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Lysophosphatidyl Choline, a Chemotactic Factor for Monocytes/T-Lymphocytes Is Elevated in Endometriosis

Department of Gynecology and Obstetrics, Emory University, Atlanta, Georgia 30322

Address all correspondence and requests for reprints to: Ana A. Murphy, Department of Gynecology and Obstetrics, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, Georgia 30322. E-Mail: amurphy@emory.edu.

	Abstract

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Inflammatory processes have been hypothesized to mediate some of the clinical sequelae associated with endometriosis. The peritoneal fluid (PF) of women with endometriosis is known to contain more inflammatory cells and their associated cytokines, chemokines, and growth factors. This work provides strong evidence for oxidative stress in the PF of women with endometriosis. 1) The low density lipoprotein (LDL) isolated from the PF of subjects with endometriosis shows a small but detectable increase in electrophoretic mobility compatible with mildly oxidized LDL compared with LDL isolated from the plasma of the same subjects and PF of controls. 2) Isolated PF-LDL of endometriosis subjects is more readily oxidized in vitro than PF-LDL of controls, or LDL isolated from plasma. 3) Vitamin E content is significantly lower in endometriosis PF compared with controls, and compared with plasma of women with endometriosis and controls. No difference is seen between plasma and PF of control subjects. 4) The ratio of phosphatidylcholine/lyso phosphatidylcholine (Ptd/lyso PtdCho) in the PF of endometriosis subjects is significantly lower compared with PF of controls.

Taken together, these data provide strong evidence for a pro-oxidant environment in the peritoneal cavity of women with endometriosis. Lyso PtdCho, a product derived from phospholipase A₂ action on peroxidized phosphatidylcholine and a potent chemotactic factor for monocytes and T-lymphocytes, is elevated in endometriosis. We hypothesize that the increased presence of lipid peroxidation products in the PF of endometriosis subjects may, at least partly, account for the recruitment of leukocytes, the increase in macrophage activation, the secretion of monocyte–macrophage-derived cytokines, and the endometrial growth- promoting activity associated with endometriosis.

	Introduction

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BOTH cellular (activated macrophages and other leukocytes) and acellular components of peritoneal fluid (PF) have been implicated in endometriosis-associated infertility (1). A significant elevation in macrophages and inflammatory cells, such as helper T-lymphocytes, and natural killer cells have been described in the PF of women with endometriosis (2). Halme et al. (3) described an increase in secretory activity and accentuated activation of the PF macrophages of women with endometriosis (3). An increase in chemotactic activity (4) and in chemotactic factors, such as monocyte chemotactic protein-1 (MCP-1) and RANTES have been observed in the PF of women with endometriosis (5, 6). A number of recent studies also have shown an increase in macrophage- secreted cytokines, such as interleukin-1 (IL-1), IL-6, IL-8, M-CSF (colony stimulating factor), and others in the PF of women with endometriosis (7, 8, 9, 10). Thus, conditions that would favor the recruitment of monocytes, their differentiation into macrophages, and secretion of chemokines and cytokines, may be intimately involved in the development of endometriosis.

Mildly oxidized low density lipoprotein (M-LDL) and extensively oxidized LDL (Ox-LDL) have been implicated in the pathogenesis of atherosclerosis (11). The oxidative modification of LDL occurs when polyunsaturated fatty acid containing lipids of the lipoprotein are oxidized. The peroxidized lipids undergo decomposition and generate products (generally aldehydes) that react with the amino groups of lysine residues of proteins or the amino groups of lipids. Amino groups that are protonated and are positively charged thus acquire a net negative charge.

Ox-LDL and its breakdown products exhibit several potent proatherogenic and inflammatory properties (11). Particularly relevant to endometriosis is the increase in lyso phosphatidylcholine (lyso PtdCho) (a monocyte and T-lymphocyte chemotactic agent) and a product of lipid peroxidation (12). Additionally, M-LDL has been shown to induce a) expression of MCP-1 (a potent monocyte and T-cell chemoattractant) (13); b) synthesis and secretion of IL-1 from monocyte-macrophages (14); c) differentiation of monocytes to macrophages (15); d) growth-promoting activity of target cells (16); and e) expression and secretion of granulocyte/macrophage-colony stimulating factor (17).

The PF of women with endometriosis has been reported to contain cytokines, chemokines, and growth factors that are also reported to be present in the atherosclerotic artery. These findings prompted us to investigate the possible role of oxidized forms of LDL and lipid peroxidation products in endometriosis.

