Unit of Lung Toxicology, Laboratory of Pneumology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
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ABSTRACT |
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The natural polyamines putrescine, cadaverine, spermidine, and spermine are found in all cells. These (poly)cations exert interactions with anions, e.g., DNA and RNA. This feature represents their best-known direct physiological role in cellular functions: cell growth, division, and differentiation. The lung and, more specifically, alveolar epithelial cells appear to be endowed with a much higher polyamine uptake system than any other major organ. In the lung, the active accumulation of natural polyamines in the epithelium has been studied in various mammalian species including rat, hamster, rabbit, and human. The kinetic parameters (Michaelis-Menten constant and maximal uptake) of the uptake system are the same order of magnitude regardless of the polyamine or species studied and the in vitro system used. Also, other pulmonary cells accumulate polyamines but never to the same extent as the epithelium. Although different uptake systems exist for putrescine, spermidine, and spermine in the lung, neither the nature of the carrier protein nor the reason for its existence is known. Some pulmonary toxicological and/or pathological conditions have been related to polyamine metabolism and/or polyamine content in the lung. Polyamines possess an important intrinsic toxicity. From in vitro studies with nonpulmonary cells, it has been shown that spermidine and spermine can be metabolized to hydrogen peroxide, ammonium, and acrolein, which can all cause cellular toxicity. In hyperoxia or after ozone exposure, the increased polyamine synthesis and polyamine content of the rat lung is correlated with survival of the animals. Pulmonary hypertension induced by monocrotaline or hypoxia has also been linked to the increased polyamine metabolism and polyamine content of the lung. In a small number of studies, it has been shown that polyamines can contribute to the suppression of immunologic reactions in the lung.
active uptake; paraquat; toxicology
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INTRODUCTION |
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THE NATURAL POLYAMINES (see Fig.
1 for structural formulas) consist of a
number of diamines (putrescine and cadaverine) and oligoamines
(spermidine and spermine) that occur in virtually all prokaryotic and
eukaryotic cells (155). According to Jänne et al.
(59), spermine was discovered by Van Leeuwenhoek as early as the 17th
century. The polyamines belong to a broader group of biologically
active amines together with the so-called biogenic amines such as
serotonin, histamine, and tryptamine, which are monoamines having
important physiological functions, particularly in inflammatory
reactions (10, 129). In addition to these endogenous amines,
there are also a large number of exogenous or synthetic amines
that have often been designed as drugs that interfere with the
endogenous amines. This review deals essentially with the natural
polyamines, i.e., putrescine, spermidine and spermine, and their
involvement in pulmonary cell physiology and pathophysiology.
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An important property of these specific polyamines is that they are positively charged at a physiological pH, and, consequently, they have a high affinity toward negatively charged cellular molecules. Thus polyamines are very soluble in water, and they exert strong cation-anion interactions with macromolecules, mainly with DNA and RNA (81), a feature that represents their best-known direct physiological role in cellular functions such as cell growth, division, and differentiation (52, 61).
The basic metabolic pathways involved in the synthesis and catabolism
of polyamines (Fig. 2) have
been reviewed by Pegg and McCann (108), Jänne and colleagues (59,
60), Tabor and Tabor (155), Pegg et al. (109), Seiler (135), and Seiler
and Heby (141) and are only described here in brief. De novo synthesis of polyamines originates from arginine (or ornithine) and methionine. Ornithine is formed from arginine in the presence of arginase, and de
novo synthesis of putrescine is formed by the decarboxylation of
ornithine by ornithine decarboxylase (ODC). Putrescine is metabolized to spermidine that is, in turn, metabolized to spermine by spermidine and spermine synthetase, respectively. Spermine and spermidine are
recycled to spermidine and putrescine, respectively, by cytosolic acetyltransferases [e.g., acetyl-CoA:spermidine/spermine
N1-acetyltransferase (SAT)] and polyamine
oxidase (PAO), a FAD-dependent polyamine oxidase (22, 32, 120). These
interconversion pathways (metabolism-catabolism) allow the cells to
provide putrescine, spermidine, and spermine when required without
using external sources. In (rat) lung, the concentrations of polyamines
are relatively low compared with those in other tissues and have been
reported to be 26-53, 450-880, and 292-460 nmol/g lung
for putrescine, spermidine, and spermine, respectively (34, 142, 166).
In addition, relatively low activities of the enzyme involved in the
polyamine interconversion pathways have also been found in the lung
(135).
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Other (catabolic) pathways may take place whereby polyamines are converted into physiologically neutral, e.g., less polycationic, products, and these derivatives are not reconverted into polyamines. An important portion of these terminal polyamine catabolic reactions are the result of oxidative deaminations by diamine oxidase (DAO) or DAO-like copper-containing amine oxidases (21, 97). The function and classification of the different amine oxidases has been discussed in detail by Morgan (91) and Seiler (134, 136). Another important strategy used by the cell to control polyamine levels is the transport (uptake and efflux) of polyamines or their derivatives as recently reviewed (71, 138, 139).
Because of the importance of cellular growth and differentiation in
carcinogenesis and tumor growth, polyamine metabolism has been
intensively studied in this specific field [reviewed by Pegg
(107) and Jänne et al. (61)]. These studies cover different
perspectives such as the enhanced metabolism of polyamines in tumoral
tissues, the active uptake of polyamines in neoplastic tissue, and the
use of several polyamine antimetabolites such as
-difluoromethylornithine (DFMO) and methylglyoxal
bis-(guanylhydrazone) (MGBG) for the treatment of malignancies.
However, in addition to their possible involvement in oncology and chemotherapy, polyamines have also received particular attention in lung research, initially in pulmonary toxicology to clarify the mechanism of selective pneumotoxicity of the herbicide paraquat and later in general pulmonary cell physiology, because polyamines appeared to play a distinctive, although not entirely elucidated, role in the pulmonary responses to injury, e.g., monocrotaline (MCT)- or hypoxia-induced vascular remodeling and pulmonary hypertension (4, 99).
