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Accelerated Clearance of Escherichia coli in Experimental Peritonitis of Histamine-Deficient Mice¹

Yoshio Hori^*,, Yoshihiro Nihei^*,, Yoshimochi Kurokawa, Atsuo Kuramasu^*, Yoko Makabe-Kobayashi^*, Tadashi Terui, Hideyuki Doi, Susumu Satomi, Eiko Sakurai^*, Andras Nagy, Takehiko Watanabe^* and Hiroshi Ohtsu^2,*

Departments of ^* Cellular Pharmacology and Dermatology, and Division of Advanced Surgical Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Japan; and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

	Abstract

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We prepared a model of experimental peritonitis by introducing Escherichia coli into the peritoneal cavity of the histamine-deficient mice generated by a disruption of the gene for histidine decarboxylase (HDC), the unique histamine-synthesizing enzyme. When we inoculated E. coli into the peritoneal cavities of the HDC^-/- (histamine-deficient) mice, they eliminated E. coli more efficiently than did the wild-type mice. Histamine was released efficiently from the peritoneal cells after E. coli inoculation in HDC^+/+ mice, although only trace amounts were detected in the peritoneal cells of HDC^-/- mice. Two histamine agonists (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)hepatanecarboxamide (H₁) and dimaprit (H₂)) impaired the clearance of E. coli from the peritoneal cavity in HDC^-/- mice, suggesting that the activation of both H₁ and H₂ receptors suppresses the clearance. In contrast, two kinds of H₁ and H₂ receptor antagonists, cimetidine and pyrilamine, promoted the clearance of E. coli in HDC^+/+ mice. Phagocytosis appeared to be enhanced in HDC^-/- mice, since the number of neutrophils in the peritoneal cavity of HDC^-/- mice was markedly increased. This enhanced recruitment of neutrophils was suppressed in the presence of the histamine agonists, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)hepatanecarboxamide and dimaprit. In this report histamine was first shown to be an important mediator in an E. coli infectious peritonitis model, causing a delay in the elimination of bacteria. This also raised the possibility of the use of antihistamine drugs for bacterial infection.

	Introduction

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The bacterial peritonitis caused by Escherichia coli infection is a clinically important problem with a high mortality rate. Mast cells are suggested to be very important cells for the host defense mechanism to E. coli-infected peritonitis (1, 2, 3). Histamine, which is formed by the decarboxylation of histidine, is a major component of mast cell granules and possesses many biological activities as an autacoid and a neurotransmitter (4). Therefore, we hypothesized that histamine modulates the defense reactions against infection. However, it has been difficult to assess the effects of histamine on the infection processes in vivo, because most observations involve the use of histamine receptor antagonists and histidine decarboxylase inhibitors. When using those agents, several problems, including unknown specificity, selectivity, side effects, and short half-life, are unavoidable. To solve these problems we used histidine decarboxylase (HDC)³ gene knockout mice that we have recently developed (5).

Whether histamine is involved in the promotion or inhibition of the inflammation process in the whole animal remains controversial, and it is difficult to deduce the conclusion from in vitro experiments. As an example for the promotion, histamine is reported to induce inflammatory cytokines such as IL-6 in vitro (6). In contrast, in support of an inhibitory action, histamine has been reported to inhibit the LPS-induced production of inflammatory cytokines TNF- (7) and IL-1 (8). The limitations of in vitro experiments for elucidating the overall effect of histamine on inflammatory responses led us to assess the activity of histamine in an experimental peritonitis model.

As a mouse model we induced experimental bacterial peritonitis by E. coli injection into the peritoneal cavity (9) and monitored the clearance of bacteria, the accumulation of neutrophils and macrophages, and the production of cytokines and chemokines. The results indicate that histamine delays the clearance of E. coli, presumably through the inhibition of phagocyte recruitment.

	Materials and Methods

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Mice

Histamine-deficient mice were prepared as described using the homologous recombination method in embryonic stem cells (5). The knockout construct lacks the putative pyridoxal phosphate-binding site within exon 8. For the comparison between wild-type and knockout animals, wild-type littermate controls were matched for age (8–10 wk) and gender (male). Studies were performed according to Tohoku University guidelines for animal use and care.

