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(Journal of Leukocyte Biology. 2001;69:33-42.)
© 2001 by Society for Leukocyte Biology

Role of mast cells in zymosan-induced peritoneal inflammation in Balb/c and mast cell-deficient WBB6F1 mice

Elzbieta Kolaczkowska*, Rolf Seljelid* and Barbara Plytycz*,{dagger}

* Department of Experimental Pathology, Institute of Medical Biology, University of Tromsø, Norway
{dagger} Department of Evolutionary Immunobiology, Institute of Zoology, Jagiellonian University, Krakow, Poland

Correspondence: Barbara Plytycz, Department of Evolutionary Immunobiology, Institute of Zoology, Jagiellonian University, R. Ingardena 6, PL-30-060 Krakow, Poland. E-mail: plyt{at}zuk.iz.uj.edu.pl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Zymosan-induced peritonitis was investigated in mast cell-deficient WBB6F1 mice and in Balb/c mice pretreated with mast cell stabilizer (cromolyn) or antagonists of histamine receptors (mepyramine, triprolidine, cimetidine, or ranitidine). The inherited mast cell deficiency in W/Wv knockouts of WBB6F1 mice impaired significantly the level of histamine and plasma exudation (measured 30 min after stimulation) as well as the influx of exudatory leukocytes, accumulation of plasma and exudate chemoattractants, and the release of proinflammatory cytokines (TNF-{alpha}, IL-1ß, and IL-6) measured at 6 h of inflammation. All of those factors were fully restored after selective intraperitoneal reconstitution of W/Wv mice with bone marrow-derived mast cells from their control +/+ counterparts. Cromolyn pretreatment of Balb/c mice reduced exclusively the early plasma exudation and histamine influx. Blocking of histamine receptors inhibited not only the early plasma exudation but also temporarily diminished primary leukocyte influx and levels of MCP-1 and IL-1ß. In conclusion, mast cells play an important role in the initiation of zymosan-induced peritonitis and modulate its further course.

Key Words: peritonitis • cromolyn • mepyramine • histamine receptors • exudate leukocytes


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Acute inflammatory reactions can be induced experimentally by a variety of substances [1 ]. Zymosan, the insoluble polysaccharide component of the cell walls of Saccharomyces cerevisiae is commonly used for induction of acute peritonitis in mice [2 3 4 5 6 7 ] and can lead to a generalized inflammation when zymosan is applied with adjuvant [8 , 9 ]. The role of mast cells in the initiation of inflammation has been demonstrated in various models of inflammation [7 , 10 11 12 ] and has been confirmed by experiments conducted on genetically mast cell-deficient animals [13 14 15 16 17 ]. Mast cells are strategically located in high density around the blood vessels that are the principal sites of plasma efflux and leukocyte transmigration. They are classified into at least two phenotypically distinct populations, the connective tissue mast cells (which contain large amounts of histamine and heparin) located in the skin, peritoneal cavity, and muscularis propia of the stomach and the mucosal mast cells [18 ]. Mast cells generate and store a large number of potent proinflammatory mediators that play a critical role in immune surveillance [19 , 20 ]. Preformed mediators include histamine, serotonin (in rodents), heparin, tryptase, chymase, VEGF, and tumor necrosis factor {alpha} (TNF-{alpha}), which can be released immediately during the initial stages of acute inflammation, and various other factors can be rapidly produced de novo upon mast cell stimulation. Inducible factors include vasoactive and chemotactic mediators like platelet-activating factor (PAF), leukotrienes, complement factors, and proinflammatory and growth-promoting cytokines [21 , 22 ].

