a Department of Pharmacology, Kyoto Pharmaceutical University, 5 Misasagi-Nakauchi, Yamashina, Kyoto 607-8414; b Department of Pneumology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8502, Japan
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Abstract |
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Introduction |
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Aerosolized antibiotics are effective against organisms causing persistent respiratory tract infections in patients with chronic pulmonary diseases. 15 Weathers et al. 16 reported that aerosolized vancomycin effectively eradicated MRSA colonization of the airways. However, aerosolized antibiotics can cause bronchospasm. 17 ,18 Therefore, Weathers et al. 16 gave vancomycin mist in combination with a nebulized ß-agonistic bronchodilator (albuterol). It is therefore very important to evaluate experimentally the effects of teicoplanin and vancomycin on airway tissue at the time of inhalation therapy trials of these drugs.
In the present study, we evaluated whether teicoplanin and vancomycin induce pulmonary tissue contraction and histamine release in pulmonary tissue specimens obtained from several species including humans, and compared these responses with anaphylactic reactions. We also studied the ability of these antibiotics to promote histamine release from monkey blood leucocytes and mouse bone marrow-derived mast cells (BMMC).
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Materials and methods |
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Teicoplanin (Hoechst Marion Roussel, Frankfurt, Germany) and vancomycin hydrochloride (Sigma Chemical Co., St Louis, MO, USA) were used. Teicoplanin was dissolved in and diluted with distilled water. Vancomycin was suspended in distilled water at 1.6 x 10-1 g/mL and dissolved by adding 1 N NaOH to the suspension, followed by dilution with distilled water to the required concentration. These preparations were prepared just before use, under shielding from light.
Animals
Male Hartley guinea pigs weighing 800950 g, 8-week-old male BALB/c mice weighing 2227 g, and male and female cynomolgus monkeys (Macaca irus) weighing 2.84.4 kg (Japan SLC, Hamamatsu, Japan) were used. The animals were used after being held in stock for 36 weeks in an air-conditioned room at a temperature of 22 ± 1.5°C and a relative humidity of 55 ± 15%. Artificial illumination was provided from 8.00 a.m. to 8.00 p.m. The animals were fed a standard laboratory diet and given water ad libitum.
The study protocol was approved by the Experimental Animal Research Committee of Kyoto Pharmaceutical University.
Human lung
Macroscopically normal portions of human lungs, which were obtained from patients undergoing resection for carcinoma, were used in experiments as soon as possible. Informed consent was obtained from all patients.
Antigens
Benzylpenicilloyl bovine -globulin (BPO-BGG) was prepared according to the method of
Levine & Redmond.
19
Mite extracts (from Dermatofagoides farinae) were kindly donated by Dr H. Nagai of
Gifu Pharmaceutical
University (Gifu, Japan). Dinitrophenylated Ascaris suum extracts (DNP-As)
were prepared according to the method of Tada & Okumura.
20
Antisera
Anti-BPO-BGG guinea pig serum was obtained by immunizing 5-week-old female guinea pigs (Japan SLC, Hamamatsu, Japan) with BPO-BGG containing Al(OH)3 as an adjuvant according to the method of Levine et al. 21 (7 day passive cutaneous anaphylaxis (PCA) titre: 1:2500). For antisera against mite extracts, mite-sensitive human atopic serum with a radioallergosorbent test value of >30% was used. Anti-DNP-As rat serum was prepared by immunizing 8-week-old male Brown Norway rats (Seac Yoshitomi, Fukuoka, Japan) with DNP-As containing Bordetella pertussis adjuvant (Kaken Pharmaceutical Co., Tokyo, Japan) according to the method of Tada & Okumura 20 (48 h PCA titre: 1:3500).
Preparation of isolated pulmonary tissues
Guinea pigs. Guinea pigs were passively sensitized by iv injection of anti-BPO-BGG guinea pig serum (1 mL/ animal). Two days later, the animals were killed by exsanguination under pentobarbital (Nembutal, Abbott Laboratories, North Chicago, IL, USA, 40 mg/kg, ip) anaesthesia, and the lung was perfused via a pulmonary artery with Ca2+-free Tyrode's solution (20 mL/animal). The lung and trachea were removed, and tissue strips were prepared as described previously. 22 ,23 In brief, the procedures were as follows. The isolated trachea was split longitudinally through the ventral cartilage; segments (two cartilage rings in width) were cut, and ligatures were tied to the cartilage end. The isolated tracheal preparation consisted of three segments. Lung parenchymal strips consisted of a piece of the lung surface cut into a cylindrical strip.
