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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. S62-S66, (2002)
© 2002 American Thoracic Society

Article

Vitamin E as an Antioxidant of the Lung

Mechanisms of Vitamin E Delivery to Alveolar Type II Cells

Ingrid Kolleck, Pranav Sinha and Bernd Rüstow

Department of Neonatology and Institute of Pathobiochemistry and Laboratory Medicine, Charité Hospital, Humboldt University Berlin, Berlin, Germany

Correspondence and requests for reprints should be addressed to Professor B. Rüstow, Charitè Hospital, Clinic of Neonatology, Schumannstr. 20/21, 10098 Berlin, Germany. E-mail: bernd.ruestow{at}charite.de

ABSTRACT

Oxidants play an important role in the development of acute and chronic lung injuries. Alveolar surfactant is the first target of air-borne oxidants. Surfactant contains, besides dipalmitoyl phosphatidylcholine, cholesterol and polyunsaturated phospholipids that play an important functional role. Therefore, vitamin E could be important for protecting surfactant lipids against oxidation and subsequent lung injury. Alveolar type II cells play a central role in synthesis and secretion of surfactant lipids and also supplement the surfactant with vitamin E during intracellular assembly. High density lipoprotein (HDL) is the primary source of vitamin E for type II cells. The uptake of vitamin E by specific lipid transfer is mediated by at least three HDL-specific receptors (scavenger receptor BI, membrane dipeptidase, and HDL-binding protein-2). In addition, cubilin and megalin mediate in a cooperative manner HDL-holoparticle uptake by alveolar type II cells. A temporary vitamin E deficiency induces a reversible change of the expression of pro- and antiinflammatory markers and of markers defining apoptosis, and reduces surfactant lipid synthesis in alveolar type II cells. These metabolic changes of type II cells may prime the lung to develop clinically manifest injury in response to an additional insult, e.g., hyperoxia.

Key Words: lung • vitamin E • alveolar type II cells • high-density lipoprotein • scavenger receptor-BI

Reactive oxygen species are thought to play an important role in the pathogenesis of lung injuries such as bronchopulmonary dysplasia and chronic obstructive pulmonary disease in newborn infants and in adults (1, 2). The damages caused by airborne oxidants are considered to be predominately mediated by radicals. One of the first targets of airborne oxidants is the lung. The alveolar surfactant, epithelial cells, and endothelial cells of the lung contain substrates for oxidants in high concentrations. To counteract oxidative damage, each compartment of the lung develops its own complex antioxidative potential consisting of water-soluble and lipophilic compounds and antioxidative enzymes (3, 4).

Normal lung function is linked to the presence of alveolar surfactant in sufficient quantities and composition. Lipids constitute about 90% of the surfactant, which contains dipalmitoyl phosphatidylcholine as the defining molecule and other functionally important molecules such as cholesterol, plasmalogens (5, 6), and polyunsaturated lipids. These lipids are extremely sensitive to oxidation (5, 7). Therefore, lipophilic antioxidants should play a special role in the antioxidative protection system of the lung. The most important lipophilic antioxidant in the lung is vitamin E (8). The exceptional role of vitamin E in the defense system of the lung is underlined by the findings that extreme oxidative burdening of the lung (smoking, ozone, paraquat) does not lead to an expected decrease but rather to an increase of the concentration of vitamin E in the lung. This result has been interpreted as mobilization of vitamin E from other tissues to maintain adequate vitamin E levels in the lung (4, 9; for review see Reference 10). Recent investigations on relation of serum levels of vitamin E and other antioxidants with the pulmonary function in the general population show that vitamin E correlates better with lung function than vitamin C or retinol (11). Furthermore, vitamin E supplementation protects rats against hyperoxia-induced lung damage (12). Rats exposed to hyperoxia do not exhibit an increase in lipid peroxidation products in the alveolar surfactant, whereas the vitamin E content significantly decreased (13). However, hyperoxia caused an increase of lipid hydroperoxides and of oxidation products of lecithin (short chain fatty acid in sn-2 position at the glycerol moiety) in plasma. These oxidized lecithin species are structurally related to the platelet-activating factor (PAF) and are called PAF-related compounds (14). Therefore, it might be hypothesized that hyperoxia indirectly prolongs and increases the risk of inflammatory lung disease by oxidant-induced changes in plasma and cells. The accumulation of lipid peroxidation products in the alveolar surfactant could, according to this hypothesis, play a secondary role. The involvement of plasma-borne lipid peroxidation products such as PAF-related compounds in lung injury has also been suggested by Henderson and coworkers (15), who demonstrated in a murine asthma model that the lung could be protected against inflammation by elevating the plasma concentrations of PAF-acetyl hydrolase. These results corroborate the idea that oxidized lipids were rapidly transferred from surfactant to plasma or that the normal vitamin E content of the alveolar surfactant is sufficient to protect the surfactant against lipid peroxidation. In this protective process the vitamin E content decreases, and consequently in compensation its turnover increases in type II cells, lamellar bodies, and bronchoalveolar lavage, whereas the turnover of the other surfactant lipids such as plasmalogens, phospholipids, and cholesterol that have to be protected against oxidation does not change (13).