Moreover, polyamines have been studied in many other fields. Recently, more attention has been given to the interaction between polyamines and G proteins (93) and to their possible involvement in allergic reactions (20), especially in the maturation of infant tissue (124). It has been argued that polyamines are essential in milk for proper development of the infant and to protect against unnecessary immune reactions (112).
In this review, we have focused on the polyamines in the respiratory tract. In the first part, polyamine uptake in the pulmonary epithelium is discussed in some detail, and we also focus on the uptake of polyamines in other lung cells. In the second part, we discuss the pulmonary pathological and/or toxicological conditions that have been linked to polyamine metabolism.
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POLYAMINE UPTAKE IN THE LUNG |
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Polyamine Uptake in Pulmonary Epithelium
Background: active uptake of paraquat in the lung. Since its introduction in agriculture in 1962 (14), the contact herbicide paraquat has caused thousands of deaths from both accidental and voluntary ingestion (101). Depending on the ingested dose, different clinical patterns and outcomes have been observed in animals and humans (77). A large dose of paraquat (>30 mg/kg in humans) rapidly leads to death from multiorgan failure, with lung damage consisting of disruption of alveolar epithelial cells, leading to hemorrhage, edema, and infiltration of inflammatory cells into the interstitial and alveolar spaces (169). Smaller doses of paraquat (from 16 mg/kg) may also induce death, but this then occurs after several days (up to 102 days) (153) as a result of a proliferative lung fibrosis, thus showing that the main target organ for toxicity of paraquat is the lung.The cellular toxicity of paraquat has been reviewed by Smith and Nemery (147, 148), Smith (146), and Lewis and Nemery (77). In brief, the cellular toxicity of paraquat is due to its cyclic reduction-oxidation: paraquat is reduced enzymatically, mainly by NADPH-cytochrome P-450 reductase but also by xanthine oxidase (128), to form a paraquat monocation free radical that is rapidly reoxidized in the presence of oxygen, thus resulting in the generation of the superoxide radical. This then sets in the well-known cascade leading to generation of the hydroxyl radical. During this process, the cellular NADPH pool is consumed (68), thus diminishing cellular reductive capacity. These events eventually lead to membrane damage through lipid peroxidation (126, 147). These biochemical events take place in any cell that paraquat has entered, but they do not account for the selective pulmonary toxicity of paraquat. For instance, the closely related agent diquat undergoes a similar redox cycling process, but it does not exhibit such a selective pulmonary toxicity. In a search for an explanation for this phenomenon, toxicokinetic studies first established that the main pool of paraquat is found in the lung (125, 145, 165), and later it was shown that the selective accumulation and retention of paraquat in that organ could provide a rational explanation for its lung-specific toxicity (146).
In 1974, Rose et al. (125) demonstrated that the accumulation of
radioactively labeled paraquat in rat lung slices was energy dependent
and obeyed saturation kinetics, exhibiting an apparent Michaelis-Menten
constant (Km) of 70 µM and a maximal uptake
(Vmax) of 300 nmol paraquat · g
wet
weight1 · h
1.
In addition, lung slices were the only tissue slices in which paraquat
accumulated at a concentration significantly greater than that in the
medium. All this suggested that paraquat was accumulated by an active
uptake process in the lung.
This and the observation (78) that in vivo the rate of accumulation of paraquat in the lung was only one-seventh of that found in vitro led to a search for compounds present in plasma and capable of blocking the uptake of paraquat in the lung. Several endogenous amines showed inhibitory properties, the most potent being the polyamines spermine and putrescine (150). Subsequent experiments showed that the polyamines, including spermidine, were themselves accumulated in rat lung slices in a saturable manner, obeying Michaelis-Menten kinetics. The affinity of the uptake system for the polyamines appeared to be sevenfold higher (i.e., exhibiting a lower Km) than that of paraquat. These findings led to the conclusion that paraquat accumulated in the lung through a system for which the polyamines are the natural substrates and that, in comparison to other organs, the lungs, or some cells in the lungs, must be endowed with a particularly active uptake system for polyamines (65, 151).
Since then, the subject of the accumulation of polyamines in the pulmonary epithelium has led a life of its own outside the context of the toxicity of paraquat (even though several researchers were toxicologists). In the 1980s, two main questions were addressed: the cellular localization within the lung of the accumulated polyamines (and paraquat) and the physicochemical properties of substrates capable of using this uptake system.
Cellular localization of the polyamine uptake system in the lung. The problem of the cellular site of the accumulation of polyamines in the lung was addressed first by identifying the cellular targets for the toxicity of paraquat and later by identifying the site of accumulation of radiolabeled paraquat and/or polyamines.
Smith and Wyatt (150) performed morphological and functional studies to localize the site of cytotoxicity of paraquat in lung slices taken from paraquat (20 mg/kg)-treated rats. Slices taken from rats 2 h after treatment did not show any morphological evidence of damage, and the accumulation of paraquat (10 µM) or putrescine (10 µM) was not altered. In contrast, slices taken after 24 h did show evidence of damage to type I and type II cells and their ability to take up putrescine or paraquat was impaired, thus suggesting that type I or type II pneumocytes are the site of uptake of putrescine and paraquat.
Another experimental approach to determine the site of polyamine uptake
has involved the use of autoradiography. Thus Waddell and Marlowe (165)
showed that after in vivo administration of [14C]paraquat (10 µM) in mice, distribution
of the label corresponded to that in alveolar type II cells. Studies
with rat lung slices by Nemery et al. (96) clearly demonstrated the
presence of radiolabeled putrescine in alveolar type II cells and also
in bronchiolar Clara cells (Fig.
3). Wyatt et al. (171), who
carried out both in vivo and in vitro studies, also showed
uptake of paraquat, putrescine, spermidine, and spermine in alveolar
type II cells and, at least in vitro, also in Clara cells.