Inhibition of inflammation-related factors has been recorded consistently in genetically mast cell-deficient WBB6F1-W/Wv (W/Wv) mice with a defect of the hemopoietic stem cells (because of lack of the c-kit receptor) leading, among others, to an age-related depletion of the connective-tissue mast cells [23 24 25 26 ]. Plasma protein permeation was significantly lower in W/Wv mice than in their congenic controls during the reverse passive Arthus reaction [27 ]. A significant delay in polymorphonuclear leukoctye (PMN) influx was described in W/Wv mice during thioglycollate-induced [10 ] and immune complex-induced peritonitis, the latter case accompanied by a reduced peritoneal TNF-{alpha} level [12 ]. In the above models, the defects of inflammation were corrected by adoptive transfer of mast cells from the bone marrow of the congenic controls [10 , 12 ]. The comparison of inflammation in W/Wv mice and their congenic (+/+) controls led to the conclusion that mast cells participate in neutrophil recruitment by the release of preformed and stored TNF-{alpha} very early during the immune complex-induced peritonitis [12 ]. The importance of mast cells and/or stem cell factors (required for mast cell maturation) in the regulation of cytokine production in the course of zymosan-induced peritonitis was also established in stem cell factor-deficient (WCB6F1/J-Sl/Sld) mice. The peritoneal lavage fluid of Sl/Sld mice showed a decreased level of interleukin (IL)-4, a markedly increased IL-1ß, and unaffected levels of TNF-{alpha} and IL-6 [28 ]. Both strains of mast cell-deficient mice, W/Wv and Sl/Sld, were used for investigations of the role of tissue mast cells in polyacrylamide gel-induced, skin-pouch inflammation. It was confirmed that mast cells play a prominent role in the PMN influx, TNF-{alpha} production, and eicosanoid formation [11 ].

In the present studies, some inflammation-related parameters were compared in zymosan-stimulated W/Wv mice with those in the +/+ controls and mast cell-reconstituted W/Wv mice (W/Wv+MC). In concordance with the results of other investigators, all the recorded parameters were decreased in animals with the genetic defects, and the intraperitoneal transfer of +/+ bone marrow-derived mast cells restored all the impaired factors fully. Furthermore, we investigated the involvement of mast cells in the zymosan-induced peritoneal inflammation in the Balb/c mice without any genetic defects. For this purpose, we have established the normal time course of the main hallmarks of the inflammatory process (such as an increased vascular permeability, exudatory leukocyte influx, accumulation of plasma and exudate chemoattractants and proinflammatory cytokines, TNF-{alpha}, IL-1{alpha},ß, and IL-6) during 24 h following irritant administration. Then we focused on the selected time points (30 min, and 2, 6, and 24 h) when we compared these parameters in the control and drug-pretreated animals.

Pretreatment with cromolyn, a well-known mast cells stabilizer protecting against degranulation [29 , 30 ], caused a significant impairment of plasma exudation at 30 min of inflammation corresponding to a significantly decreased level of histamine, one of the most potent vasoactive factors released from activated mast cells [1 ]. Cromolyn action, however, was short-lasting because the level of histamine returned to the control level as soon as 2 h after induction of peritonitis. In contrast, the pharmacological blockade of histamine receptors impaired not only the early plasma exudation (at 30 min) but also exudatory leukocyte influx (at 2 h). Also, the levels of monocyte chemoattractant protein-1 (MCP-1) and IL-1ß were reduced significantly at 2 and 6 h of inflammation, respectively.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Mice
Balb/c male mice (4–6 weeks old, 23–25 g body weight) were purchased from Harlan Olac Ltd. (Bicester, Oxon., U.K.). Males of mast cell-deficient W/Wv mice and their normal littermates WBB6F1-+/+ (+/+) were purchased from The Jackson Laboratory (Bar Harbor, ME) and used at the age of at least 12 weeks (26–29 g body weight) when the number of mast cells in W/Wv animals was <0.2% of the control +/+ mice [23 ]. All mice were housed 5–6 per cage at a room temperature of 20 ± 2°C and 50 ± 10% relative humidity with lights set on and off gradually during 30 min (7:30–8:00 a.m. and 19:30–20:00 p.m.). Initial treatment of animals always began between 9:30 and 10:30 a.m.

Reconstitution of mast cells in W/Wv mice
Bone marrow cells harvested from femurs of male +/+ mice were cultured for 3 weeks in WEHI 3-conditioned medium as described previously [31 ]. Mast cells (>98% purity, 1x107 cells/mouse) were injected intraperitoneally (i.p.) into W/Wv mice 3 weeks before induction of peritonitis [10 , 12 , 13 ]. Selective administration of mast cells (but not bone marrow cells) restores only the mast cell deficiency [32 ].

Induction of peritonitis
Peritoneal inflammation was induced according to Doherty et al. [2 ]. Zymosan A (Sigma Chemical Co., St. Louis, MO) was prepared freshly (2 mg/ml) in sterile, 0.9% w/v saline, and 0.5 ml was injected i.p. At the selected time points, animals were killed by cervical dislocation. The peritoneal cavity was lavaged with 1.5 ml saline, and after a 30-s gentle manual massage, 1 ml exudate was retrieved, centrifuged at 3000 g for 3 min, and frozen at -20°C prior to cytokine or chemotactic-factor assessment. Alternatively, 1.5 ml exudate was collected and used freshly for cell counts and cytospin preparations.