VITAMIN E IS AN INTEGRAL CONSTITUENT OF THE LUNG SURFACTANT

Alveolar type II cells play a central role in the biosynthesis of surfactant lipids and in the assembly of the alveolar surfactant. Therefore, changes of the composition and of the turnover of lipids in the alveolar surfactant must be regarded as the metabolic capacity of alveolar type II cells, and we postulate that vitamin E reaches the alveolar space as an integral constituent of the alveolar surfactant secreted by type II cells. We have tested this hypothesis using several experimental setups (7), and we can demonstrate that vitamin E is actively secreted by cultured type II cells with the same kinetic characteristics as surfactant phospholipids in response to ß-adrenergic stimuli or in response to the addition of surfactant protein A. To exclude the possibility that the secretion of surfactant lipids and vitamin E is simply caused by their lipophilic properties, we tested if cholecalciferol, another lipophilic vitamin, would exhibit the same kinetic characteristic as vitamin E. The secretion of vitamin E together with surfactant lipids increased in response to isoproterenol, whereas the secretion of cholecalciferol did not exhibit any such changes. After intraperitoneal application of 3H-labeled {alpha}-tocopherol and 14C-labeled palmitic acid in rats, the amount of both isotopes in bronchoalveolaral lavage obtained in situ (resident surfactant) decreased, and the content of both isotopes in bronchoalveolar lavage after isoproterenol stimulation increased (nascent surfactant). However, the ratio of 3H-labeled {alpha}-tocopherol to 14C-labeled phospholipids in resident and nascent surfactant did not change (Figure 1) . From these results, we deduce that vitamin E is associated with the alveolar surfactant during its assembly in type II cells and that vitamin E is an integral constituent of lung surfactant (7).



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  		Figure 1. Rats obtained 3H-labeled {alpha}-tocopherol and 14C-labeled palmitic acid by intraperitoneal application. After 3 hours rat lungs were lavaged in situ (resident surfactant). Thereafter, isoproterenol-containing buffer was filled into the lungs in situ. After 30 minutes the lungs were again lavaged (nascent surfactant). The radioactivities of the individual lavages of the resident and nascent surfactant were measured. The ratio of 3H-labeled {alpha}-tocopherol to 14C-labeled phospholipids was determined in the pooled lavages of resident and nascent surfactant, respectively (7).