Recently, Hoet and colleagues have also visualized
radiolabeled putrescine in type II pneumocytes in hamster (58) and
human (55) lung slices. On the basis of light microscopy, it was
impossible to establish definitely that uptake also took place in
alveolar type I cells, but autoradiography at the electron-microscopic
level clearly demonstrated labeling in the alveolar type I cell in rat
(29) and human (55) lung slices (Fig.
4). A comparable study of
putrescine uptake in rabbit lung slices by Saunders et al. (133) also
showed putrescine labeling over bronchiolar and alveolar epithelia, but
in another study, Saunders et al. (132) found that
although spermidine was located mainly in type II pneumocytes, moderate
labeling was also found over alveolar macrophages, a finding that no
other study had made. The authors concluded that, taking into
consideration kinetic data collected with isolated cells (130, 131),
the accumulation of polyamines in the rabbit lung was located in both
alveolar type II cells and alveolar macrophages.
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Further studies investigated polyamine uptake in isolated lung cells
and demonstrated an active accumulation of putrescine in primary
cultures of alveolar type II cells isolated from the rat (62, 64, 101,
122), hamster (58), rabbit (130), and human (57) (see Table
1). For unknown reasons, it
has been much more difficult, if not impossible, to study the uptake of paraquat itself in cell cultures (101).
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Structural requirements for the pulmonary polyamine uptake system. An important aim of the early studies into pulmonary polyamine uptake was to discover the structural requirements for substrates of the transport system to find possible antagonists capable of preventing paraquat from entering its target cells. Thus Ross and Krieger (127) established that to act as a substrate for the pulmonary polyamine uptake system, a molecule must possess 1) two or more positively charged nitrogen atoms, 2) maximum positivity of charge surrounding these nitrogens, 3) a nonpolar group between these charges, and 4) a minimum of steric hindrance. Gordonsmith et al. (42) have demonstrated that the optimum distance between the nitrogen centers is four methylene groups (6.6 Å), although a spacing between four and seven methylene groups is tolerated. These data explain how polyamines and paraquat (with 7.0 Å between two positively charged nitrogens) can share a common uptake system, but also why paraquat (with its steric hindrance of the nitrogens by the pyridine rings) is a less successful substrate.
Later, O'Sullivan et al. (104) showed that many putrescine analogs competitively inhibit putrescine and paraquat uptake. The authors established that the inhibition of putrescine uptake by analogs decreases with increasing N-alkylation and that analogs with a bulky substituent of the butyl chain do not inhibit the uptake at all. The strongest inhibition was found with N-(4-aminobutyl)aziridine; this cytotoxic compound seems not to alter the polyamine Vmax but might fit into the substrate binding site of the receptor. This aziridine has also been found to inhibit amine oxidase (25).
Although a large amount of kinetic and other data is available on the pulmonary polyamine uptake system in mammalian lung epithelium, the uptake system itself has not been characterized. However, polyamine transport systems have been isolated from Escherichia coli (39, 66). One periplasmic transport system, transporting both putrescine and spermidine, is composed of four proteins: a membrane-associated protein, two transmembrane proteins each having six transmembrane segments, and a substrate-binding protein. Another putrescine transport protein containing 12 transmembrane segments is in the genomic information linked to ODC and is suppressed under standard conditions. However, this type of information is not yet available for mammalian polyamine transport.
Polyamine Uptake in Other Pulmonary Cells
Although polyamine uptake was initially predominantly found in the epithelial cells of the lung, more and more cell types appear to accumulate polyamines too.Several nonepithelial pulmonary cells have been found to transport polyamines in vitro. Thus Sokol et al. (152) showed uptake of putrescine in human pulmonary arterial endothelial cells isolated from the main pulmonary artery. The transport occurred via two transport systems, one with a high affinity and one with a low affinity, and was inhibited by various amines. Moreover, all the well-known putrescine uptake inhibitors reduced the accumulation of putrescine. In the absence of fetal calf serum, the uptake of polyamines by endothelial cells was reduced by 38%.
Haven et al. (51) showed a saturable spermidine uptake in cultured smooth muscle cells from bovine pulmonary arteries. The Vmax for the uptake of spermidine was increased fourfold in the presence of DFMO (1 mM) in the culture medium. In subsequent studies (7, 8), the uptake of polyamines (putrescine, spermidine, and spermine) was found to be ATP dependent. The polyamine accumulation was studied under "standard" (PO2 > 100 mmHg), "normoxic" (PO2 50-70 mmHg), and "hypoxic" (PO2 18-30 mmHg) conditions. In hypoxia, polyamine uptake was enhanced, with Vmax being increased two- to threefold for putrescine, spermidine, and spermine. However, it must be noted that the concentrations of polyamines used to calculate kinetic properties in these studies were not optimal because the calculated Km values found for spermidine and spermine proved to be considerably lower than the lowest substrate concentration studied (0.1 µM). Moreover, because these uptake studies were performed with low-density cultures (seeding density 75,000 cells/well in six-well cluster plate), it is likely that the smooth muscle cell cultures were proliferating, which is a stimulating factor for polyamine uptake (82, 111).
It should be noted that although the above data clearly show energy-dependent polyamine accumulation in both pulmonary endothelial cells and smooth muscle cells, autoradiographic studies (29, 55, 58, 96, 133, 171) have consistently failed to show any significant accumulation of label in cells other than those of the pulmonary epithelium in rat, hamster, or human lung slices when incubated with a radiolabeled natural polyamine. As indicated above, Saunders et al. (131) showed that freshly isolated rabbit macrophages took up putrescine at a higher rate than freshly isolated rabbit pulmonary type II cells. These rather surprising data have been confirmed in our laboratory, and we have also found that freshly isolated rabbit alveolar macrophages take up putrescine more intensively than lung epithelial cells. However, the alveolar macrophages of rat, hamster, or human do not accumulate putrescine in such a pronounced way (unpublished data).