Vascular permeability
Evans blue (Sigma) was suspended in saline (10 mg/ml) and injected i.v. into the caudal vein (0.3 ml/mouse). Thirty minutes later, the animals were killed, and the peritoneal cavity was lavaged with 1.5 ml saline as described above. The lavage fluid was centrifuged, and the absorbance of dye in the supernatant was measured at 650 nm with a Titer-Tech, 96-well multiscanner following transfer of 200 µl aliquots to a 96-well plate [3 ].

Histamine content
Histamine content in the peritoneal fluid was measured by a Histamine ELISA kit (ICN Pharmaceuticals, Inc., Cost Mesa, CA). The assay was carried out as indicated by the manufacturer.

Cell counts
Total and differential cell counts were done with a hemocytometer following staining with Turk’s solution (0.01% crystal violet in 3% acetic acid) and on May-Grunwald Giemsa-stained cytospin preparations. Mast cell staining with alcian blue (stains connective tissue and mucosal mast cells) and safranin O (specific for connective tissue mast cells; Sigma) was performed as described previously [10 ].

Plasma collection
Blood was obtained from the interior vena cava and immediately centrifuged at 300 g for 10 min. Then the plasma was collected and stored at -20°C prior to evaluation of the leukocyte chemoattractant activity.

Cytokine content
The peritoneal exudate content of mouse TNF-{alpha} and IL-1ß was measured by DuoSet ELISA (Genzyme Corp., Cambridge, MA), and the immunoreactive MCP-1 was measured by an immunoassay it (BioSource International, Camarillo, CA). The assays were carried out as indicated by the manufacturers.

Cytokine bioactivity
Bioassays for IL-1{alpha} and ß, TNF-{alpha}, and IL-6 were performed on WEHI 164 clone 13, D-10.G.4 and B9 cell lines, respectively, according to the well-established procedures [33 34 35 ].

Chemotaxis assay
A 48-well microchemotaxis chamber (Neuro Probe, Inc., Gaithersburg, MD) was used to assess the leukocyte chemoattractant activity [36 ]. The lower wells of the apparatus were filled with 27 µl control culture media or samples of plasma (in triplicates) from intact or zymosan-treated animals and covered with a nitrocellulose filter (nucleopore membrane; Neuro Probe), 5 µm pore size. The upper wells were filled with 50 µl bone marrow leukocyte suspension washed out from femurs of intact mice (1.5x106 cells/ml). The bone marrow leukocytes were used for chemotaxis assay, because they are the main source of murine leukocytes [37 ]. Following 3 h incubation at 37°C, the cells remaining on the upper surface of the filter were removed, the filter was fixed in 4% buffered formaline, stained with Harris’ hamatoxyline (40 min), and cleared in xylene (15 min). The cells accumulated within the filter were counted per high-power field (40x) on three to four levels and pooled. The procedure was repeated in three independent fields, and the mean value was calculated for each well. The mean values from triplicate wells of each sample (within the same filter) were used for statistical analysis.

Evaluation of the effects of drug pretreatment
Mast cell stabilizer
Sodium cromoglycate (cromolyn; Sigma) [29 , 30 ] is used commonly for mast cell stabilization at various doses and routes of administration. Our pilot experiments (unpublished results) led to selection of a dose (one for each route) that inhibited zymosan-induced vascular permeability by approximately 50% (ED50). The ultimate chosen doses were as follows: subcutaneously (s.c.; 160 mg/kg; 39 mM), i.p. (160 mg/kg; 39 mM), i.p. (400 mg/kg; 97 mM), or intravenously (i.v.; 200 mg/kg; 48 mM) [38 ]. Cromolyn was dissolved in saline and administered (200 µl/mouse) 30 min before i.p. injection of zymosan, followed by i.v. injection of Evans blue when necessary.

Histamine receptor antagonists
Mepyramine and cimetidine (Sigma) were administrated s.c. in a vol of 1 ml/kg [39 40 41 42 ]. Cimetidine base was dissolved in a small quantity of 0.1 N HCl, neutralized with NaOH, and made up to the required volume. Triprolidine and ranitidine (ICN Pharmaceuticals) were administrated i.p. in a volume of 10 ml/kg [41 ]. Antagonists were administered 30 min before i.p. injection of zymosan followed by i.v. injection of Evans blue when necessary.