Bacterial peritonitis model

Mice were injected with a sublethal dose of live E. coli (1 x 10⁸ CFU) into the abdominal cavity (9). The mice were anesthetized by the inhalation of diethylether and were sacrificed by dislodging the cervical vertebrae. Blood was collected from the carotid artery for the TNF-, macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1) assay. Five milliliters of PBS was injected into the peritoneal cavity and, after slight massage, was collected as the peritoneal lavage fluid. E. coli CFU were calculated from the colony numbers on the Luria-Bertoni agar plates after overnight culture with serial 10-fold dilutions.

Evaluation of neutrophil and monocyte accumulation

Myeloperoxidase (MPO) and nonspecific esterase (NSE) activities in peritoneal lavage fluid were measured as previously described (10, 11). Briefly, 1 ml of the fluid was centrifuged at 1000 x g for 5 min at 4°C. The cell pellet was resuspended in 0.5 ml of 1.0% Triton X-100 and incubated for 1 h to extract the enzymes. MPO activity was calculated from the spectrophotometric absorbance at 470 nm with guaiacol as the substrate. NSE activity was determined from the rate of hydrolysis of o-nitrophenyl butyrate by measuring the decrease in absorbance at 414 nm in the presence of eserine (10 mM), which would eliminate any possible interference by cholinesterase. Cytocentrifuge preparations of peritoneal cells at 1 h after E. coli inoculation were stained with May-Grünwald/Giemsa for the identification of neutrophils and macrophages.

TNF-, chemokine, and histamine assay

Serum TNF-, MCP-1, and MIP-2 levels were measured with ELISA kits (Endogen (Cambridge, MA) for TNF-; R&D Systems (Minneapolis, MN) for MCP-1 and MIP-2) according to the manufacturers’ specifications. To assess the extent of E. coli-induced histamine release, we measured the amounts of residual (releasable) histamine in peritoneal cells instead of measuring the released histamine (11), because histamine once released from the peritoneal cells is rapidly metabolized. At the designated time points after inoculation, mice peritonea were instilled with 5 ml cold PBS to stimulate the peritoneal cells to release histamine. The peritoneal lavage fluid was recovered and centrifuged to remove cells. The amount of histamine in the fluid was determined using an HPLC system as previously described (12).

Administration of histamine agonists and antagonists

For assessment of the effect of histamine via H₁ and H₂ receptors, we used an H₁ receptor agonist (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)hepatanecarboxamide (HTMT; 10 mg/kg body weight; Tocris, Ballwin, MO) (13, 14) and an H₂ receptor agonist (dimaprit, 200 mg/kg body weight; Tocris) (15, 16) in HDC^-/- mice. These agonists were administered i.p. concomitantly with E. coli inoculation to determine their effects on E. coli elimination, phagocyte infiltration, and the amount of chemoattractants in the peritoneal cavity. The doses of these agonists were determined in preliminary dose-response experiments. We also assessed the effect of histamine receptor blockade by concomitant introduction of an H₁ antagonist (pyrilamine, 5 mg/kg body weight) or H₂ antagonist (cimetidine, 20 mg/kg body weight) into the peritoneal cavity of HDC^+/+ mice. The dose chosen for pyrilamine was most effective in the preliminary experiment and was the same dose used previously (11). The dose for cimetidine was adjusted to the dose used in past reports (17, 18).

Phagocytic activity of peritoneal cells

The peritoneal cavity was washed with 5 ml PBS containing 0.1% BSA and 10 mM EDTA. The peritoneal cells were collected and resuspended in HBSS as 10⁶ cells/ml. After 5 min of preincubation, the cell suspension was incubated with E. coli (10⁷/ml) at 37°C for 1 h with mild shaking. The cells were removed as the pellet after centrifugation at 200 x g for 10 min, and E. coli number in the supernatant was counted.

In vitro direct effect of histamine, histamine agonists, and histamine antagonists on E. coli proliferation

CFU of E. coli (1 x 10⁴) was incubated in Luria-Bertoni medium with histamine (0.1 mg/ml), HTMT (0.05 mg/ml), dimaprit (0.5 mg/ml), pyrilamine (0.025 mg/ml), or cimetidine (0.1 mg/ml) for 6 h at 37°C with shaking to assess the direct effect of histamine-related agents on the proliferation of E. coli. The dose chosen for each agent was 10–100 times higher than the dose used in previous reports (19, 20, 21) to attain effects from these agents. The CFU of live E. coli were determined as stated above.

