 ml, 59 ± 10pg/O.1 ml was still measured Previous work from this laboratory has pertinent experiments are those of Macafter 45 min incubation at 37° C. Super- shown that basophils and human lung Glashan and colleagues (2), who showed natants from control cells incubated in mast cells are activated in hyperosmolar that an IgE-dependent stimulus could be PAOCM decreased from 70 ± 5 to 46 environments and that this activation varied experimentally so that cell surface ± 10 pg P002/0.1 ml in the same time. process is substantially different from IgE was more or less extensively crossBecause it was possiblethat hyperos- IgE-dependent activation (6, 7). For in- linked. With a weaker signal (less crossmolar buffers interfered with the hydrol- stance, histamine release is optimal at linkage) the same disassociation of mediysis of AA from membrane phospholip- 32° C rather than 37° C and is enhanced ator release was seen that we report here. ids and because exogenous AA has been rather than decreased by cAMP-active If the transduction of a weaker signal shown to enhance antigen-induced hista- drugs. Calcium requirements also differ may lead to specific cellular response, mine release from basophils (5), the ef- from those for IgE-dependent histamine then altering transduction by osmoticalfect of exogenous arachidonic acid on the release, in that basophil activation is on- ly modifying cell volume and membrane response to stimulation with hyperosmo- ly partially Ca2+ dependent and osmotic potential may also lead to specific cellular solutions was examined, Basophils mast cell activation is optimal at fivefold lar responses. The biologic significance from ragweed-allergic donors were first higher Ca 2 + concentrations (7). Finally, of this distinctive response is not dear, incubated with 10 J.l.M arachidonic acid in PAOCM for 5 min, then stimulated with 640 mosmol/kg mannitol or with TABLE 2 antigen E, 10-4 to 10-6 ug/rnl. As shown EFFECT OF 10 11M ARACHIDONIC ACID (AA) ON THE RESPONSE OF in table 2, antigen-induced histamine reBASOPHILS TO ANTIGEN AND HYPEROSMOLAR STIMULI lease was slightly but significantly enAntigen E + hanced following the addition of arachiPAGCM 640 mosmol/kg Antigen E 640 mosmol/kg donic acid, from 36 to 50010' of total cellular histamine (p < 0.05). Hyperosmolar Histamine, % release Control 2±2 27 ± 13 36 ± 23 79 ± 9 histamine release was not affected. An4±6 AA 30 ± 15 50 ± 26' 84 ± 7 tigen also induced LTC4 / 04 formation, but this process was not enhanced by ex- LTC.ID., pg/0.1 ml Control 199 ± 408 202 ± 435 1176 ± 1512 213 ± 338 ogenous arachidonic acid (1175 versus AA 268 ± 553 152 ± 295 1247 ± 1299 293 ± 476 1247 pg/O.1 ml; p > 0.5), , p < 0.05; n = 5. Another preformed mediator, mast cell tryptase, was measured in five experiTABLE 3 ments by measuring its TAME esterase activity (17). Levels of this mediator, RELEASE OF HISTAMINE AND TAME ESTERASE ACTIVITY FROM MAST CELLS BY ANTI-lgE AND HYPEROSMOLAR BUFFERS shown in table 3, varied concordantly with histamine. In supernatants from Anti-lgE Anti-lgE + cells stimulated with anti-IgE, concenPAGCM 460 mosmol/kg (1 I1g/ml) 460 mosmol/kg trations were strikingly higher (22 ± Histamine, % release 11 ± 4 9 ± 3 31 ± 11' 36 ± 11 4.9% release) than in buffer controls (3.6 TAME esterase, % release 4 ± 0.4 22 ± 5t 6 ± 2 34 ± 6 ± 0.4% release; p < 0.05). The release Mean ± SEM. of TAME esterase activity, like that of , p < 0.05 versus PAGCM; n = 5. t p < 0.05 versus PAGCM; n = 4. histamine, was not significantly increased CONCENTRATIONS OF PGD, AND LTC,ID. IN SUPERNATANTS AND CELL LYSATES OF HUMAN LUNG MAST CELLS