Based on dose studies (see Fig. 5), 2 mg/kg (5 µM) mepyramine was chosen for further investigations.

Statistical analysis
All values are shown as means ± SE. Kinetic changes of each parameter were analyzed by one-way analysis of variance (ANOVA), comparing the values recorded at the individual time points with that at time 0 (in intact animals). Differences between treated and control animals were analyzed by Student’s t-test. Differences were considered statistically significant at p < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Kinetics of zymosan-induced inflammation in Balb/c mice
The data summarized in Figure 1 show the sequence of events during first 24 h after i.p. injection of zymosan into Balb/c mice (1 mg in 0.5 ml/mouse).



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  		Figure 1. Kinetics of zymosan-induced peritoneal inflammation in Balb/c mice. Animals were i.p. injected with zymosan (1 mg in 0.5 ml) and sacrificed at selected time points after treatment; time 0 represents the untreated control animals. The blood plasma and peritoneal exudate were retrieved and analyzed for the amount of soluble factors or exudate cell numbers. a) Changes of vascular permeability (solid symbols) measured by albumin-bound Evans blue leakage into peritoneal cavity 30 min after i.v. dye injection and changes of histamine level (open symbols). b) Exudate cell numbers: solid square symbols, total number of PTL; open square symbols and broken line, number of PMN; solid oval symbols and broken line, number of monocytes/macrophages (MO/MF). c) Level of plasma chemotactic factors measured as the number of bone marrow cells (per high-power field) from intact mice responding to tested plasma from zymosan-treated animals in a 48-well chemotactic chamber (solid symbols); MCP-1 content in the peritoneal exudate fluid estimated by ELISA (open symbols and broken line). d) Bioactivity of proinflammatory cytokines (TNF-{alpha}, IL-1, and IL-6) in the peritoneal exudate. All results are shown as means ± SE in groups of 5–6 mice. a–c) Mean values not sharing letters are statistically significant according to ANOVA.

 
Plasma protein exudation
The earliest event of inflammation was an increase in vascular permeability leading to a plasma protein exudation, which peaked 30 min after zymosan injection and then declined to the control level 4 h after stimulation (Fig. 1a) .

Histamine level in the peritoneal fluid
Histamine content was negligible in control mice and sharply increased after zymosan stimulation with a peak at 30 min but was still above the control level 24 h after stimulation (Fig. 1a) .

Accumulation of exudate leukocytes
The number of peritoneal leukocytes (PTL) decreased slightly immediately after zymosan injection, perhaps because of their increased adherence to the peritoneal lining, a phenomenon also recorded in other studies [2 , 43 ]. Following this initial drop, the number of PTL increased gradually with a maximum at 6 h after zymosan injection and then decreased slightly but was still far above the control level 24 h after injection (Fig. 1b) and even 7 days after induction of peritonitis (unpublished results). Among exudate PTL, the PMN dominated at the early stages of inflammation and then were gradually replaced by mononuclear leukocytes (Fig. 1b) .

Chemotactic factors
The cell recruitment at the inflammatory focus correlated with the presence of chemotactic factors (total and MCP-1) in the peritoneal fluid (Fig. 1c) .

Proinflammatory cytokines
Peritoneal exudate fluid was also a rich source of proinflammatory cytokines, which appeared in a characteristic sequence, with TNF-{alpha}, IL-1{alpha} and ß, and IL-6 reaching maximum bioactivity at 4, 6, and 12 h after zymosan injection, respectively (Fig. 1d) . The TNF-{alpha} level measured by enzyme-linked immunosorbent assay (ELISA) showed two distinct peaks, the first one almost immediately after zymosan injection and the second one 2–4 h later (Fig. 2a ). The IL-1ß kinetics measured by ELISA also showed two peaks and a lower level than that measured by bioassay, which detects IL-1{alpha} and IL-1ß (compare Fig. 2b with Fig. 1d ).



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  		Figure 2. Kinetics of TNF-{alpha} (a) and IL-1ß (b) content in the peritoneal exudate fluid at selected time points after i.p. zymosan injection (1 mg in 0.5 ml). Mean values ± SE.