Statistical analysis

Statistical analysis of most data was performed using unpaired Student’s t test. A value of p < 0.05 was considered significant and is indicated expressed as an asterisk in all figures.

	Results

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Histamine inhibits the clearance of E. coli from the peritoneal cavity of the E. coli-inoculated peritonitis model

Mice were injected with 1 x 10⁸ CFU of E. coli into the peritoneal cavities, and the numbers of live E. coli at 1, 3, and 6 h after inoculation were monitored (Fig. 1A). The clearance of bacteria from the peritoneal cavity was quite rapid in HDC^-/- mice (Fig. 1A). The number of E. coli in HDC^-/- mice had fallen below 5 x 10⁶ CFU/ml by 1 h after the inoculation. On the other hand, the number in HDC^+/+ mice was >5 x 10⁶ CFU/ml even at 3 h after inoculation. HDC^-/- mice eliminated E. coli rapidly.

View larger version (17K): [in this window] [in a new window]   FIGURE 1. The effect of histamine on the clearance of E. coli from the peritoneal cavity. A, The CFU of E. coli in peritoneal lavage fluid at the indicated time points after i.p. injection of 108 CFU of E. coli. B, The amount of residual histamine in peritoneal cells. The effect of histamine agonists (C) or antagonists (D) on i.p. bacterial number was assessed. HTMT (0.2 mg) and dimaprit (4 mg) were i.p. administered to HDC-/- mice (C) or 0.1 mg pyrilamine and 0.4 mg cimethidine were administered to the mice (D) together with the E. coli inoculation. The number of E. coli in the lavage fluid was counted at 1 h after the inoculation. All values are the mean ± SEM of at least six mice for each group (*, p < 0.05).

The effect of the knockout could be attributed to not only the deficiency of the enzymatic product, but also to the deficiency of the enzyme and/or the gene. The numbers of peritoneal mast cells were similar in HDC^+/+ and HDC^-/- mice (3.78 ± 0.91 x 10⁴ for HDC^+/+ and 3.23 ± 0.54 x 10⁴ for HDC^-/- mice). However, as stated in the previous report, the character of the secretory granule of the peritoneal mast cell was quite different in the two groups of mice (5). We therefore administered both the H₁ receptor agonist HTMT and the H₂ receptor agonist dimaprit to HDC^-/- mice concomitant with the E. coli suspension to assess the effect of the stimulation of histamine receptors on E. coli clearance. The amount of E. coli was significantly (p < 0.05) increased at 1 h after inoculation by HTMT or dimaprit treatment (Fig. 1C). The activation of both H₁ and H₂ receptors suppressed the clearance of E. coli in the peritoneal cavity. In contrast, the H₁ and H₂ receptor antagonists, cimetidine and pyrilamine, promoted the clearance of E. coli in HDC^+/+ mice (Fig. 1D). In HDC^-/- mice there appeared to be no significant difference in the clearance of E. coli after histamine receptor antagonist administration. These data confirm that histamine causes a delay in the elimination of bacteria from the peritoneal cavity.

Dominant migration of neutrophils into the peritoneal cavity of HDC^-/- mice

The migration of macrophages and neutrophils into the peritoneal cavity was observed by histological examination at 1 h after E. coli inoculation (Fig. 2). In the peritoneal lavage fluid, phagocytic (granulocytes, macrophages) infiltrates were seen extensively in HDC^-/- mice. The total macrophage numbers per lavage per mouse were 2.47 ± 0.30 x 10⁶ (HDC^+/+) and 3.57 ± 0.37 x 10⁶ (HDC^-/-). The total neutrophil numbers were 8.17 ± 0.31 x 10⁴ (HDC^+/+) and 26.17 ± 3.42 x 10⁴ (HDC^-/-). Both types of phagocytes were significantly more abundant in the peritoneal cavity of HDC^-/- mice (p < 0.05 for macrophages, p < 0.01 for neutrophils). On the other hand, the total macrophage numbers were 3.38 ± 0.29 x 10⁶ (HDC^+/+) and 3.51 ± 0.18 x 10⁶ (HDC^-/-), and the total neutrophil number was <5 x 10³ in both genotypes before E. coli inoculation (p > 0.05 for each cell lineage). Therefore, the migration of neutrophils was enhanced in HDC^-/- mice.