Monkey. Animals were killed by exsanguination from the cervical artery under ketamine hydrochloride (Sigma Chemical Co., 13 mg/kg, ip) and pentobarbital (1020 mg/kg, ip) anaesthesia. The lung was then perfused via a pulmonary artery with Ca2+-free Tyrode's solution (50 mL/animal). The lung and trachea were removed, and strips of trachea, bronchus, and lung parenchyma were prepared as follows. The isolated trachea was split longitudinally through the ventral cartilage; segments (one cartilage ring in width) were cut, and the isolated tracheal preparation consisted of one segment. Bronchial strips, 1.5 mm in width and 2 cm in length, were prepared by cutting the primary bronchus spirally. After removing the pleura, cylindrical lung strips, 3 mm in diameter and 2 cm in length, were prepared from the peripheral lung. These preparations were passively sensitized with a ten-fold dilution of human atopic serum (1 mL/preparation for trachea and bronchi, and 2 mL/preparation for lung parenchyma) for 1.5 h at 37°C. After completion of sensitization, the preparation was washed with Ca2+-free Tyrode's solution before suspension in a Magnus bath.
Humans. Bronchial and lung parenchymal strips were prepared as described elsewhere. 22 ,23 Bronchial spiral strips, 1.5 mm in width and 2 cm in length, were prepared. Lung cylindrical strips were prepared as described for the monkey. These preparations were passively sensitized with human atopic serum as described above.
Measurement of movement of isolated pulmonary tissue preparation
The isolated airway tissue preparations were suspended in a 5 mL Magnus bath. The temperature was 37 ± 0.1°C and the loading weight 300 mg. Movement of the smooth muscle was recorded isotonically using a TD-112S isotonic transducer and RGJ 4124 recorder (Nihon Kohden, Tokyo, Japan) through amplification (AA-601H amplifier and EG-650H isotonic coupler; Nihon Kohden). Before beginning the experiments, 5 x10-6 M acetylcholine chloride (Ovisot; Daiichi Pharmaceutical Co., Tokyo, Japan) was repeatedly applied to the isolated preparations until almost equal contractions were observed, indicating that the sensitivity had stabilized. In preparations from guinea pigs and humans, 10-5 M histamine dihydrochloride (Wako Pure Chemical Industries, Osaka, Japan) was then also applied, and the induced contraction was recorded.
Effects of teicoplanin and vancomycin on the resting tonus of the trachea, the bronchus, or lung parenchyma were assessed as follows: Teicoplanin or vancomycin, both at 10-6 10-3 g/mL, was applied cumulatively at 10 min intervals. After drug application, preparations were washed with Tyrode's solution and antigen corresponding to the respective species was added to give a final concentration of 10-5 g/mL; induced contractions were monitored for 10 min. After antigen challenge, KCl was applied ( 10-2 g/mL) to determine maximum contractions.
Reaction solutions in the bath were collected just before and after the cumulative application of teicoplanin or vancomycin and antigen application. The collected medium was then centrifuged (4°C, 15,000g, 2 min) and the resulting supernatant was stored at -20°C until measurement of histamine concentration.
Preparation of lung fragments
Guinea pig. Conditions for passive sensitization of the guinea pig and preparation of lung fragments are described elsewhere. 24 In brief, the isolated lung, obtained from guinea pigs passively sensitized as described above, was cut into pieces measuring 0.25 x 0.25 x 0.25 mm. After washing the lung fragments with Ca2+-free Tyrode's solution, Tyrode's solution (1 mL/100 mg wet tissue) was added to the fragments.
Monkey. As reported previously, 24 the isolated lung was cut into pieces measuring 0.7 x 0.7 x 12 mm and washed with Ca2+-free Tyrode's solution. The fragments were passively sensitized by incubation with five-fold diluted human atopic serum for 1.5 h at 37°C. After completion of sensitization, the fragments was washed with Ca2+-free Tyrode's solution and suspended in Tyrode's solution (100 mg wet tissue/mL).
Human. Conditions for preparation of human lung fragments and passive sensitization were similar to those described above and previously for monkeys. 24 ,25
Differentiation and culture of BMMC
BMMC were obtained as described elsewhere.
26
,27
In brief, bone marrow cells
from BALB/c mice were cultured for 5 weeks in -medium supplemented with 20%
horse
serum, 100 µM 2-mercaptoethanol, 100 µM non-essential amino acids, 60
µg/mL kanamycin sulphate and 10% or 20% conditioned medium. After 5
weeks of
culture, the BMMC were >95% pure as assessed by Alcian Blue staining. BMMC (
106
cells/mL) were passively sensitized by adding 0.1 volume
of anti-DNP-As rat serum to the cell suspension, which was then incubated at 37°C for 24
h. After completion of sensitization, the BMMC were washed and suspended in Tyrode's
solution containing 0.1% bovine serum albumin (BSA) to give a cell concentration of
4 x 105 cells/mL.
Preparation of monkey peripheral blood leucocyte suspension
Peripheral blood was drawn in the presence of heparin sodium (Takeda Chemical Industries, Osaka, Japan) from the cervical artery of monkeys under ketamine and pentobarbital anaesthesia. Ten millilitres of the blood was added to 1.75 mL of 6% dextran (Nacalai Tesque, Kyoto, Japan); the mixture was allowed to stand at room temperature for 2 h and the leucocyte layer was collected. After washing with Ca2+-free Tyrode's solution, the obtained leucocytes were passively sensitized by incubation with human atopic serum at 37°C for 1 h. Then, the leucocytes were washed with Ca2+-free Tyrode's solution and suspended at 2 x 107 cells/mL in Tyrode's solution containing 0.1% BSA.