 
HIGH-DENSITY LIPOPROTEIN IS THE MAJOR SOURCE OF VITAMIN E FOR TYPE II CELLS

Lipoproteins are transport vehicles for plasma vitamin E. A specific transfer protein has not been found. Therefore, alveolar type II cells can accumulate vitamin E only by specific receptor-mediated interaction with lipoproteins. A receptor-mediated interaction with low-density lipoprotein (LDL) has been proposed to be the most important supply mechanism of vitamin E to cells (16). However, we have demonstrated that type II cells can specifically interact with high-density lipoprotein (HDL), LDL, and very low-density lopoprotein (VLDL) (17). The expressions of the classic LDL receptor (18), of megalin (a VLDL-specific receptor found on fetal type II cells), and of cubilin detected in the total lung has been described (19, 20). We measured the uptake of vitamin E bound to HDL, LDL, or VLDL, respectively (21) and concluded from our results that HDL might be the primary source of vitamin E for type II cells. Moreover, it might be correct to assume that the uptake of vitamin E from this lipoprotein, which is the most important supplier of vitamin E for alveolar type II cells, changes with the cellular vitamin E status. This idea is strongly supported by the finding that vitamin E depletion in rats caused an increase of the vitamin E uptake by isolated type II cells from HDL but not from LDL or VLDL (Figure 2) . The idea that HDL may be the prime donor of vitamin E for type II cells also fits with the morphologic peculiarity of type II cells (Figure 3) . Intercalated within the alveolar epithelium, type II cells do not have any physical contact with plasma and can therefore only interact with lipoproteins present in the interstitial fluid, which contains predominately HDL-typical apoproteins (22, 23).



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  		Figure 2. Type II cells were isolated from rats fed diets containing vitamin E in different concentration. Adherent type II cells were cultured in presence of 20 mg HDL-protein, 20 mg LDL-protein, and 5 µg VLDL protein per ml and 106 cells for 2 hours. The lipoprotein fractions contained trace amounts of 3H-labeled vitamin E. According to the kinetic data of the vitamin E uptake, the added lipoproteins represent saturation concentration of vitamin E (for details see Reference 21).

 


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  		Figure 3. HDL-specific receptors and their possible function in mediating vitamin E uptake by alveolar type II cells. SR-BI, HB2, and MDP mediate the vitamin E uptake from HDL by specific lipid transfer (21, 27). Megalin and cubilin are expressed on alveolar type II cells and mediate, in concert, uptake of HDL-holoparticle (30). AI and AII represent the major HDL-apolipoprotein (apo-AI and apo-AII) predominantly present in the interstitium.

 
HDL-SPECIFIC RECEPTORS EXPRESSED BY ALVEOLAR TYPE II CELLS

It is generally accepted that HDL interactions with cell surfaces and HDL-dependent lipid exchange processes are mediated by specific receptors. Convincing evidence has been provided that the scavenger receptor-BI (SR-BI) functions as an HDL receptor and a selective transporter of cholesterol and cholesterol esters in vivo in the liver and steroidogenic glands (24). We have shown that SR-BI is also expressed by type II pneumocytes and that vitamin E regulates the SR-BI expression in type II cells and in HepG2 cells (21, 25). In addition, numerous attempts to purify and characterize other candidate HDL receptors have been reported, but structural information was only available in a few cases (reviewed in Reference 24). Two HDL-binding proteins, HB1 and HB2, were detected in the rat lung at approximately the same expression level as in the liver (26). Together, these results are consistent with the view that a variety of HDL-binding proteins may exist even on the same cell type. We purified two HDL-binding proteins using standard procedures from rat lung tissue. One of these membrane glycoproteins was identified by N-terminal sequencing and with a specific antibody as HB2, whereas the other was identified as a glycosyl phosphatidylinositol-anchored membrane dipeptidase (27). The expression of membrane dipeptidase and HB2 in type II pneumocyte membranes of rats increases when plasma lipoprotein concentrations were reduced by treatment with 4-aminopyrazolo[3,4-d]-pyrimidine. Furthermore, the decrease of lipoproteins is accompanied by a decrease of the vitamin E concentrations in plasma. The HDL-binding proteins were also dramatically upregulated in type II cells by feeding rats with a vitamin E–depleted diet. This suggests that HB2 and MDP may have a special role in vitamin E uptake (27). Besides the receptors that are responsible for specific lipid transfer from HDL, cubilin and megalin, which mediate HDL-particle uptake, were found in the lung (18, 19). Cubilin is a peripherial membrane protein, and convincing evidence has been presented that cubilin and megalin interact in concert to mediate particulate uptake of HDL in cells (28, 29). Recently we have shown that type II cells also exhibit HDL-holoparticle uptake (30). By this mechanism, vitamin E uptake is facilitated together with the other constituents of HDL-particles. In Figure 3 we have summarized the mechanisms of vitamin E uptake from HDL by type II cells. This uptake can be mediated by different receptor types responsible for the specific lipid transfer or for HDL-holoparticle uptake, respectively.

