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LYSOPHOSPHATIDIC ACID REDUCES THE ORGAN INJURY CAUSED BY ENDOTOXEMIA-A ROLE FOR G-PROTEIN-COUPLED RECEPTORS AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-γ

Murch, Oliver; Collin, Marika; Thiemermann, Christoph

doi: 10.1097/01.shk.0000235086.63723.7e
Basic Science Aspects
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Exogenous lysophosphatidic acid (LPA) has been shown to beneficial in renal ischemia/reperfusion injury, wound healing and colitis. LPA acts via specific G-protein-coupled receptors and also peroxisome proliferator-activated receptor-γ (PPAR-γ). However, activation of PPAR-γ is dependent on the presence of an unsaturated acyl chain. Here we investigate the effects of saturated LPA (18:0) and unsaturated LPA (18:1) on the organ injury associated with endotoxemia and the receptors mediating LPA activity. Male Wistar rats received either lipopolysaccharide (LPS, 6 mg/kg i.v.) or vehicle. The PPAR-γ antagonist GW9662 (1 mg/kg i.v.), the LPA receptor antagonist Ki16425 (0.5 mg/kg i.v.) or vehicle was administered 30 min after LPS. LPA 18:0 or LPA 18:1 (1 mg/kg i.v.) or vehicle was administered 1 h after injection of LPS. Endotoxemia for 6 h resulted in an increase in serum levels of aspartate aminotransferase, alanine aminotransferase and creatine kinase. Therapeutic administration of LPA 18:0 or 18:1 reduced the organ injury caused by LPS. LPA 18:0 also attenuated the increase in plasma IL-1β caused by LPS. Ki16425, but not GW9662, attenuated the beneficial effects of LPA 18:0, however, Ki16425 and GW9662 attenuated the beneficial effects of 18:1. In conclusion, LPA reduces the organ injury caused by endotoxemia in the rat. Thus, LPA may be useful in the treatment of shock of various aetiologies. The mechanism of action is related to acyl chain saturation, with LPA 18:0 acting via G-protein-coupled receptors and LPA 18:1 acting via G-protein-coupled receptors and PPAR-γ.

Centre for Experimental Medicine, Nephrology & Critical Care, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom

Received 13 Apr 2006; first review completed 12 May 2006; accepted in final form 12 Jun 2006

Address reprint requests to: Christoph Thiemermann, Centre for Experimental Medicine, Nephrology & Critical Care, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom. E-mail: c.thiemermann@qmul.ac.uk.

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INTRODUCTION

Lysophosphatidic acid (LPA) has been shown to be immunomodulatory in vitro, including causing chemotaxsis, increasing T-cell and macrophage survival (1), causing platelet aggregation (2) and enhancing wound healing (3). Circulating LPA is produced by platelets and red blood cells, however, a majority of LPA is produced by catalytic action on other lipid species, especially lysophospholipase D acting on lysophosphatidylcholine. LPA binds to specific G-protein-coupled receptors belonging to the endothelial differentiation gene (Edg) subfamily, LPA1 LPA2 LPA3. Receptor activation results in signal transduction via Ras-MAP kinase, Rho/Rac, phospholipase C and inhibition of adenylyl cyclase (4). A forth membrane bound receptor not belonging to the Edg subfamily has been reported, although its biological significance has not been fully established (5). LPA is also abundant in cytoplasm and has recently been reported to be a ligand for PPAR-γ, although not PPAR-α or PPAR-δ (6, 7).

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. PPARs regulate gene transcription by the formation of heterodimers with retinoid X receptors and binding to specific PPAR response elements. This results in activation or suppression of the target genes. Ligands for PPAR-γ have been shown to have anti-inflammatory properties both in vivo and in vitro (8, 9). Notably, ligands for PPAR-γ have previously been shown to protect against the multiple organ injury associated with endotoxemia (10, 11), administration of Gram-positive and Gram-negative cell wall fragments (12), polymicrobial sepsis (13), zymosan induced shock (14) and hemorrhagic shock (15). The role of PPAR-γ in regulating inflammatory responses and potential therapeutic approaches for PPAR-γ ligands in sepsis, inflammation and ischemia/reperfusion injury has recently been reviewed (16). As mentioned above, LPA has been reported to activate PPAR-γ. Specifically, it has been reported that (unsaturated) LPA 18:1 competes with radiolabeled PPAR-γ ligands for binding to PPAR-γ, however, (saturated) LPA 18:0 was less effective at competing for PPAR-γ (6). Also activation of PPAR-γ by various LPA species has been reported to be dependant on acyl chain saturation. Specifically, unsaturated LPA (LPA 18:1, LPA 18:2, LPA 18:3 and LPA 20:4) significantly activated PPAR-γ, however saturated LPA (LPA 16:0, LPA 18:0 and LPA 20:0) did not activate PPAR-γ (7). The specific PPAR-γ antagonist GW9662 has also been shown to attenuate PPAR-γ activation by unsaturated LPA both in vitro and in vivo (7).