964

EGGLESTON, KAGEY-SOBOTKA, PROUD, ADKINSON, AND LICHTENSTEIN

but it demonstrates that, just as mast cells It is also possible that other factors, such are heterogeneous, the response of a giv- as airway cooling or neuroendocrine en cell to various stimuli may be hetero- stimuli, playa role in cold, dry air challenge. For instance, hyperosmolarity has geneous as well. It does not appear that cell damage is been shown to enhance the release of an explanation for the isolated release of histamine and various eicosanoids inpreformed mediators. In previous experi- duced by physical stimuli (29). Whatever ments, osmotically activated cells have the source of the other mediators found shown no ultrastructural evidence of cell in nasal cold, dry air challenges, the presdeath (6) and do not release StCr(7). Fur- ent experiments indicate that at least part thermore, histamine release is an active of the response may be explained by hyprocess in that it is modified by Ca", tem- perosmolar mast cell activation. perature, IgE-dependent stimuli, and Acknowledgment pharmacologic agents. As a model of the airway response to The writers thank Kim Mudd for technical hyperventilation, and possibly of exer- assistance and Donna Dieterich for secretarcise-induced asthma, Togias and his col- ial help. leagues exposed the nose to cold, dry air and showed that subsequent nasal lavages References contained increased concentrations of 1. Peters SP, MacGlashan DW Jr, Schulman ES, histamine, TAME esterase activity, ki- et al. Arachidonic acid metabolism in purified hunins, PGD z, and LTC4 (20-24). Because man lung mast cells. J Immunol1984; 132:1972-8. the pattern of mediators was very simi- 2. MacGlashan DW Jr, Peters SP, Warner J, lar to that seen after allergen challenge Lichtenstein LM. Characteristics of human basophil sulfidopeptide leukotriene release: releasability de(25) and because it was not seen follow- fined as the ability of the basophil to respond to ing exposure to warm, moist air, the dimeric cross-links. J Immunol1986; 136:2231-9. authors concluded that mast cell activa- 3. Schleimer RP, MacGlashan DW, Peters SP, Pintion resulted from cold, dry air exposure; ckard RN, Adkinson NF, Lichtenstein LM. Charthey speculated that release had been ini- acterization of inflammatory mediator release from purified human lung mast cells. Am Rev Respir tiated by evaporation of water from the Dis 1986; 133:614-7. nasal epithelium, which increased mu- 4. Lichtenstein LM, Schleimer RP, MacGlashan cosal osmolality. When this hypothesis DW Jr, et al. In vitro and in vivo studies of mediawas tested by Silber and his colleagues tor release from human mast cells. In: Kay AB, Austen KF, Lichtenstein LM, eds. Asthma: physi(9) by instilling hyperosmolar buffers into ology, immunopharmacology and treatment. New the nose, histamine was elevated in wash York: Academic Press, 1984; 1-15. fluid but the concentrations ofother me- 5. Peters SP, Schleimer RP, Marone G, Kagey-Sodiators, such as TAME esterase activity, botka A, Siegel MI, Lichtenstein LM. Lipoxygenase products of arachidonic acid: role in modulation kinins, and leukotrienes, were lower than of IgE-induced histamine release. In: Samuelsson those found after either cold, dry air or B, Pagletti R, eds. Leukotrienes and other lipoxyallergen challenge. genase products. New York: Raven Press, 1982; The present in vitro experiments sug- 315-23. gest that two mediators seen during na- 6. Findlay SR, Dvorak AM, Sobotka AK, Lichtenstein LM. Hyperosmolar triggering of histamine sal challenges, histamine and TAME es- release from human basophils. J Clin Invest 1981; terase activity, may have appeared as the 67:1604-13. result of hyperosmolar mast cell activa- 7. Eggleston PA, Kagey-Sobotka A, Lichtenstein tion. The leukotrienes seen following LM. A comparison of the osmotic activation of and human lung mast cells. Am Rev hyperosmolar nasal challenges are not basophils Respir Dis 1987; 135:1043-8. likely to have come from osmotically ac- 8. Banks JR, Kagey-Sobotka A, Lichtenstein LM, tivated mast cells, and the origin of the Eggleston PA. Spontaneous histamine release afeven wider array of mediators seen in ter exposure to hyperosmolar solutions. J Allergy cold, dry air challenges is unclear. We Clin Immunol 1986; 78:51-7. 9. Silber G, Proud D, Warner J, et al. In vivo recould speculate that osmotic activation lease of inflammatory mediators by hyperosmolar of other cells is responsible since airway solutions. Am Rev Respir Dis 1988; 137:606-12. mucosal cells (26, 27) and inflammatory 10. Siraganian R. An automated continuous flow cells likely to be found in the airway (21- system for the extraction and fluorometric analyof histamine. Anal Biochem 1974; 57:283-94. 23) form prostaglandins and leukotrienes sis 11. Schulman ES, MacGlashan DW Jr, Peters SP, when activated. However, no data exist Schleimer RP, Newball HH, Lichtenstein LM. Huon the osmotic activation of these cells. man lung mast cells; purification and characterAlso, the other mediators found during ization. J Immunol 1984; 129:2662-7. cold, dry air challenge could appear as 12. Gilbert HS, Ornstein L. Basophil counting with a new staining method using Aldan blue. Blood a secondary phenomenon; for instance, 1975; 46:279-86. histamine has been shown to increase 13. Hayes E, Lombardo D, Girard Y, et aJ. Meaprostaglandin formation by airways (28). suring leukotrienes of slow reacting substance of