It may also be mentioned here that no accumulation of putrescine could be demonstrated in slices of human pulmonary squamous carcinomas or adenocarcinomas in contrast to the surrounding pulmonary tissue (56). These observations were somewhat unexpected, especially for the adenocarcinomas, if one considers that at least some of these tumors probably originate from type II pneumocytes that (originally) possessed an active polyamine uptake system (80, 156).
Summary of polyamine uptake in the lung. Table 1 summarizes the kinetic parameters for the uptake of several compounds by the polyamine uptake system in the lung, including the polyamines putrescine, spermidine, spermine, and cadaverine as well as of the endogenously occurring disulfide cystamine and two xenobiotic compounds, paraquat and MGBG.
Rao and Mehendale (118, 119) claimed that polyamines are only accumulated passively into rat and rabbit lungs. These studies were carried out with relatively high substrate concentrations (1 µM up to 20 mM), and it was shown that polyamine accumulation was linear at concentrations of 0.1-5 mM. It was concluded that polyamine accumulation in the lung predominantly occurred via diffusion. At these concentrations, the uptake system for putrescine is saturated, and this logically results in an uptake profile that becomes linear with medium concentration. Therefore, these data have not been included in Table 1.
The kinetic parameters reported in different papers show some variation. This is particularly true for the human lung where more interindividual differences are to be expected, although no significant effects were apparent with regard to gender, age, or underlying disease (15, 55). Differences between laboratories may be due not only to technical factors but also to the method of calculation of kinetic parameters, particularly if passive diffusion is not taken into account or if linearization techniques, such as the Lineweaver-Burk plot, are used.
In the perfused lung, the accumulation of polyamines, and in particular paraquat, was different compared with other systems. Paraquat accumulation was shown to occur predominantly by diffusion during the first hour where, after uptake increased (2- to 3-fold) and accumulation became saturable, it was considered to occur via a carrier-mediated uptake (117). The polyamine accumulation in lung slices and type II cell cultures are all on the same order of magnitude. In cultured endothelial cells and pulmonary arterial smooth muscle cells, the maximum accumulation (Vmax) is smaller, whereas the affinity for polyamines (Km) is within the same order of magnitude.
In general, the kinetic parameters comparing the same in vitro system found in the different species studied are within the same orders of magnitude except perhaps for the Km values for the hamster, which appeared to be relatively high.
The most widely studied compound is putrescine. The uptake system of putrescine has proven to be competitively inhibited, or at least inhibited in a partially competitive manner, by all other compounds studied. The other natural polyamines, spermidine and spermine, seem to accumulate more easily in the pulmonary epithelium, and these polyamines can block putrescine uptake in a dose-dependent manner, whereas putrescine can block only a portion of the uptake of spermidine and spermine (64, 116). This indicates that spermidine and spermine probably use a more compound-specific uptake system besides the putrescine uptake system.
For the disulfide cystamine, which is also accumulated through the polyamine uptake system, two uptake systems, one with a low and one with a high affinity, have been described, with only the high-affinity system being strongly inhibited by polyamines (76).
The active uptake of the two xenobiotic compounds, paraquat and MGBG, is somewhat different from that of the endogenous compounds: the uptake of paraquat shows poor affinity (i.e., high Km), whereas MGBG is a relatively poor substrate because the Vmax is small.
Characteristics of Pulmonary Polyamine Uptake
Smith and Wyatt (150) and Lewis et al. (76) showed that the uptake of putrescine and cystamine in rat lung slices was not dependent on the Na+ concentration in the medium. In contrast to these observations, Rannels et al. (116) found that in type II pneumocytes the uptake of putrescine and spermidine was dependent on Na+, whereas spermine uptake was not dependent on extracellular Na+, indicating that polyamine uptake may take place via different uptake systems. In bovine arterial smooth muscle cells, Aziz et al. (7) and Jänne et al. (61) demonstrated some Na+-dependent polyamine uptake. However, in these experiments, the nature and concentration of the ions used to replace Na+ were probably critical factors because it has been shown that a supplement of NaCl, LiCl, or choline significantly reduced the uptake of polyamines due to increasing osmotic pressure (116). On the other hand, Kumagai and Johnson (72) showed that replacement of Na+ with mannitol or sucrose did not modulate putrescine uptake in rat enterocytes, whereas replacement by choline, lithium, N-methyl-D-glucamine, or tetramethylammonium did. It was hypothesized that cations can interact with the carrier but that no cotransport of Na+ is involved in putrescine uptake.Another issue is whether there is one or more pulmonary polyamine
uptake system. In bovine arterial smooth muscle cells, Aziz et al. (7)
and Jänne et al. (61) found that putrescine was accumulated
through an uptake system that is also used by spermidine, spermine,
paraquat, and MGBG, but spermidine and spermine were also accumulated
through a different uptake system insensitive to putrescine and
paraquat and only partially sensitive to the presence of MGBG.
Similarly, two studies using isolated type II pneumocytes (23, 102)
have shown that putrescine uptake was inhibited by paraquat in a
partially competitive way and not in a simple competitive manner,
although such partially competitive inhibition was not found in other
studies using hamster (58) or human (57) type II pneumocytes. More
recently, van Klaveren et al. (161) showed that the
Vmax of putrescine in rat type II pneumocytes was
reduced by ~25-30% in the presence of serine borate (5-20
mM) and acivicin (5 mM), two known inhibitors of
-glutamyltransferase, and that putrescine (but not paraquat) was a
substrate for
-glutamyltransferase. Furthermore, a good correlation
was observed between the level of activity of
-glutamyltransferase
in type II pneumocytes and part of the uptake of putrescine (162).
Therefore,
-glutamyltransferase, which is located in the outer
membrane of type II pneumocytes (28), is probably partially responsible
for the uptake of putrescine but not for the uptake of paraquat, at
least in rat lung.