Interestingly, LPA has been shown to be protective in animal models of inflammation, including renal ischemia-reperfusion (17), wound healing (18) and colitis (19), and there is evidence that ligands of PPAR-γ are also beneficial in these conditions (20). Thus, LPA may provide a novel therapeutic opportunity for reducing the multiple organ injury associated with endotoxemia as i) LPA has been previously shown to be protective in animal models of inflammation (17-19) and ii) saturated species of LPA are ligands for PPAR-γ (6, 7) and that other ligands for PPAR-γ have previously been shown to be beneficial in animal models of inflammation (10, 12-14).

Hence, this study was undertaken to investigate the effects of both (saturated) LPA 18:0 and (unsaturated) LPA 18:1 (Fig. 1 on i) the hemodynamic alterations, ii) the liver injury, iii) the neuromuscular injury and iv) the alterations in plasma IL-1β and IL-6 levels caused by severe acute endotoxemia in the rat. We have also investigated whether activation of LPA of either i) LPA G-protein-coupled receptors or ii) PPAR-γ mediates any of the observed effects using the specific antagonists Ki16425 and GW9662 (2-choloro-nitrobenzanilide), respectively.

Fig. 1

Fig. 1

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MATERIALS AND METHODS

Surgical procedure and quantification of organ injury/dysfunction

This study was carried out on 118 male Wistar rats (Charles River, Kent, UK) weighing 230-320g, receiving a standard diet and water ad libitum. The investigation was performed in accordance with the Home Office Guidance on the Operation of the Animals (Scientific Procedures) Act 1986, published by HMSO, London. All animals were anaesthetized with thiopentone sodium (Intraval®, 120 mg/kg, i.p.), and anesthesia was maintained by supplementary injections of thiopentone sodium (approximately 1-2 mg/kg/h i.v.) as required. The general surgical procedures were performed as previously described (21). Briefly, a tracheostomy was performed to maintain airway patency and facilitate spontaneous breathing and polyethylene catheters were positioned in the carotid artery, for mean arterial pressure (MAP) and heart rate (HR) monitoring, jugular vein, for administration of drugs, vehicles and/or saline, and bladder to prevent post renal failure. Upon completion of the surgical procedure, MAP and HR were allowed to stabilize for 20 min. 6 h after administration of LPS, 1.5 ml of blood was collected from the carotid into a serum gel S/1.3 tube (Sarstedt, Germany) from a catheter placed in the carotid artery, and plasma values for indices of liver (22) and neuromuscular injury (23) were examined as previously described.

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Experimental design

A dose of 1 mg/kg LPA has been previously shown to prevent renal ischemia-reperfusion injury and was therefore included in this study. GW9662 has previously been reported to antagonize PPAR-γ in the nanomolar range (24) and doses of 0.3-1 mg/kg have been shown reduce organ protection afforded by PPAR-γ ligands in this animal model (10). Thus, a dose of 1 mg/kg was used in this study. Animals were assigned to 15 different groups (Table 1):