EFFECT OF VITAMIN E DEPLETION ON METABOLIC FUNCTIONS OF ALVEOLAR TYPE II CELLS

Vitamin E deficiency only occurs in a rare genetic disorder named FIVE, the familial isolated vitamin E deficiency (31). Furthermore, secondary causes such as malabsorption syndromes or liver dysfunctions may lead to vitamin E deficiency. In these cases the deficiency is alleviated with effective treatment of the primary disorder (32). Preterm and term neonates physiologically exhibit vitamin E deficiency (33, 34). In parallel, preterm neonates exhibit increased risk for the development of acute or chronic lung diseases (35). Recent results of our group show that both events seems to be causally linked. Vitamin E deficiency decreases the de novo synthesis of dipalmitoyl phosphatidylcholine in alveolar type II cells of rats by inhibition of the glycerol-3-phosphate acyltransferase and the acylation of lysolecithin (paper under review).

Whereas the beneficial effect of vitamin E supplementation against oxidative stress, inflammation, and infection is well documented (36, 37), it is not known whether alimentary vitamin E deficiency induces metabolic changes in type II cells. The analysis of the expression of heat shock proteins that represent an early and very sensitive marker of cellular stress may be a good test to examine whether vitamin E deficiency causes metabolic changes in alveolar type II cells. Recently, we demonstrated that alimentary vitamin E deficiency in rats resulted in a strong increase in the expression of heme oxygenase-1 (HSP32) in alveolar type II cells (38). Furthermore, we demonstrated that vitamin E depletion led to a reversible increase of pro- and antiinflammatory marker molecules (immunologic dysregulation) that seemed to be mediated by a strong protein kinase C activation in type II cells. The expression of the adhesion molecules ICAM-1 and CD166 increased, whereas the secretion of TNF-{alpha} decreased and the IL-10 synthesis and secretion increased (39). Furthermore, vitamin E deficiency induces a reversible proapoptotic response in type II cells (40).

In accordance with the clinical experience suggesting that vitamin E depletion does not cause clinically manifest lung injury if there is no additional insult, these events may prime type II cells to develop clinically manifest lung injury in response to an additional insult. The fact that hyperoxic treatment of vitamin E–deficient rats strongly increased the apoptosis of type II cells (40) supports this hypothesis.