Conclusion
Although a considerable amount of information has been obtained regarding the kinetics and localization of polyamine uptake in the lung, there are still important gaps in our understanding of this system. One of these questions is the role of antizyme in the lung. In most cell types studied, antizyme induces a rapid degradation of ODC (85, 95, 154), and in mammalian cell lines, it also controls a feedback inhibition of polyamine transport (86, 154), thus controlling polyamine levels in the cell. No data are available with regard to the role of antizyme on the biosynthesis or uptake of natural polyamines in the lung or, more specifically, in isolated epithelial or endothelial pulmonary cells. Other unanswered questions are whether the pulmonary polyamine transport is dependent on cell cycle, whether the transport is located at the apical or basal side of the cellular layers, how the transport is regulated, and whether it can be induced or reduced in certain physiological circumstances.Possible Practical Consequences of the Pulmonary Epithelium Polyamine Uptake System
Initially, this uptake system was studied as a possible protection against paraquat toxicity in the lung. Although paraquat proved to be a rather "poor" substrate for the polyamine uptake system, it is undoubtedly accumulated into the lung through this system. It has also been shown that strains of E. coli, which accumulate more polyamines because they are deficient in spermidine synthesis, are much more susceptible for paraquat toxicity, thus indicating that an increased uptake of paraquat increases its toxicity (84). However, although competitive or partially competitive inhibition of paraquat uptake by polyamines has been demonstrated in vitro (30, 31, 104), until now it has not been possible to significantly block the in vivo accumulation of paraquat in the lung or to mitigate its toxicity by administering such uptake inhibitors. The reasons for this failure to provide a mechanistically sound therapy for paraquat intoxications have not been entirely elucidated. One consideration is that the intracellular amounts of paraquat that are required to cause cellular toxicity are probably so low that even in the presence of competitors for the entry of paraquat into the cells, significant oxidant-mediated damage can be achieved by its continuous cycling and the nonstoichiometric production of reactive oxygen species, particularly in view of the high partial pressure of oxygen in the lung compared with that in other tissues. Therefore, the use of hypoxic conditions in the treatment of paraquat poisoning (27, 121) is of vital importance, although hypoxia can enhance polyamine uptake (7). The increased survival in hypoxia after paraquat intoxication is the result of the reduced generation of toxic oxygen species in hypoxia (54).It has been investigated whether the propensity of lung epithelial cells to accumulate polyamines could be utilized to selectively supply these cells with some compounds to treat or to protect the pulmonary epithelium. Thus Wyatt et al. (170) have shown that some radioprotective agents such as WR-2721 and its analogs could competitively inhibit the uptake of putrescine in rat lung slices, meaning that they probably are themselves accumulated into the pulmonary epithelium. The protective mechanism of these compounds is not well known, but recently it has been shown that in the presence of WR-1065 polyamine levels were increased in rat liver hepatoma cells. The increased polyamine level resulted from a WR-1065-induced delay in antizyme synthesis (87). The disulfide cystamine, which can be metabolized to taurine, was also known to be actively accumulated into cultured rat type II pneumocytes (76). Thus because pulmonary tumors do not significantly accumulate putrescine (56), one could envisage making use of the property of the pulmonary epithelium to accumulate radioprotective agents or antioxidant agents (such as cystamine) (41) to try and protect it against radiation or chemotherapy.
On the other hand, as reviewed by Pegg et al. (109) and Jänne et al. (59), blocking the uptake and metabolism of the natural polyamines in neoplastic tissues could represent an alternative or additional approach to chemotherapy. In the specific instance of pulmonary squamous carcinomas or adenocarcinomas (56) where no polyamine uptake has been found, it would not appear to be a promising route, although it is likely that these tumors will induce polyamine uptake in response to deprivation of polyamines (172).
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POLYAMINES IN PULMONARY PATHOLOGY AND TOXICOLOGY |
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As indicated in POLYAMINE UPTAKE IN THE LUNG, the uptake kinetics of polyamines in normal lungs have been well documented, although the exact nature of this uptake and its physiological significance are still obscure. Nevertheless, the effects of various toxicological interventions on pulmonary polyamine metabolism and uptake have been investigated. A first field of study concerns the toxicity of paraquat and the polyamines themselves. A second object of study concerns the toxicity of other agents such as MCT and pure oxygen.
Pulmonary Toxicity of Polyamines
Although polyamines are endogenous molecules found in relatively high concentrations in all living beings, these agents have been found to exhibit a surprising degree of toxicity when present in excess (113, 140).In the rat, Foster et al. (38) had hoped to protect the lungs against oxidative stress and, in particular, that caused by paraquat by the inhalation of spermidine. However, a 6-h inhalant exposure to spermidine proved to be toxic itself because necrosis of Clara cells (from 6 mg spermidine/m3) and type II pneumocytes (from 17 mg spermidine/m3) was observed. Clara cells were replaced without evidence of abnormal cell proliferation; type II pneumocytes were less sensitive to spermidine, but the injury was irreversible and the initially observed alveolitis developed to a subchronic pneumonitis by day 14. The increase of polyamine content in the lungs due to the administration of spermidine had almost been cleared by the first day, but 5 days postadministration, a considerable increase in spermidine and spermine together with an increase in DNA metabolism was observed.
These findings were difficult to interpret, but a few more recent observations might clarify the picture.
1) Indeed, it has been shown that the oxidation of spermine and
spermidine in the presence of bovine serum amine oxidase (a copper-dependent DAO present in mature bovine serum but not or very
little in fetal bovine serum) can be an important source of hydrogen
peroxide, aldehydes, and ammonia in vitro (Fig.
5). This might explain why
cultured cells exposed to high concentrations of spermidine and/or
spermine (in the presence of serum) show a reduced growth (3, 5, 67).