Table 1

Table 1

  1. Sham Control. Rats received vehicle for LPS (1 ml/kg saline i.v.), 10% DMSO (vehicle for Ki16425 and GW9662, 1 ml/kg i.v.) and 2% BSA in PBS (vehicle for LPA, 1 ml/kg i.v., n = 11).
  2. Sham 18:0. Rats received vehicle for LPS (1 ml/kg saline i.v.), 10% DMSO (vehicle for Ki16425 and GW9662, 1 ml/kg i.v.) and were treated with LPA 18:0 (1 mg/kg i.v., n = 7).
  3. Sham 18:1. Rats received vehicle for LPS (1 ml/kg saline i.v.), 10% DMSO (vehicle for Ki16425 and GW9662, 1 ml/kg i.v.) and were treated with LPA 18:1 (1 mg/kg i.v., n = 5).
  4. Sham Ki16425. Rats received vehicle for LPS (1 ml/kg saline i.v.) and 2% BSA in PBS (vehicle for LPA, 1 ml/kg i.v.) and were treated with Ki16425 (0.5 mg/kg i.v., n-5).
  5. Sham GW9662. Rats received vehicle for LPS (1 ml/kg saline i.v.) and 2% BSA in PBS (vehicle for LPA, 1 ml/kg i.v.) and were treated with GW9662 (1 mg/kg i.v., n = 4).
  6. LPS Control. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later received the vehicle for vehicle for Ki16425 and GW9662 (1 ml/kg i.v. 10 % DMSO) and 1 h after LPS received vehicle for LPA (1 ml/kg i.v. 2% BSA in PBS, n = 12).
  7. LPS + Ki16425. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later were treated with Ki16425 (0.5 mg/kg i.v.) and 1 h after LPS received vehicle for LPA (1 ml/kg i.v. 2% BSA in PBS, n = 5).
  8. LPS + GW9662. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later were treated with GW9662 (1 mg/kg i.v.) and 1 h after LPS received vehicle for LPA (1 ml/kg i.v. 2% BSA in PBS, n = 7).
  9. LPS + 18:0. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later received the vehicle for vehicle for Ki16425 and GW9662 (1 ml/kg i.v. 10 % DMSO) and 1 h after LPS received LPA 18:0 (1 mg/kg i.v., n = 9).
  10. LPS + Ki16425 + 18:0. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later received Ki16425 (0.5 mg/kg i.v.) and 1 h after LPS received LPA 18:0 (1 mg/kg i.v., n = 8).
  11. LPS + GW9662 + 18:0. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later received GW9662 (1 mg/kg i.v.) and 1 h after LPS received LPA 18:0 (1 mg/kg i.v., n = 9).
  12. LPS + 18:1. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later received the vehicle for vehicle for Ki16425 and GW9662 (1 ml/kg i.v. 10 % DMSO) and 1 h after LPS received LPA 18:1 (1 mg/kg i.v., m = 9).
  13. LPS + Ki16425 + 18:1. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later received Ki16425 (0.5 mg/kg i.v.) and 1 h after LPS received LPA 18:1 (1 mg/kg i.v., n = 9).
  14. LPS + GW9662 + 18:1. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later received GW9662 (1 mg/kg i.v.) and 1 h after LPS received LPA 18:1 (1 mg/kg i.v., n = 9).
  15. LPS + Ki16425 + GW9662 + 18:1. Rats received LPS (6 mg/kg i.v. over 10 min), 30 min later were co-administered with Ki16425 (0.5 mg/kg i.v.) and GW9662 (1 mg/kg i.v.) and 1 h after LPS received LPA 18:1 (1 mg/kg i.v., n = 9).
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Plasma IL-1β measurements

Carotid blood was taken 6 h after LPS administration and centrifuged at 10,000 RPM. Plasma samples were frozen and stored at −80°C until analyzed as previously described (25). Following the manufactures protocol, sandwich ELISAs from R&D Systems (Minneapolis, USA) were performed to determine the plasma levels of IL-1β and IL-16. Samples were analyzed using a microplate reader set to 450 nm and corrected at a wavelength of 540 nm. All samples were analyzed in duplicate.

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Materials

LPA suspensions were prepared in PBS containing 2% BSA and ultra-sonnicated for 15 seconds. Ki16425 and all other materials were purchased from Sigma-Aldrich Company Ltd. (Poole, UK), unless otherwise stated. LPA 18:0 (1-stearoyl-2-hydroxy-sn-glycero-3-phosphate) and LPA 18:1 (1-Oleoyl-2-Hydroxy-sn-Glycero-3-Phosphate) were purchased from Avanti Polar Lipids (Alabaster, Alabama, USA). GW9662 was purchased from Axxora (UK) Ltd (Nottingham, UK). Thiopentone sodium (Intraval Sodium®) was purchased from Rhône Mérieux Ltd. (Harlow, UK). Non-pyrogenic saline (0.9% NaCl) was acquired from Baxter Healthcare Ltd. (Thetford, UK). PBS was attained from Invitrogen (Paisley, UK).