View larger version (99K): [in this window] [in a new window]   FIGURE 2. Histological study of peritoneal lavage fluid. Peritoneal lavage fluid was stained with May-Grünwald/Giemsa staining at 1 h after the inoculation. Neutrophils (broken arrow), macrophages (arrow), and E. coli (arrowhead) were identified.

View larger version (27K): [in this window] [in a new window]   FIGURE 3. Biochemical assessment of peritoneal lavage fluid. MPO (A) and NSE (B) activities were determined at the represented time points after E. coli inoculation. The effects of the histamine agonists HTMT and dimaprit on MPO (C) and NSE (D) activities were assayed in peritoneal lavage fluid 1 h after inoculation. All values are the mean ± SEM of six mice for each group (*, p < 0.05).

Increased concentrations of TNF-, MIP-2, and MCP-1 in HDC^-/- mice

TNF-, one of the crucial mediators in peritonitis, triggers inflammatory responses partly through the influx of neutrophils (3, 22, 23). Therefore, we measured the level of TNF- as one of the factors for the augmented neutrophil recruitment seen in HDC^-/- mice. The serum TNF- level in HDC^-/- mice was about 2-fold higher than that in HDC^+/+ mice at 1 h after E. coli injection (Fig. 4A). In rodents, MIP-2 and MCP-1 are two of the representative chemokines with direct chemotactic activities to neutrophils and mononuclear phagocytes. The concentrations of both chemokines in the serum were significantly higher in HDC^-/- mice than in HDC^+/+ mice at 1 h after inoculation (Fig. 4A). These cytokines in the peritoneal cavity showed a similar tendency as those in serum (Fig. 4B). However, the differences were not significant in peritoneal lavage fluid.

View larger version (21K): [in this window] [in a new window]   FIGURE 4. A, The concentrations of serum TNF-, MIP-2, and MCP-1 in HDC+/+ and HDC-/- mice were determined 1 h after the inoculation. B, The concentrations of TNF-, MIP-2, and MCP-1 in peritoneal lavage fluid were determined at 1 h after the inoculation. These concentrations were determined with the ELISA method described in Materials and Methods. All values are the mean ± SEM of six mice for each group (*, p < 0.05; **, p < 0.01).

To compare the phagocytic activities of the peritoneal cells of each genotype, they were incubated with E. coli for 1 h, and E. coli free from the cells were counted with colony formation. The colony number indicated that there were no significant differences in phagocytic activity between the peritoneal cells of HDC^+/+ mice and those of HDC^-/- mice (Fig. 5A).

View larger version (31K): [in this window] [in a new window]   FIGURE 5. A, The CFU of E. coli in the supernatant after centrifugation of incubated peritoneal cell suspension with E. coli. The peritoneal cells from HDC+/+ and HDC-/- mice were incubated with E. coli (107) for 1 h at 37°C, and the number of E. coli free from the cells was counted. B, The proliferation of E. coli after 6 h of mixing culture with histamine (HA), histamine agonists, or histamine antagonists. The data were measured as CFU and are the mean ± SEM.

The results reported above indicate that histamine inhibits the clearance of E. coli in the peritoneal cavity. It is possible that histamine directly enhances the proliferation of E. coli. To address this possibility, we incubated E. coli in Luria-Bertoni medium with histamine, histamine agonists, or histamine antagonists and counted the number of E. coli after 6-h incubation at 37°C with shaking. There were no significant differences in E. coli numbers among these different conditions (Fig. 5B), indicating that histamine does not directly stimulate the proliferation of E. coli. The direct effect of histamine on E. coli proliferation seems to be negligible.

	Discussion

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We observed here that E. coli inoculated into the peritoneal cavity was eliminated rapidly in the absence of histamine. The histamine-induced delay in the elimination of E. coli from the peritoneal cavity could be established because we used histamine-deficient mice instead of histamine antagonists. Since the mice have no histamine (5), the effect of histamine in physiological and pathological conditions could be assessed by comparing the phenotypes between HDC^+/+ and HDC^-/- mice. The results also suggest that antihistamine could have therapeutic value in treatment of the early phase of bacterial infection. Because the histamine receptor antagonists did not directly suppress the proliferation of E. coli, there is a possibility that these drugs could be applied with bacteria-directed agents, e.g., antibiotics for a bacterial infection.