This phenomenon is often accompanied by a reduction in the GSH content
of the treated cells (1, 18), presumably through the binding of GSH to
acrolein. The growth inhibition could be reduced by blocking the
oxidative deamination (by DAO) of polyamines (2, 40, 53), although this
was not true for BHK cells in serum-free medium exposed to polyamines
(19). The addition of catalase, preventing the formation of hydrogen
peroxide, and aldehyde dehydrogenase, which is normally sufficiently
active in most tissues, diminished the growth inhibition significantly
(6). This may be related to the fact that, at least in developing
embryos, hydrogen peroxide and aldehydes (rather than acrolein) are
important triggers in the onset of apoptosis (105, 106).
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2) Both polyamines (spermidine and spermine) when present in excess may exert their toxicity simply by binding to the genomic information, condensing chromatin (46), thus hindering transcription and translation (113, 144), which, in turn, can also lead to apoptosis. However, this information contradicts the findings of Grassilli et al. (44), who observed apoptosis after ODC activation and a "paradoxical" polyamine decrease. These contradictory observations can be explained by the finding that extreme polyamine levels, both too low and too high, can be detrimental to cells (16, 44, 46, 105, 113, 144).
3) Another potentially important factor in the toxicity of polyamines in the pulmonary epithelium may be related to their containing positive charges (123). Indeed, polycations such as poly-L-lysine and poly-L-arginine have been shown to exert a strong toxic effect on epithelial cell layers (163). Synthetic polyamines also exert a strong toxicity after inhalation or intratracheal instillation (24, 94). This toxicity is accompanied by a disruption of the barrier function of the epithelium, resulting in pulmonary edema and the invasion of inflammatory cells (24, 110, 158).
In an attempt to explain the observations described by Foster et al. (38), it is plausible that two processes took place: on one hand, the induction of some terminal catabolic reactions (DAO) to degrade the excess of spermidine, resulting in an acute toxic effect, and on the other hand, the effect of the overload with polycations of the pulmonary epithelium, resulting in an inflammatory response.
Paraquat Toxicity
The history of pulmonary uptake of polyamines is closely associated with the toxicity of paraquat and has been discussed in some detail in POLYAMINE UPTAKE IN THE LUNG.MCT-Induced Pulmonary Hypertension
The pyrrolizidine alkaloid MCT is a natural compound that has been used as a model to study pulmonary hypertension. A single subcutaneous injection of MCT in rats causes altered endothelial functions in the lung; after an initial pulmonary vascular injury, a progressive increase in pulmonary arterial pressure can be detected. In response to this increased arterial pressure, the right ventricle of the heart progressively undergoes hypertrophy. The enlargement of the right ventricle is often used as an indirect quantitative measure of the degree of pulmonary hypertension (167).Olson et al. (98) found a significant increase in polyamines in rat lungs 10, 20, and 35 days after a single subcutaneous injection of MCT (30 mg/kg). Both the pulmonary hypertension and the increase in polyamine content of the lung were decreased by adding DFMO (2%) to the drinking water from day 10 on (98), whereas a supplement of ornithine (2% on day 10) partially abrogated this effect (47). Therefore, it has been hypothesized that the stimulation of polyamine synthesis is a key step in the development of pulmonary hypertension (48, 98, 99, 103). Subsequent work (102) indicated that the increase in putrescine and N-acetylspermidine in the lung was already apparent at doses of MCT that did not induce pulmonary hypertension, indicating, according to the authors, that the augmentation of spermidine and spermine were causative factors for the expression of pulmonary hypertension.
Another study (48) has shown that a reduction in the daily food intake
to 8 g (from a normal value of 18 g · day1 · rat
1)
protects against MCT-induced pulmonary hypertension and is also associated with an inhibition of increased lung polyamine and DNA
synthesis, which normally occurs in the lung during the development of
MCT-induced pulmonary hypertension.
These studies clearly showed that blockade of polyamine synthesis reduces the effects of MCT.
It has been indicated by Lai et al. (74) that after 1 wk, before the vascular changes, MCT treatment (60 mg/kg subcutaneously) resulted in an increase in pulmonary resistance, a decrease in pulmonary compliance, and an elevation in inflammatory cells. However, these physiological changes are accompanied by elevated levels (weeks 1-3) of the tachykinin substance P and a decrease in neutral endopeptidase (75, 173). Moreover, pretreatment of rats with capsaicin, depleting the tachykinins, attenuates or prevents the effects of MCT (173), strongly indicating the important role of tachykinins, but it also challenges the primary role of polyamines in MCT-induced pulmonary hypertension.
Yet, Wilson and Segall (168) have shown that besides causing endothelial toxicity, MCT also causes epithelial changes in the lung, consisting of hypertrophy and a decrease in the population density of type II pneumocytes. Moreover, type II pneumocytes cultured in the presence of 3.2 mM MCT showed vacuolization, which was accompanied by a reduction in the active uptake and cellular concentration of spermidine. The activities of two key enzymes important in the synthesis of polyamines, ODC and S-adenosylmethionine decarboxylase, were reduced (posttranscriptionally), whereas the activity of SAT, which is involved in the recycling (interconversion) of spermine and spermidine, was augmented (12). The physiological consequences of these observations are unknown. In cultured porcine pulmonary arterial endothelial cells, Aziz et al. (9) demonstrated that, as in the whole lung, polyamine concentrations and ODC activity were increased in MCT-treated endothelial cells. A fascinating new finding in this setup is that dimethylthiourea, an oxygen radical scavenger, can reduce MCT-induced polyamine disturbance.
Oxygen Tension and Oxidative Stress
Exposure to either hyperoxia or hypoxia as well as to ozone, which is a particularly toxic form of oxygen, results in various alterations in lung biochemistry and function. Here we focus only on those observations in which polyamines have been investigated.Hyperoxia. It is well known that exposure to hyperoxia leads to increased activity of protective antioxidant enzyme systems (17). However, in addition to this response, it has been observed that the lungs of rats kept in an atmosphere of 85% oxygen also show changes in polyamine metabolism (49). Thus ODC activity in the whole lung was found to double after 1 day and to have risen 25-fold after the third day, whereas the putrescine content had doubled by that time. Spermidine and spermine contents were increased together with the S-adenosylmethionine decarboxylase activity from the third day on. These increases were a good reflection of the cellular repair (DNA synthesis) that was apparent from the third day on (49). Food restriction during hyperoxia had a negative effect on the survival of rats. Because ODC activity as well as polyamine content was strongly reduced by food restriction, the authors (35) suggested that impaired DNA synthesis and repair were the basis for this enhanced toxicity.