VITAMIN E CONCENTRATION AND SR-BI EXPRESSION DURING FETAL DEVELOPMENT

Preterm infants after birth exhibit plasma vitamin E concentrations that are about 15% of that of term infants (41). This amount further decreases to about 9% by Day 8 (41). However, vitamin E concentration increases during the first week of life in term neonates but not in preterm infants (41). These slow changes of the vitamin E status of preterm infants occurred even though the vitamin E intake of these infants was similar to that of term infants. From these results it might be concluded that the mechanism(s) for the vitamin E uptake from HDL are not active in preterm neonates (42). However, the uptake of vitamin E by fetal tissues is not well investigated. Vitamin E is certainly accumulated together with cholesterol from maternal lipoproteins. Recently, the central role of the HDL receptor was demonstrated by the observation that the expression of SR-B1 in extraembryonic and intraembryonic tissues correlates with the uptake of fluorescence from maternal Dil-labeled HDL. Wyne and Woollett (43) showed that the clearance of maternal HDL by placenta, yolk sac, and decidua decreased during perinatal development. These results might explain why we found that the relative proportion of plasma HDL, vitamin E, and cholesterol decreased in parallel during perinatal development of rats (42). Furthermore, we have shown that the HDL-specific receptor SR-BI is not present on type II pneumocytes before birth. This situation may be of relevance for oxidative lung damage associated with preterm delivery. We hypothesize that the insufficiency of the preterm lung to cope with the relative oxygen-rich environment ex utero is due to the absence of SR-BI on lung cells in this developmental phase. This might lead to a lack of vitamin E in the preterm surfactant (42). However, it is difficult to conclude whether these results also reflect fetal development in humans. If the concentration of dipalmitoyl phosphatidyl choline in pulmonary surfactant is regarded as a common indicator of lung maturity, it might be assumed from our results that the protection of the lung of preterm infants against oxidative injury by treatment with vitamin E would only be successful after the 35th week, when SR-B1 is expressed on alveolar type II cells.

OPEN QUESTIONS OF VITAMIN E RESEARCH IN THE LUNG

Vitamin E in the lung can act as an antioxidant and also exhibits nonantioxidative effects that are at least in part mediated by the modulation of the activity of protein kinase C. However, there are some open questions regarding both properties of vitamin E in the lung. Presently, it is not clear at which cellular concentrations vitamin E levels reflect oxidative stress or a sufficient protection of lipids and proteins in cellular membranes. This is where this lipophilic vitamin is predominately located. It should be noted that an optimum vitamin E intake differs strongly and depends on the physiologic function to be protected (44). Therefore, the optimum vitamin E level in different compartments of the lung may vary. For instance, the immune system responds to changes of the dietary vitamin E level well before other signs of vitamin E deficiency are observed. However, it is not clear which parameters indicate sufficient vitamin E concentrations. There are some indications that the concentrations of cytoplasmic antioxidants or total antioxidant capacity are insufficient markers to indicate suboptimal vitamin E levels in cells. Jain and coworkers (45) showed that an elevated level of vitamin E-quinone reflects an increased oxidative stress in red blood cells more accurately than other parameters. Whether this result can be transferred to the lung is not clear. The nonantioxidative effect of {alpha}-tocopherol on the expression of different proteins has been not well understood. However, it appears that {alpha}-tocopherol regulates the expression of a number of proteins that mediate pathophysiologic events caused by suboptimal {alpha}-tocopherol levels (46). Recently {alpha}-tocopherol–associated proteins were characterized in different organs, and these proteins differ clearly from the {alpha}-tocopherol transfer protein in the liver (47). It could be hypothesized that {alpha}-tocopherol–associated proteins mediate the transcriptional and posttranscriptional events that are induced by modulating the vitamin E content in lung cells. Term and preterm infants exhibit a physiologic vitamin E deficiency and a tendency to develop an increased risk for acute and chronic lung diseases. Oxidative lung damage in preterm infants is characterized by inflammation and surfactant deficiency and also by apoptotic destruction of alveolar type II cells. Although the protective effect of vitamin E against oxidative stress, inflammation, and infection is well documented, it is largely unknown whether temporary vitamin E deficiency predisposes to lung injury and whether inflammation, surfactant deficiency, and type II cell apoptosis are causally linked with vitamin E deficiency.

FOOTNOTES

This work was supported by Grants Ru 517/1–1 and Ru 517/5–1 from the Deutsche Forschungsgemeinschaft, and by Grant 01ZZ9511 from the Bundesministerium für Bildung und Forschung Germany.

Received in original form June 14, 2002; accepted in final form October 2, 2002

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