 
Effects of mast cell stabilizer
Pretreatment of mice with cromolyn inhibited significantly (but never completely) zymosan-induced plasma exudation regardless of the route of drug administration (s.c., i.p., or i.v.; Fig. 3a ).



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  		Figure 3. Effects of cromolyn on vascular permeability (a) and histamine content in the peritoneal fluid (b) during zymosan-induced peritonitis in Balb/c mice. For evaluation of vascular permeability (a), animals were pretreated s.c., i.p., or i.v. with cromolyn 30 min before i.p. injection of zymosan (1 mg in 0.5 ml) followed by i.v. injection of Evans blue. The amount of blue dye was spectrophotometrically estimated at 650 nm in the peritoneal exudate retrieved 30 min after zymosan/dye treatment. For evaluation of histamine content (b), mice were i.p. injected with saline (VEH) or cromolyn (CRO; 160 or 400 mg/kg, i.e., 39 and 97 mM, respectively) 30 min before i.p. injection of zymosan and sacrificed at the selected time points. All results are shown as means ± SE in groups of 5–6 mice. Differences of mean values not sharing letters are statistically significant according to ANOVA.

 
The level of histamine was negligible in intact Balb/c mice, and it increased to 60 ng/ml 30 min after zymosan treatment. The histamine influx was decreased to 28 and 13 ng/ml in animals pretreated with cromolyn (160 and 400 mg/kg, respectively), but the difference was statistically significant only for the latter dose (Fig. 3b) .

Cromolyn doses used here (160 and 400 mg/kg, i.p.) had no effects on PTL number, the level of plasma chemoattractants, and TNF-{alpha}, IL-1ß, and IL-6 levels measured 2, 6, and 24 h after zymosan stimulation (Fig. 4 ).



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  		Figure 4. Effects of cromolyn on selected parameters of zymosan-induced peritoneal inflammation. Thirty minutes before zymosan injection (1 mg in 0.5 ml), Balb/c males were i.p. injected with saline (VEH) or mast cell stabilizer cromolyn (CRO; 160 or 400 mg/kg, i.e., 39 and 97 mM, respectively). At 2, 6, or 24 h after zymosan injections, some parameters were compared between the control vehicle-treated (open bars, VEH) and cromolyn-treated experimental animals (hatched bars, CRO). a) Exudate PTL numbers; b) PMN numbers; c) plasma chemoattractant level measured as the number of bone marrow cells (per high-power field) responding to plasma from zymosan-treated animals; d–f) ELISA-estimated amounts of proinflammatory cytokines (MCP-1, TNF-{alpha}, IL-1ß, respectively) in exudate fluid; g) bioactivity of IL-6. All results are shown as means ± SE in groups of 5–8 mice. ND, not determined.

 
Effects of antagonists of histamine receptors
Zymosan-induced plasma exudation (measured 30 min after zymosan injection) was reduced significantly in animals pretreated 30 min earlier with antagonists of H1-histamine receptors (mepyramine or triprolidine) and H2-histamine receptors (cimetidine or ranitidine) used separately (Fig. 5 ) or in combination (unpublished results).



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  		Figure 5. Effects of antagonists of histamine receptors on early vascular permeability during zymosan-induced peritonitis in Balb/c mice. Animals were pretreated with H1-receptor antagonists (mepyramine or triprolidine) or H2-receptor antagonists (cimetidine or ranitidine) 30 min before i.p. injection of zymosan (1 mg in 0.5 ml) followed by i.v. injection of Evans blue. The amount of blue dye was estimated at 650 nm in peritoneal exudate retrieved 30 min after zymosan/dye injection. All results are shown as means ± SE in groups of 6–8 mice. *p < 0.5 when compared with the saline-pretreated control (zymosan only).

 
Measurements performed 2 h after zymosan treatment revealed that mepyramine pretreatment (2 mg/kg; 5 µM) had diminished significantly the numbers of PTL and PMN and the level of MCP-1 at 2 h after zymosan injection (Fig. 6a 6b, and 6d ), and the level of IL-1ß was reduced significantly at 6 h of inflammation (Fig. 6f) . All other parameters measured 2, 6, and 24 h after zymosan injection were similar in mepyramine- and vehicle-treated mice (Fig. 6) .