When both mice and rats were exposed to hyperoxia, some striking differences have been observed. Rats can adapt to hyperoxia, whereas mice cannot. Looking at polyamine metabolism, both species developed increased ODC activity and putrescine content, but in mice, in contrast to rats, no increased S-adenosylmethionine decarboxylase activity or increases in spermidine and spermine content were observed on exposure to 85% oxygen. Furthermore, the rat lung responded to hyperoxia with increased DNA synthesis, whereas the mouse lung did not. The results suggested that in addition to increased activity of protective enzymes, increased repair processes in the rat lung may play a role in its capacity to adapt to hyperoxia. The incomplete response of polyamine metabolism in mice may contribute to their inability to adapt in hyperoxia (157).
Ozone. Ozone inhalation has also been found to strongly stimulate ODC activity in the lung in parallel with the labeling of DNA, reflecting repair and de novo synthesis (34). The polyamine content was also strongly increased by 85 and 23% for putrescine and spermine, respectively. Rats exposed to ozone (0.5 parts/million for 5 days) on a vitamin E-deficient diet showed similar responses, but a supplement of vitamin E (1,000 IU) diminished these responses (33). The authors speculated that the change in polyamine content reflects antioxidant and anti-inflammatory functions of the polyamines.
Hypoxia. Taking into consideration the macroscopic effects in the lungs of animals exposed to hypoxia, the observations are to some extent comparable to those seen after treatment with MCT because they include a thickening of the pulmonary arterial walls and hypertrophy of the right ventricle. Paralleling these changes, an increase in polyamine content in the lung has been measured in rats (4). Administration of DFMO decreased the effect of chronic hypoxia, but it did not influence the vasoconstriction caused by acute hypoxia. From these observations, it has been suggested that DFMO, by decreasing polyamine production, inhibits the vascular remodeling (4) and, consequently, reduces the development of pulmonary hypertension.
In contrast to MCT-induced pulmonary hypertension, a decrease in ODC activity in the whole rat lung has been found (143); this reduction in de novo polyamine synthesis was compensated for by increased uptake and interconversion by SAT. In cultures of bovine pulmonary arterial smooth muscle cells, these findings were confirmed: polyamine accumulation was increased (8, 51) and the activity and mRNA expression of ODC were decreased after 6 h in the presence of 1% oxygen (50).
Polyamines and Pulmonary Inflammation
The lung is an important target for inhaled sensitizing compounds. As reviewed by Seiler and Atanassov (137) in 1994, it has been suggested that polyamines play a regulatory role in several immunologic processes.The lysis of lysosomes, inducing inflammation, by active oxygen species of guinea pig polymorphonuclear leukocytes (63) and the inflammatory effects of ozone (34) were successfully prevented by polyamines. These observations indicate that polyamines may be important in the reduction of inflammatory responses (13) and thus indirectly reduce bronchial hyperreactivity.
Mast cells can be activated by either an antigenic pathway, involving antigen binding and IgE binding to a specific high-affinity receptor, or a peptidergic pathway, sensitive to peptides and polyamines (better defined as basic secretagogue molecules), which is not related to antigens. Mast cells from different species and tissues exhibit different sensitivities to these basic secretagogue molecules [reviewed by Mousli et al. (93)]. In vitro, natural polyamines and metabolites can stimulate the phosphorylation of phosphatidylinositol in mast cells, but they seem not to stimulate phospholipase C. Maximum effects were observed at 1 mM concentrations of polyamines, but this is relatively high compared with concentrations of polyamines found in human body fluids, which are in the low micromolar range (2.3-3.8 µM) (73). Vliagoftis et al. (164) found that spermine and spermidine can inhibit the release of 5-hydroxytryptamine and histamine from rat peritoneal mast cells that were stimulated immunologically or by compound 48/80. This inhibition was only apparent in the presence of mature bovine serum, which contains relatively high copper-containing amine oxidase activity, and not in the presence of fetal bovine, human, or rat serum, which do not contain this DAO (120, 164). Aminoguanidine, an inhibitor of DAO, blocked the polyamine effect, indicating that the inhibition of mast cell secretion probably derives from aldehydes produced from spermidine or N1-acetylspermidine. The locomotion of human neutrophils has been inhibited by polyamines in the presence of DAO (36). Moreover, acrolein has also been shown to inhibit the locomotion of neutrophils (36), whereas ammonia, another breakdown product of this DAO, reduced the viability of the neutrophils. Therefore, these copper-containing amine oxidases have been suggested as regulators of the inflammatory response.
As indicated in Pulmonary Toxicity of Polyamines, polyamines also play a crucial role in the control of apoptosis (45), an important feature of several (auto)immune events (16, 159).