In this study, we provide evidence for a significant oxidative stress in PF of women with endometriosis when compared with control subjects. Additionally, we report, for the first time, an increase in lyso PtdCho, a chemotactic agent for monocytes and T-lymphocytes, in the PF of women with endometriosis.

	Materials and Methods

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Subjects

Twenty-five subjects undergoing laparoscopy for pelvic pain, infertility, or suspected endometriosis were found to have endometriosis. Classification with Revised American Fertility Society (rAFS) revealed 17 minimal to mild (rAFS Stage I-II) and 8 moderate to severe (rAFS Stage III-IV) cases. Twenty-five subjects undergoing laparoscopy for sterilization were found to have a normal pelvis. Control subjects were excluded for associated gynecological pathology. These subjects constitute the study population that comprised all of the studies. All subjects could not be used for all studies, and sample size is indicated in Results.

The patient population was defined before entry with exclusion/inclusion criteria as follows and were enrolled: adult nonsmoking women, age 18–45 yr, with normal menstrual cycles who had not been on any hormonal medication for at least 3 months. Criteria for subject exclusion included current medical illnesses such as diabetes, cardiovascular heart disease, hyperlipidemia, systemic lupus erythematosus, or rheumatological disease; positive human immunodeficiency virus/acquired immune deficiency syndrome; active infection; or current medication use, such as antiinflammatory medications, including corticosteroids. There was no difference in mean patient age.

Surgery was performed in the follicular phase of the menstrual cycle, because cyclic fluctuation in the number of pelvic macrophages has been described in association with the cycle phase (6). All studies involving human subjects and animals were approved by the Human Investigations Committee of Emory University, Atlanta, Georgia.

LDL and lipid analysis

LDL was isolated from heparinized plasma and PF using a Beckman TL-100 tabletop ultracentrifuge (Beckman, Palo Alto, CA) as described earlier (18). LDL samples were subjected to oxidation immediately after isolation. Oxidation was performed using 5 µM copper. Oxidation of LDL was followed by measuring the formation of conjugated dienes in an SLM-Aminco DB-3500 spectrophotometer (Urbana, IL) equipped with a 12-chamber cuvette changer. Samples and references were measured continuously for periods of up to 6 h. LDL (100 µg/mL) was incubated in PBS with 5 µM copper (18).

Lipids were extracted, and phospholipids were separated by thin-layer chromatography using chloroform/methanol/water (65:35:6 vol/vol/vol) as solvent (19). Samples were visualized by exposure to iodine vapor. Phosphatidylcholine and lyso PtdCho were included as standards. Appropriate bands were scraped and analyzed for inorganic phosphorous (12).

Agarose gel electrophoresis for lipoproteins using a commercially available kit was performed. The gels were run in O.2 M barbital buffer at 90 mV for 35 min as suggested by the manufacturer. Lipoproteins were visualized by Fat-Red staining. SDS-PAGE was run on all the samples using the Laemmelli’s method. Proteins were stained with Coomassie brilliant blue.

The plasma and PF vitamin E was extracted using the method of Cheeseman et al. (20). Briefly, to 100 µg protein from samples in 1 mL water, 1 mL 10% SDS, 2 mL ethanol, and 1 mL n-hexane were added and mixed. The samples were spun at 2000 rpm for 10 min, and the top hexane layer was saved. The hexane extraction was repeated twice. Both hexane supernatants were mixed and evaporated to dryness under nitrogen. The dried samples were then suspended in methanol, mixed, and then injected into a high-performance liquid chromatograph (Rainin Instruments, Emeryville, CA). Vitamin E was separated on a C 18 Microsorb reverse phase column, with a 100% methanol as the solvent system, a 1 mL flow rate, and wavelength at 292 nm (21). -Tocopherol standard (Sigma Chemical Comp., St. Louis, MO) was used as the standard. The vitamin E was quantified as nmoles of vitamin E per milligram of protein.

ANOVA with post hoc testing was used if more than two comparisons were made. An unpaired t test was used to compare two different groups, and a paired t test was used for evaluation of paired plasma and PF in the same patient. Results are reported as mean ± SEM.