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  		Figure 6. Effects of blocking histamine H1 receptors on the selected parameters of zymosan-induced peritoneal inflammation. Thirty minutes before zymosan injection (1 mg in 0.5 ml), Balb/c males were s.c. injected with saline or mepyramine, an antagonist of H1-histamine receptor (H1; 2 mg/kg, 5 µM). At 2, 6, or 24 h after zymosan injections, some parameters were compared between the vehicle-treated control (open bars, VEH) and the mepyramine-treated (hatched bars, H1) experimental animals. a) Exudate PTL numbers; b) PMN numbers; c) plasma chemoattractant level measured as number of bone marrow cells (per high-power field) responding to plasma from zymosan-treated animals; d–f) ELISA-estimated amounts of proinflammatory cytokines (MCP-1, TNF-{alpha}, IL-1ß, respectively) in exudate fluid; g) bioactivity of IL-6. All results are shown as means ± SE in groups of 5–6 mice. Some differences between the corresponding control and experimental groups are significant at 0.05 > p > 0.01 (*) or 0.01 > p > 0.001 (**). ND, not determined.

 
Inflammation in mast cell-deficient mice
Among WBB6F1 mice, mast cells were absent in peritoneal cavities of W/Wv knockouts. In +/+ mice, there were 4.5 x 104 mast cells per peritoneal cavity, 10% of them stained positively with alcian blue and 90% with safranin. Three weeks after adoptive transfer of mast cells, there were 6 x 104 mast cells per peritoneal cavity of W/Wv + MC mice, 10% of them stained with alcian blue, 7% with safranin, and 83% with both, indicating the lack of full differentiation of bone marrow-derived mast cells into those specific for the peritoneal cavity. Despite the lack of full differentiation, the restoration of several mast cell-related parameters was recorded extensively in W/Wv + MC mice [10 , 12 13 14 ]. This was also achieved in our studies.

In the course of zymosan-induced peritonitis in mast cell-deficient W/Wv mice, all investigated inflammation-related factors were decreased significantly when compared with +/+ congenic controls and reached the level specific for +/+ mice in mast cell-reconstituted W/Wv animals (W/Wv+MC). Basal levels in the vehicle-treated mice were the same in all three groups of animals (Figs. 7 and 8 ). Protein leakage and histamine content in the peritoneal fluid at 30 min of inflammation were significantly lower in W/Wv animals than in +/+ and W/Wv + MC mice (Fig. 7a and 7b) . At 6 h after zymosan treatment, the number of exudate cells (total PTL and PMN) and the levels of cytokines (TNF-{alpha}, IL-1ß, and IL-6) were reduced significantly in W/Wv compared with those in +/+ and W/Wv + MC mice (Fig. 8) .



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  		Figure 7. Vascular permeability (a) and histamine content in the peritoneal fluid (b) during zymosan-induced peritonitis in WBB6F1 mice. Control (+/+, solid bars), mast cell-deficient (W/Wv, open bars), and mast cell-reconstituted W/Wv mice (W/Wv+MC, dotted bars) were i.p. injected with saline (vehicle, VEH) or zymosan (1 mg in 0.5 ml, Z). Vascular permeability was measured as the amount of blue dye spectrophotometrically estimated at 650 nm in the peritoneal exudate retrieved 30 min after i.v. injection of Evans blue. All results are shown as means ± SE in groups of 6–8 mice. Some differences between W/Wv versus +/+ or W/Wv + MC versus +/+ groups are significant at p < 0.5 (*).

 