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Statistical evaluation

All data are presented as means ± SEM of n observations, where n represents the number of animals or blood samples studied. For repeated hemodynamic measurements a two-way analysis of variance (ANOVA) was performed followed by a Bonferroni post test. Data without repeated measurements (multiple organ injury and cytokines analysis) was analyzed by one-way ANOVA, followed by a Bonferroni post hoc test for multiple comparisons. A P value of less than 0.05 was considered statistically significant.

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RESULTS

Effects of LPA on the circulatory failure associated with endotoxemia

Prior to LPS administration, mean baseline values for MAP (Table 2) and HR (data not shown) were similar in all experimental groups. Values ranged from 116 ± 4 to 132 ± 4 mm Hg and 397 ± 7 to 443 ± 8 beats per minute (bpm), respectively. Compared to Sham Controls, animals administered with either Ki16425, GW9662, LPA 18:0 or LPA 18:1 alone exhibited similar hemodynamics (P > 0.05).

Table 2

Table 2

When compared to Sham-operated rats, administration of LPS (6 mg/kg) resulted in a significant, biphasic fall in MAP from 132 ± 4 (baseline) to 85 ± 3 mm Hg at 6 h after injection of LPS. Administration of either LPA 18:0 or LPA 18:1 did not affect the fall in MAP caused by endotoxin at any time point (P > 0.05).

When compared to Sham-operated animals, endotoxemia for 6 h resulted in a significant increase in HR from 401 ± 10 (baseline) to 482 ± 10 beats per min (data not shown). This tachycardia was not affected by either LPA 18:0 or LPA 18:1 (P > 0.05). Administration of Ki16425 or GW9662 without LPA had no effect on the biphasic fall in MAP or tachycardia resulting from endotoxemia in any experimental group (P > 0.05).

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Effects of LPA on the organ injury caused by endotoxemia

When compared to Sham-operated controls, endotoxemia for 6 h resulted in significant increases in serum levels of aspartate aminotransferase (AST, Fig. 2) and alanine aminotransferase (ALT, Fig. 3), both markers of liver injury, and creatine kinase (CK, Fig. 4), a marker of neuromuscular injury (P < 0.05).

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Fig. 4

Fig. 4

When compared to LPS controls, treatment of animals with LPA 18:0 1 h after LPS administration caused a significant reduction in the serum levels of AST (Fig. 2A), ALT (Fig. 3A) and CK (Fig. 4A) (P < 0.05). When compared to animals administered with LPS and treated with LPA 18:0, infusion of the specific LPA receptor antagonist Ki16425 significantly attenuated the organ protection provided by LPA 18:0 (P < 0.05). However, administration of the specific PPAR-γ receptor antagonist, GW9662, had no effect on the organ protection afforded by LPA 18:0.

Interestingly, when compared to LPS controls, treatment of animals with LPA 18:1 1 h after LPS administration caused a significant reduction in the serum levels of AST (Fig. 2B), ALT (Fig. 3B) and CK (Fig. 4B) (P < 0.05). However, when animals were infused with either the specific LPA receptor antagonist, Ki16425, or the specific PPAR-γ receptor antagonist, GW9662, this protective effect was reduced. Furthermore, when compared to animals receiving LPS and LPA 18:1 alone, co-administration with both Ki16425 and GW9662 significantly attenuated the organ protective effects of LPA 18:1 (P < 0.05).

When compared to Sham-operated controls, animals receiving either Ki16425, GW9662 or LPA18:0 or LPA 18:1 without causing endotoxemia, showed similar serum levels of the AST, ALT and CK (data not shown, P > 0.05). Animals receiving LPS and receptor antagonists without LPA showed similar organ injury to LPS controls (Table 3, P > 0.05).

Table 3

Table 3

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Effects of LPA 18:0 on the increased circulating levels of IL-1β and IL-6 associated with endotoxemia

Endotoxemia resulted in a significant rise in circulating IL-1β and IL-6 levels 6 h after LPS administration when compared to Sham Control animals (Fig. 5, P < 0.05). When compared to LPS controls, administration of LPA 18:0 significantly reduced plasma IL-1β levels (Fig. 5A, P < 0.05). Serum from endotoxemic animals receiving both LPA 18:0 and Ki16425 showed attenuation of LPA 18:0 induced IL-1β reduction, which were not significantly different from animals receiving LPS alone (P > 0.05). Inhibition of PPAR-γ by GW9662 did not attenuate the reduction in circulating levels of IL-1β afforded by LPA 18:0. When compared to animals receiving LPS alone, LPA 18:0 reduced circulating levels of IL-6, although this was not significant (Fig. 5B, P > 0.05).