	Results

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As expected, agarose gel electrophoresis did not indicate the exclusive presence of oxidized LDL, which would have a distinctly increased electrophoretic mobility. This increase is caused by the modification of the lysine residues on the apoprotein, producing a net negative charge. However, agarose gel electrophoresis showed that LDL isolated from PF showed a small but detectable and consistent increase in electrophoretic mobility. In 25 paired samples analyzed, plasma LDL and PF-LDL of subjects with endometriosis showed electrophoretic mobilities of 0.98 ± 0.06 and 1.24 ± 0.11 cm, respectively (P < 0.005). M-LDL prepared from the same native LDL samples showed a mobility of 1.26 ± 0.09 cm, and Ox-LDL showed a mobility of 2.46 ± 0.25 cm. LDL from the PF of controls (n = 5 or those with lipoproteins) and endometriosis subjects (n = 20) showed electrophoretic mobility of 1.14 ± 0.12 compared with 1.24 ± 0.18 cm, respectively. Fifteen control subjects could not be analyzed because they lacked lipoproteins in the PF. These data suggest that M-LDL exist in PF but not Ox-LDL. Although the trend is obvious, these data must be interpreted with caution because these control subjects were not representative of the control population and because of the low number of control samples.

LDL from endometriosis (n = 5) and control (n = 5) PF was isolated and subjected to oxidation with the same subject’s plasma LDL. Again, the control population was skewed, because only those with lipoproteins could be examined. LDL isolated from endometriosis PF (119.7 ± 45 min) was more readily oxidized than control PF (172 ± 65 min; P < 0.05). There was no difference in oxidation between plasma of endometriosis (106 ± 48 min) and control (151 ± 54 min; P < 0.07) subjects. An example is shown in Fig. 1. The LDL isolated from endometriosis PF was more readily oxidized than plasma LDL and generated a shorter lag time (125 vs. 220 min). The vitamin E level of the PF-LDL in the example was 55% less than the plasma LDL. On the other hand, partially oxidized LDL may also show resistance to further oxidation because of depletion of polyunsaturated fatty acids. Indeed, in the few samples in which there was considerable increase in electrophoretic mobility of PF-LDL, the LDL was not only more resistant to further oxidation, but also showed much lower levels of conjugated dienes after oxidation. Therefore, it is essential to characterize LDL by several parameters rather than by focusing only on lag time.

View larger version (14K): [in this window] [in a new window]   Figure 1. Oxidation of plasma and PF-LDL in endometriosis. LDL (100 µg/mL) was incubated with 5 µM of copper sulfate solution in a total volume of 1 mL PBS. Conjugated diene formed was measured continuously at an optical density of 234 nm in a spectrophotometer.

Previous studies have shown that lyso PtdCho is formed from LDL during oxidation as a breakdown product of phospholipid peroxidation and phospholipase A₂ action (22, 23). Lyso PtdCho and PtdCho were quantitated in PF of women with endometriosis and controls (n = 9 and n = 4, respectively). Four control subjects were excluded because PF was minimal. The ratio of PtdCho/lyso PtdCho and lyso PtdCho was significantly decreased in women with endometriosis compared with controls (P < 0.05), indicating increased lipid peroxidation. There was no difference in PtdCho levels in endometriosis and control subjects (Table 1) despite a significant conversion of PtdCho to lyso PtdCho.

	Discussion

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Lyso PtdCho was found in the PF of both subjects with endometriosis and controls, but lyso PtdCho was higher and the ratio of PtdCho/lyso PtdCho in PF was significantly lower in women with endometriosis. In other words, endometriosis is associated with more extensive lipid peroxidation. Usually, the PtdCho/lyso PtdCho ratio in LDL is > 8. During oxidation the ratio gradually drops and, in an extensively oxidized LDL, it is usually < 3. The ratio found in endometriosis subjects (4.1 ± 0.10) suggests the presence of less extensively oxidized LDL or M-LDL. This is consistent with the findings on agarose gel electrophoresis. Given the high concentrations of LDL in the PF of women with endometriosis, it is very likely that the high levels of lyso PtdCho resulted, at least in part, from oxidation of lipoproteins. Lyso PtdCho could also, in theory, have resulted from other sources, such as phospholipase A₂ activity. However, this reaction alone could not have accounted for such a dramatic increase in lyso PtdCho levels.

Lyso PtdCho has attracted considerable attention in recent years because of its proatherogenic properties, which include monocyte chemotaxis, T-lymphocyte chemotaxis, inhibition of EDRF (endothelium derived relaxing factor), induction of cell adhesion molecules (vascular cell adhesion molecule-1 and intracellular adhesion molecule), and increased uptake of LDL (25). The chemotactic action of lyso PtdCho has been attributed to the intracellular formation of diacylglycerol. This in turn promotes protein kinase activity. Lyso PtdCho joins three other chemotactic factors that have so far been identified and shown to be increased in the PF of women with endometriosis. To date, MCP-1; RANTES; and "a factor that attracts macrophages, is secreted by endometriotic tissue, and may be a member of the immunophilin family;" have been shown to be increased in endometriosis (13, 26, 27, 28). Conditions that favor the recruitment of monocytes, their differentiation into macrophages, and the secretion of chemokines, cytokines, and growth factors are quite likely to be of major importance in the pathogenesis of endometriosis.