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  		Figure 8. Selected parameters of zymosan-induced peritoneal inflammation in WBB6F1 mice: control (+/+), mast cell-deficient (W/Wv), and mast cell-reconstituted W/Wv (W/Wv+MC). At time 0 (0 h, intact mice) and 6 h after zymosan injections (6 h, animals with peritonitis), some parameters were compared between the control (+/+, solid bars), mast cell-deficient (W/Wv, open bars), and mast cell-reconstituted W/Wv mice (W/Wv+MC, dotted bars). a) PTL numbers; b) PMN numbers; c) plasma chemoattractant level measured as the number of bone marrow cells (per high-power field) responding to plasma from zymosan-treated animals; d and e) ELISA-estimated amounts of proinflammatory cytokines (TNF-{alpha}, IL-1ß, respectively) in exudate fluid; f) bioactivity of IL-6. All results are shown as means ± SE in groups of 6–8 mice. Some differences between W/Wv versus +/+ or W/Wv + MC versus +/+ groups are statistically significant at 0.05 > p > 0.01 (*), 0.01 > p > 0.001 (**), or p < 0.001 (***).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
General pattern of zymosan-induced peritonitis
In Balb/c mice, zymosan-induced peritonitis started with a pronounced intraperitoneal plasma exudation connected with an increased histamine level. It was followed by influx of neutrophils and mononuclear leukocytes, with increased levels of plasma/peritoneal fluid chemoattractants (including MCP-1) and with a sequential appearance of exudate proinflammatory cytokines (TNF-{alpha} followed by IL-1ß and IL-6; Figs. 1 and 2 )—a pattern of inflammation typical of zymosan-induced peritonitis. As recorded previously by Lokesh et al. [44 ], the accumulation of serum proteins in the peritoneum is considerably more rapid and stronger after zymosan injection than when induced by some other stimulants given i.p. A gradual replacement of PMN by mononuclear cells was recently described in detail [6 , 45 , 46 ]. The two peaks of TNF-{alpha} activity recorded in our studies were also detected by Zhang et al. [12 ], who concluded that the early influx of TNF-{alpha} originated from mast cell granules (containing preformed TNF-{alpha}), and the second peak probably represented newly synthesized TNF-{alpha} of neutrophilic origin. In our samples, the second peak of TNF-{alpha} estimated by a bioassay was slightly delayed versus that detected by ELISA, perhaps because the presence of TNF-{alpha} soluble receptors could mask its bioactivity at low concentrations [47 ].

Cromolyn inhibition of mast cell degranulation
The cromolyn blockade of zymosan-induced mast cell degranulation in Balb/c mice led to significant (but not total) inhibition of early vascular permeability (Fig. 3a) and peritoneal histamine levels at 30 min of inflammation (Fig. 3b) . However, at the later stages of peritonitis (2, 6, and 24 h), the histamine content and all measured parameters (the number of peritoneal leukocytes and level of proinflammatory cytokines) were the same in drug-treated animals and their vehicle-treated counterparts (Fig. 4 and Table 1 ).


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  		Table 1. Effects of Mast Cells/Histamine on Zymosan-Induced Peritonitis

 
In our experiments, the cromolyn treatment abolished zymosan-induced plasma exudation to <50% after s.c. application (160 mg/kg; 39 mM) and >50% after i.v. or i.p. administration at 160–400 mg/kg (39–97 mM; Fig. 3a ). These high doses were also required for studies on cantharidin-induced ear inflammation in mice but still did not reach ED30 [38 ]. The lack of cytotoxic effects of cromolyn on a variety of cells (including mast cells and leukocytes) was found in several studies [48 49 50 ].

Tanizaki et al. [51 ] demonstrated that the mode of action of cromolyn is connected with the inhibition of influx of Ca2+ into the mast cells, which in turn suppresses the release of histamine. In our experiments, such a phenomenon seems to be reflected by the significantly decreased histamine level correlated with the decreased vascular permeability in the cromolyn-treated mice at 30 min of inflammation (Fig. 3a and 3b) . Nevertheless, it is interesting that cromolyn blocks only certain activities of mast cells because they can produce many mediators without degranulation [1 , 19 , 20 ]. Furthermore, clinical studies show that cromolyn is short-lived [52 ], and this feature might explain the lack of the apparent effects at the later stages of inflammation.

Mepyramine blockade of histamine receptors
Zymosan-induced vascular permeability was reduced significantly in animals pretreated with antagonists of H1-histamine receptors (mepyramine and triprolidine) or with antagonists of H2-histamine receptors (cimetidine and ranitidine; Fig. 5 ).

The H1-histamine receptors are involved mainly in smooth-muscle contraction and vascular permeability [53 ], and H2 receptors mediate gastric-acid secretion [54 ], although both participate in vasodilatation [55 ]. Therefore, mepyramine was chosen for the subsequent experiments because it is the principal selective antagonist (KD=0.8 nM) of H1-type histamine receptors [56 ].

The pharmacological blockade of H1-histamine receptors (mepyramine 2 mg/kg; 5 µM) inhibited almost completely the vascular permeability (Fig. 5) and had a significant impact on further stages of peritonitis, including decreased exudate cell counts (PTL and PMN) and cytokine (MCP-1, IL-1ß, and IL-6) levels (Fig. 6) . This indicates that the effects of histamine (detected here by the blockade of H1 receptors) extend beyond induction of vascular leakage (Table 1) , maybe through activation of H2-type histamine receptors.