General Conclusion
Our knowledge concerning the normal polyamine concentrations in the lung or the activity of the polyamine interconversion pathways is still insubstantial. Compared with this poverty, pulmonary polyamine uptake has been studied in some detail. It is clear that we cannot delineate a unique pulmonary polyamine uptake system. Apparently, different pulmonary cell types accumulate in vitro polyamines using one or more uptake systems. The kinetics of several of these cell-specific pulmonary polyamine uptake systems have been well characterized, and it is evident that polyamine uptake characteristics differ significantly from cell type to cell type. Unfortunately, their physiological functions have been much less examined, let alone understood.Polyamine uptake in the lung has been best studied in the pulmonary epithelium. Important gaps in our knowledge here are regulation of the uptake (and why there is such a pronounced constitutive polyamine uptake in the epithelium), the efflux of polyamines, and even de novo synthesis of polyamines in the lung (26). Also, the role of antizyme is unclear because it generally downregulates both de novo synthesis (through ODC deactivation) and polyamine uptake. In the vascular endothelium and arterial smooth muscle cells, polyamine uptake and de novo synthesis have been the subject of several investigations in pathological (hypoxia) or toxicological (MCT) conditions, both resulting, in vivo, in pulmonary hypertension. In the presence of MCT, polyamine levels are increased due to stimulated uptake and synthesis (studied in the whole lung and in endothelial cells), whereas in hypoxia, polyamine concentrations are elevated solely due to supplementary accumulation (studied in the whole lung and smooth muscle cells). It has been suggested that MCT toxicity is accompanied by oxidant injury (9), indicating that the mechanism of toxicity of MCT differs fundamentally from that of hypoxia, thus partially explaining the differences in polyamine homeostasis. Despite all efforts, the role of the polyamines in MCT- or hypoxia-induced pulmonary hypertension remains unclear. It is known that polyamines are essential for endothelial cell growth (92) and that polyamine concentrations are elevated in damaged lungs preparing for growth (114). Thus the question whether the observed increase in polyamine content during the onset of pulmonary hypertension is a fundamental cause of this disease or if it is rather the reflection of the high proliferative activity (and the vascular remodeling) after the pulmonary damage has not been solved.
From the available data, we propose here a few possible processes that might be closely linked to pulmonary polyamine uptake and responses to pulmonary insults.
1) In 1986, it was shown by Hougaard and Larsson (58a) that protein and peptide secretory cells have a high need for both biogenic amines and natural polyamines. This hypothesis was based on observations made on several secretory cells. The authors found that in the cells studied, the secretory granules were often closely associated with amines. Therefore, they suggested that polyamines play a crucial role in the exocytic processes in the cells studied, although the nature of this role was and is still unclear. Unfortunately, alveolar type II cells were not among these studied cells, although the pulmonary epithelium is also very active in secreting alveolar lining fluid and its constituents, mainly surfactant. It is unknown whether the secretion of surfactant is related to polyamine uptake or content in the pulmonary epithelium, but this aspect deserves further investigation.
2) The whole lung, specifically the pulmonary epithelium, is
uniquely exposed to a high oxygen tension and numerous inhaled environmental agents (e.g., ozone, cigarette smoke). It has been demonstrated that polyamines can protect against radicals in two different ways: first, by direct quenching of free radicals (34, 46,
63, 79) and second, by condensing the DNA, in other words, by
protecting the genomic information (34). Polyamines might thus act as
one of the many defense lines against free radical attack in the lungs,
protecting against DNA strand breaks due to reactive oxygen species
(46, 69, 70). On the other hand, it has also been shown that the
interconversion of polyamines results in the production of cytotoxic
compounds such as hydrogen peroxide and aldehydes (1, 2, 5, 89). Thus
by controlling polyamine levels simply by membrane transport (uptake
and efflux), the lungs can use the accumulated polyamines against
naturally occurring radicals, but how the lungs handle the oxidized
polyamines is unknown. In several studies (12, 98, 99,
103), it was found that as soon as de novo synthesis of
the natural polyamines had been stimulated in the lung, often when
cells were stimulated to proliferate after a toxic event, a disturbance
of the cellular and physiological functions was observed, apparently
due to the recycling pathways and the subsequent production of toxic
metabolites. However, as soon as polyamine interconversion has been
stimulated, this protection could turn into a radical attack. We do not
have any information on the levels of PAO in the normal pulmonary
epithelium or endothelium, but in the whole lung, this
activity is 2.6 µmol · g1 · h
1,
which is low compared with that in other organs (136), possibly indicating that this metabolic step is "avoided" in the lung. In
the A549 cell line (a human type II tumor cell line), PAO activity is
also very low, but it can be induced by oxidative stress (22).
3) The central role of arginine in polyamine and nitric oxide (NO) synthesis has been the subject of speculation regarding the subtle balance between cell differentiation or normal function (NO synthesis) and cell proliferation or remodeling (polyamine synthesis) (62a, 90). It has been hypothesized that arginine pools of the lung are reserved for NO synthesis, controlling smooth muscle tension in airways and blood vessels to control the flow of air and blood in the lungs rather than for the synthesis of polyamines that are easily taken up from the circulation (11, 37). From this point of view, it seems logical that an increase in polyamine concentration in cultures of bovine pulmonary arterial smooth muscle cells during hypoxia is solely due to polyamine accumulation (8, 51) and not to de novo synthesis (50).
4) The pulmonary epithelium is the first target of many inhaled allergens. Polyamines seem to be able to protect the lung against pulmonary inflammation and/or allergic reactions. A few mechanisms may play a role in this function. Polyamines can simply bind to negatively charged allergens, polyamines can interact with the inflammatory system (36, 164), and/or polyamines can reduce inflammatory responses through the scavenging of radicals (34, 63).
Despite the large efforts made to understand the major functions of polyamines in the cell, numerous questions remain to be answered. In the lung, polyamine uptake has been characterized in some detail. The questions, what does the pulmonary system gain by this energy-consuming uptake of polyamines and how is this uptake regulated, remain unsolved. These questions open interesting research lines to understand better the basic polyamine biochemistry of the cell and, more particularly, the physiological functions of polyamines in the pulmonary epithelium.
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ACKNOWLEDGEMENTS |
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The work described herein has been mainly supported by Onderzoeksfonds, Katholieke Universiteit Leuven Grant OT/89/24, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen Grant G.0267.98, and the European Union.
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FOOTNOTES |
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Address for reprint requests and other correspondence: B. Nemery, K. U. Leuven, Pneumologie, Longtoxicologie, Herestraat 49, B-3000 Leuven, Belgium (E-mail: ben.nemery{at}med.kuleuven.ac.be).
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