anaphylaxis: development of a specific radioimmunoassay. J Irnmunol 1983; 131:429-37. 14. Schulman ES, Newball HH, Demers LM, Fitzpatrick FA, Adkinson NF Jr. Anaphylactic release of thrornboxane A z, prostaglandin D, and prostacyclin from human lung parenchyma. Am Rev Respir Dis 1981; 124:402-9. 15. Imanari T, Kaizu T, Yoshida H, Yatesk, Pierce IN, Pisano JJ. Radiochemical assays for human urinary, salivary and plasma kallikreins. In: Pisano J J, Austen KF, eds. Chemistry and biology of the kallikrein-kinin system in health and disease. Washington, D.C.: DHEW Publication No. 76-791, 1976; 205-13. 16. Eggleston PA, Kagey-Sobotka A, Schleimer RP, Lichtenstein LM. Interaction between hyperosmolar and IgE-mediated histamine release from basophils and mast cells. Am Rev Respir Dis 1984; 130:86-91. 17. Baumgarten CR, Nichols RC, Naclerio RM, Lichtenstein LM, Norman PS, Proud D. Plasma kallikrein during experimentally-induced allergic rhinitis: role in kinin formation and contribution of TAME-esterase activity in nasal secretions. J Immunol 1986; 137:977-82. 18. Lawrence ID, Warner JA, Cohan VL, Hubbard WB, Kagey-Sobotka A, Lichtenstein LM. Purification and characterization of human skin mast cells: evidence for human mast cell heterogeneity. J Immunol 1987; 139:3062-9. 19. Findlay SR, Lichtenstein LM, Grant JA. Generation of slow reacting substance by human leukocytes. II. Comparison of stimulation byantigen, anti-IgE, calcium ionophore and C5-peptide. J Immunol 1980; 124:238-42. 20. Togias AG, Naclerio RM, Proud D, et al. Nasal challenge with cold, dry air results in release of inflammatory mediators: possible mast cell involvement. J Clin Invest 1985; 76:1375-81. 21. Kouzan S, Brady AR, Nettesheim P, Eling T. Production of arachidonic acid metabolites by macrophages exposed in vitro to asbestos, carbonyl iron particles, or calcium ionophore. Am Rev Respir Dis 1985; 131:624-32. 22. Borgeat P, Samuelsson B. Arachidonic acid metabolism in polymorphonuclear leukocytes: effects of ionophore A23187. Proc Nat! Acad Sci USA 1979; 76:2148-52. 23. Weller PF, Lee CW, Foster DW, Corey EJ, Austen KF, Lewis RA. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C•. Proc Nat! Acad Sci USA 1983; 80:7620-6. 24. Togias AG, Naclerio RM, Peters SP, et al. Local generation of sulfidopeptide leukotrienes upon nasal provocation with cold, dry air. Am Rev Respir Dis 1986; 133:1133-7. 25. Naclerio RM, Meier HL, Kagey-Sobotka A, et al. Mediator release after nasal airway challenges with allergen. Am Rev Respir Dis 1983;128:597-602. 26. Holtzman MJ, Aizawa H, Nadel JA, Goetzl EJ. Selective generation of leukotriene B. by tracheal epithelial cells from dogs. Biochem Biophys Res Commun 1983; 82:4633-7. 27. LeikaufGD, Veki IF, Nadel JA, Widdicombe JH. Bradykinin stimulates Cl secretion and prostaglandin E z release by canine tracheal epithelium. Am J Physiol 1985; 248:F48-55. 28. Gravelyn TR, Pan PM, Eschenbacher WL. Mediator release in an isolated airway segment in subjects with asthma. Am Rev Respir Dis 1988; 137: 641-6. 29. Steel L, Platshon L, Kaliner M. Prostaglandin generation by human and guinea pig lung tissue: comparison of parenchymal and airway responses. J Allergy Clin Immunol1979; 64:287-93.

Disassociation of the release of histamine and arachidonic acid metabolites from osmotically activated basophils and human lung mast cells.

Upon activation by most stimuli, basophils and human lung mast cells simultaneously release histamine and arachidonic acid metabolites. Hyperosmolar a...
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