We are unaware of other studies on the effects of pharmacological blockade of histamine receptors on murine peritonitis. Nevertheless, our results correspond with those by Woodward and Owen [57 ] on another model of inflammation, namely cutaneous inflammation in guinea pigs, where mepyramine and cimetidine, alone or in combination, had pronounced effects on the initial phase of inflammation [57 ].

Pharmacological treatments
Histamine is known to initiate early vascular changes during inflammatory reactions by inducing vasodilatation and partial dissociation of the endothelium [58 ]. In our experiments, the cromolyn-induced inhibition of mast cell histamine release seems to have been incomplete and short-lasting (Fig. 3b) , and the effects of mepyramine (H1-receptor antagonist) were stronger and longer lasting. It is possible that in the cromolyn-treated mice, the early vascular changes were induced by histamine originated from other sources than the mast cells (e.g., the vascular wall cells [59 ]). Moreover, the involvement of other vasoactive factors such as serotonin, eicosanoids, certain clotting factors, their derivatives, and bradykinins cannot be excluded [27 , 60 , 61 ].

A reduced number of PMN and a decreased level of MCP-1 at 4 h of zymosan-induced peritonitis were recently demonstrated by Ajuebor et al. [7 ] in Swiss mice depleted of intact peritoneal mast cells by the pretreatment of the animals 3 days earlier with a degranulating agent (compound 48/80). In our experimental system, such effects were induced by mepyramine blocking of H1-type histamine receptors but were absent after cromolyn-induced mast cell stabilization. Taken together, these data support the previous statement that cromolyn effects are short-lasting and insufficient for a total blocking of histamine release. Another explanation could be that histamine from other sources or other factors like serotonin (of platelets origin) are sufficient to promote the subsequent steps of inflammation in cromolyn-treated animals.

In humans, histamine enhances IL-1{alpha}-induced IL-1ß synthesis at the level of transcription [62 ] as well as IL-1-induced IL-6 gene expression and protein synthesis [63 ]. This corresponds with our results that the level of IL-1 was reduced in mice with the blocked histamine receptors.

In conclusion, in the normal organism mast cells and histamine are involved mainly in the early stages of zymosan-induced peritonitis.

Peritonitis in mast cell-deficient mice
Zymosan-induced peritonitis was also induced in WBBF1 males, controls +/+ and their mast cell-deficient W/Wv littermates with several other genetic defects [23 , 64 65 66 ]. Additionally, some W/Wv mice were reconstituted selectively with mast cells of +/+ bone marrow origin. It has been shown previously that histamine content in the whole body of W/Wv mice is about 5–10% that of +/+ mice and in some organs like spleen, liver, and stomach, can reach up to 8, 15, and 34%, respectively [67 ]. In our experiments, zymosan-treated W/Wv animals showed a strong impairment of histamine level, plasma exudation, and all other inflammation-related factors during the course of inflammation (Figs. 7 and 8 , and Table 1 ). It should be noted that the levels of these factors in the untreated or vehicle-treated W/Wv and +/+ animals are similar (Figs. 7 and 8) , and the number of granulocytes and platelets in the blood of adult W/Wv mice is normal [68 , 69 ].

Despite the lack of full differentiation of +/+ bone marrow-derived mast cells into connective tissue mast cells, the course of inflammation was restored in W/Wv + MC mice, because the histamine content and all other parameters were similar in +/+ and W/Wv + MC animals. Complete inhibition of vascular permeability in mast cell-deficient mice was expected because mast cells produce and store a wide range of vasoactive factors [19 20 21 22 ]. The partial inhibition observed here might be attributed to the presence of histamine of another origin or, most likely, to the contribution of vasoactive factors originating from other cell types.

Restoration of all investigated parameters observed in W/Wv + MC animals indicates that presence of peritoneal mast cells is essential for the maximal response at the early as well as later stages of the zymosan-induced peritonitis. The mast cell-mediated impact on the later steps of the inflammation seems to be a consequence of the optimal early stage. Therefore, most probably, mast cell deficiency affects the later steps of the inflammation as a consequence of the impairment of its early phase.


   ACKNOWLEDGEMENTS
 
The work (B. P.) was supported in part by IZ/DS/ZIE

Received August 30, 1999; revised August 9, 2000; accepted September 20, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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