The increase in lyso PtdCho led us to explore the peroxidation of lipoproteins in the PF of women with endometriosis. LDL from the PF of women with endometriosis shows a small but detectable increase in electrophoretic mobility. This is evidence for a partially oxidized or M-LDL but not Ox-LDL. These results are not very surprising, because Ox-LDL is very rapidly cleared, at least from plasma, with a half-life of < 10 min.

The increase in mobility of PF-LDL suggests a mild degree of oxidation and an enhanced oxidative susceptibility of this LDL to further oxidation. To test this, LDL from endometriosis and control PF was isolated and subjected to oxidation with the same patient’s plasma. The LDL from endometriosis PF was more readily oxidized than control PF and plasma LDL of endometriosis and controls. Thus again suggesting a pro-oxidant milieu in the peritoneal cavity of women with endometriosis.

The antioxidant content of lipoproteins and their susceptibility to oxidation in PF has never been compared with their plasma counterpart in endometriosis or control populations. One would expect lower vitamin E content in PF if there were a pro-oxidant/proinflammatory milieu, because antioxidants are consumed during oxidation reactions. We have shown that vitamin E content of endometriosis PF is significantly lower than control PF. There is also a significant difference in vitamin E levels between PF and plasma of endometriosis subjects. Thus there is less antioxidant protection in PF of endometriosis subjects, which correlates with the decrease in lag time of PF-LDL. Because the decrease in vitamin E is not reflected in the plasma of endometriosis subjects, it suggests that depletion occurs while traversing the endothelium, in the peritoneal cavity itself, or both. This finding is not entirely surprising, because PF is an interstitial fluid. The vulnerability to oxidation of lipoproteins isolated from interstitial fluid has been well established (29, 30, 31).

Alternatively, the decrease in vitamin E may be the result of increased oxidative stress brought about by the presence of activated macrophages in PF of women with endometriosis, which are capable of inducing oxidation (32). Moreover, we have shown that macrophages and oxidative modification of proteins exist in the stroma of endometriosis tissue, which suggests another possible source for oxidative stress in PF (33). The lack or small amounts of lipoproteins/lipids in control PF vs. endometriosis PF may also contribute to the difference in oxidative stress in PF of these two groups.

It should be noted that the control group in these studies was skewed. Approximately two thirds of the control group was excluded from the oxidation of LDL and vitamin E studies because of lack of lipids or lipoproteins in PF. However, these data are skewed towards concluding that no difference exists, when in actuality one does and is an error. Despite the skewed nature of the data, significant differences were found with relatively small sample sizes. Nevertheless, these data should be interpreted with caution.

Both modified lipid protein complexes (adducts) and lipid peroxidation products formed during the oxidation of LDL possess a number of properties that suggest their potential involvement in the pathology associated with endometriosis. Lyso PtdCho, a component of oxidized LDL, has chemotactic properties for circulating monocytes and T-lymphocytes, (11, 34) and may therefore contribute to the increased number of these cells found in the PF of women with endometriosis (1). Lipid-protein adducts, formed by covalent binding of reactive peroxidized fatty acids to free amino groups of lysine residues of apoprotein or other proteins, constitute a substrate or ligand for the macrophage scavenger receptors (SCRs). Furthermore, Ox-LDL has been shown to activate macrophages and induce their uptake through SCR(s) (11). Their presence in PF may account for the increased expression of SCRs on activated peritoneal macrophages of women with endometriosis (35). Furthermore, both oxidized lipids and modified proteins have potent biological properties, such as the induction of IL-1 synthesis by macrophages (14, 36), MCP-1 (37), macrophage colony-stimulating factor-1 (17), and cytotoxicity (32). These cytokines and chemokines have all been shown to be increased in the PF of women with endometriosis (5, 7, 10).

In conclusion, our data provides strong evidence for the occurrence of an oxidative stress in PF of women with endometriosis. The genesis of the increased levels of oxidative stress found in PF of women with endometriosis, remains to be established. A number of PF constituents, including lipoproteins and other proteins such as albumin, exhibit evidence of oxidative modification (35). Although the increased presence of lipid peroxidation products in patients with endometriosis does not provide evidence for its pathogenic role, oxidized lipoproteins possess a number of properties that suggest their potential involvement in the pathogenesis of endometriosis.

Received July 11, 1997.

Revised January 19, 1998.

Accepted February 10, 1998.

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