The mechanism behind the histamine-delayed elimination of E. coli with histamine may be very complex, but it seemed at least to involve suppressed phagocyte recruitment and activation. It was reported that phagocytic recruitment was inhibited by a histamine receptor antagonist in a staphylococcal enterotoxin peritonitis model (18) and in the reaction to implanted biomaterials (11). In contrast, there is a report that histamine suppresses the effect of chymase for the recruitment of neutrophils and macrophages (24). Therefore, we could not have anticipated whether histamine acts for the inhibition or the promotion of phagocyte recruitment in this E. coli inoculation model. To elucidate the mechanism behind the augmented phagocyte recruitment, we used the H₁ and H₂ agonists and confirmed the suppression of the recruitment in HDC^-/- animals.

TNF- is known to be released from mast cells and cause an influx of neutrophils in the peritoneal cavity in immune complex peritonitis (22) and in Klebsiella pneumoniae-infected peritonitis (3). Assuming that TNF- is derived predominantly from mast cells, it is conceivable in the present case that the released histamine from the mast cells autoregulates the release of TNF- via its own cell surface histamine receptor (7). In this experiment TNF- was detectable in the plasma only at 1 h after inoculation in both genotypes. The level of TNF- in the knockout mice was higher than that in the wild-type mice, suggesting that a part of the recruitment of neutrophils was triggered by the action of TNF-. TNF- is known not only to induce the influx of neutrophils in vivo (22), but also to stimulate endothelial cells and macrophages to release chemokines such as MIP-2, a mouse IL-8 equivalent, and MCP-1 (25). In an experimental peritonitis model, MIP-2 and MCP-1 were shown to attract phagocytes into the peritoneal cavity, resulting in the efficient elimination of E. coli (26, 27, 28, 29). Therefore, it is possible that cytokines, including TNF-, MIP-2, and MCP-1, cooperatively acted for the recruitment of phagocytes into the peritoneal cavity. However, it is also possible that the inhibitory effect of histamine on the migration of phagocytes (30, 31, 32) works in this model.

The increased amount of these cytokines in HDC^-/- mice seemed not to be attributed to the increased releasability from mast cells, because we observed the dose-response fashion of bone marrow-derived mast cells using -hexosaminidase as the indicator of the intragranular enzyme and found that the dose-response relations are very similar between the mast cells of HDC^+/+ and HDC^-/- mice (33). The amount of TNF- and MCP-1 released from mast cells of HDC^-/- mice was smaller than those of HDC^+/+ mice (our unpublished observations). Therefore, we tentatively assume that the source of the augmented release of cytokines is not mast cells.

Histamine has been discussed as an important chemical mediator that prompts both hyperemia and the enhanced expression of endothelial adhesion molecules such as P-selectin (34, 35). Up-regulation of endothelial adhesion molecules enhances the arrest and diapedesis of phagocytic cells through the endothelial barrier. Accordingly, it was expected that histamine would enhance phagocytic recruitment, but our data definitely indicate that, on the contrary, the clearance of E. coli was delayed in the presence of histamine. We still do not know what kind of cell is the target of histamine to reduce the amount of chemokines. Relevant in vitro evidence is still lacking. Although further information on the role of histamine in this experimental peritonitis model is needed, histamine-deficient mice will enable progress toward elucidating the role of histamine in various physiological and pathological conditions.

	Acknowledgments

 
We thank Dr. T. Nakamura for helpful discussion. We also thank the members of the Department of Pharmacology, Tohoku University School of Medicine, for their help.

	Footnotes

 
¹ This work was supported by grants-in-aid from the Ministry of Education, Science, and Culture of Japan and grants form the Mochida Memorial Foundation for Medical and Pharmaceutical Research.

² Address correspondence and reprint requests to Dr. Hiroshi Ohtsu, Department of Cellular Pharmacology, Tohoku University School of Medicine, Seiryo-cho 2-1, Aoba-ku, Sendai 980-8575, Japan. E-mail address: ohtsu{at}mail.cc.tohoku.ac.jp

³ Abbreviations used in this paper: HDC, histidine decarboxylase; HTMT, 6- [2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)hepatanecarboxamide; MIP-2, macrophage inflammatory protein-2; MCP-1, monocyte chemoattractant protein-1; MPO, myeloperoxidase; NSE, nonspecific esterase; PLF, peritoneal lavage fluid.

Received for publication April 12, 2002. Accepted for publication June 12, 2002.

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