Histamine release from lung fragments or cells
The suspension of lung fragments or cells was preincubated at 37°C for 10 min, then 10-6 10-3 g/mL of teicoplanin or vancomycin, or the appropriate antigen (final concentration 10-5 g/mL, except for BMMC (10-7 g/mL)) was added to the suspension followed by 30 min incubation at 37°C. The reaction was terminated by filtration of the fragments on gauze or by cooling the cell suspension. The reacted solution was centrifuged (4°C, 1700g, 10 min), and the resulting supernatant was stored at -20°C until assay of histamine.
Histamine assay
Histamine in the supernatant was assayed fluorimetrically by HPLC over a cation exchange column (TSK gel SP-2SW, 4.6x 50 mm, Tosoh, Tokyo, Japan) as described by Itoh et al., 28 who modified the method of Yamatodani et al. 29 To estimate the histamine contents of tissues or cells that had not been treated with drug or antigen, specimens were placed in a boiling water bath for 10 min after addition of perchloric acid at the final concentration of 3%. After centrifugation at 15,000g for 2 min at 4°C, histamine in the supernatant was measured as described above.
Statistical analyses
Statistical analysis was performed by one-way analysis of variance. If a significant difference was detected, the individual group difference was determined by Bonferroni's multiple test. A P value of <0.05 was considered to indicate statistical significance.
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Results |
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Guinea pig trachea and lung parenchyma. As shown in Figure 1 and Table I, neither teicoplanin nor vancomycin induced contraction of, or histamine release from, guinea pig trachea or lung parenchyma. In contrast, antigen provoked both contraction of, and histamine release from, both preparations.
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Lung fragments. Lung fragments from guinea pigs, monkeys and humans spontaneously released about 1% of their total histamine content. Neither teicoplanin nor vancomycin promoted spontaneous histamine release, whereas anaphylactic stimulation significantly increased such release (Table IV).
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Discussion |
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Sahai et al.
14
reported that intravenous
infusion of vancomycin to humans is associated with a high frequency of `red man
syndrome', the severity of which is positively correlated with the increment in histamine
concentration in peripheral blood. The occurrence of vancomycin-induced `red man
syndrome' has been reported to be inhibited by treating patients with an H1-receptor antagonist.
30
O'Sullivan et al.,
31
however, found no relation
between this adverse effect and increased blood histamine concentrations, suggesting that other
mediators might participate in the development of ` red man syndrome'. Not only
histamine
32
,33
,34
but also cholinergic agonists,
33
,34
cysteinyl
leukotrienes,
34
,35
,36
thromboxane A2,
37
,38
prostaglandin D2,
38
prostaglandin F2,
38
and endothelins,
39
,40
cause marked contraction of
human bronchi. Monkey trachea is known not to respond to histamine.
41
,42
These previous results and
those of the present study suggest that the vancomycin-induced contractions of human bronchus
and monkey trachea might be caused primarily by the release or production of mediators other
than histamine. However, we cannot rule out the possibility that vancomycin directly causes
contraction of smooth muscle. Further studies are needed to elucidate the mechanism of
vancomycin-induced contractions.
Polk et al. 43 attempted to predict the severity of `red man syndrome' after intravenous infusion of vancomycin on the basis of the cutaneous response to intradermally administered vancomycin in healthy adults, but noted no significant correlation between the vancomycin-induced flare and the severity of `red man syndrome'. Consistent with the results of that study, we found that vancomycin did not cause the contraction of monkey bronchus, monkey lung parenchyma or human lung parenchyma. In general, relatively central airway tissue is known to contract more in response to neurotransmitters, such as cholinergic agonists, than in response to chemical mediators, such as histamine and arachidonic acid metabolites; the opposite holds true for relatively peripheral airway tissue. These characteristics of airway tissues considered with the organ-specific action of vancomycin lead us to speculate that vancomycin may potently induce contractions of human trachea, although such tissue was not available for the present study.
Neither teicoplanin nor vancomycin induced histamine release from lung fragments of three species, or from BMMC or monkey blood leucocytes. Results of the lung fragment studies agree with those of the experiments using a Magnus bath. The lack of histamine release from BMMC and monkey leucocytes indicates that the sensitivity of these cells to vancomycin differs substantially from that of unidentified cells that are thought to release histamine after intravenous infusion of vancomycin.
In conclusion, our results suggest that, compared with vancomycin, teicoplanin may be associated with a lower risk of bronchoconstriction when used for inhalation therapy and a lower risk of `red man syndrome' when used for infusion therapy.
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Acknowledgments |
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Notes |
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References |
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Received 19 May 1998; returned 13 July 1998; revised 31 July 1998; accepted 17 September 1998