Fig. 5

Fig. 5

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DISCUSSION

We demonstrate here that acute severe endotoxemia resulted in liver injury, as measured by serum AST and ALT levels, and neuromuscular injury, as measured by serum CK levels. Furthermore, endotoxemia resulted in circulatory failure (hypotension and tachycardia) and increased circulating levels of IL-1β and IL-6.

Previously LPA has been reported to be protective in animal models of renal ischemia-reperfusion (17), wound healing (18) and colitis (19). Here we demonstrate for the first time that administration of either saturated (18:0) or unsaturated (18:1) LPA significantly attenuated the liver and neuromuscular injury caused by acute severe endotoxemia in the rat. Notably, this protective effect was observed when administration of LPA occurred 1 h after administration of LPS. It has been suggested that many therapeutic approaches for septic shock have failed in clinical trials due to the utilization of prophylactic treatment regimes in experimental settings, rather than therapeutic administration (after the onset of shock and inflammation). Thus our findings, that LPA given after the induction of endotoxemia protects the liver and neuromuscular tissue against the associated injury, interestingly suggests a broader window for the therapeutic use of LPA against the systemic inflammatory response.

LPA has been reported to activate both specific G-protein-coupled receptors and PPAR-γ (6, 7). Importantly, the activation of PPAR-γ has been shown to be dependent on the saturation of the acyl chain. Specifically, it was reported that the (unsaturated) LPA 18:1 competes with radiolabeled PPAR-γ ligands (rosiglitazone and azelaic phosphatidylcholine) for binding to PPAR-γ, however, (saturated) LPA 18:0 was less effective at competing for PPAR-γ (6). Zhang and colleagues have shown that activation of PPAR-γ by various LPA species was dependant on acyl chain saturation, with unsaturated LPA (LPA 18:1, LPA 18:2, LPA 18:3 and LPA 20:4) significantly activating PPAR-γ and saturated LPA (LPA 16:0, LPA 18:0 and LPA 20:0) showing no PPAR-γ dependent effect (7). Previously, we and others have shown ligands for PPAR-γ to be protective in animal models of endotoxemia (10, 11), systemic inflammation caused by Gram-positive and Gram-negative bacterial cell wall components (12), polymicrobial sepsis (13), zymosan induced shock (14) and hemorrhagic shock (15). Thus, using specific receptor antagonists for LPA G-protein-coupled receptors (LPA1-3, Ki16425) and PPAR-γ (GW9662), we investigated the possible role of these receptors in the organ protection afforded by both LPA 18:0 and LPA 18:1.

We found that the organ protection (liver and neuromuscular) provided by LPA 18:0 was associated with LPA G-protein-coupled receptor but not PPAR-γ activation. Conversely, the organ protection provided by LPA 18:1 was associated with both G-protein-coupled receptor activation and, importantly, PPAR-γ activation. In animals receiving both LPS and LPA 18:1, co-administration of Ki16425 and GW9662 resulted in a significant attenuation of the protection afforded by LPA 18:1. Thus, LPA 18:1 reduces organ injury associated with endotoxemia by activating two distinct pathways. Interestingly, Ki16425 and GW9662 did not increase the injury in animals subjected to LPS alone, indicating that endogenous LPA provides no protection in this model of acute severe endotoxemia. We have previously shown that endogenous ligands for PPAR-γ are protective in a model of hemorrhagic shock but not in this model of endotoxemia (10, 15).

Interestingly, the fall in blood pressure caused by LPS was not prevented by either saturated or unsaturated LPA. This is not entirely surprising, as many agents which do not affect the fall in blood pressure in these models do reduce organ injury (26), while others which do attenuate the fall in blood pressure may not (27). Thus, there is no strict correlation between hemodynamic effects and outcome in this model. Furthermore, we have recently reported that the co-administration of LPS and PepG, which does not cause a fall in MAP, does cause a significant degree of organ injury/dysfunction as well as systemic inflammation (28). Also, there is clinical evidence that an improvement in blood pressure alone does not necessarily prevent organ dysfunction and injury. For instance, Le Doux and colleagues have shown that increasing MAP from 65 to 85 mm Hg with norepinephrine does not significantly affect systemic oxygen metabolism, skin microcirculatory blood flow, urine output or splanchnic perfusion in patients with septic shock (29). Thus, we believe that the observed beneficial effects of LPA are not due to a hemodynamic effect.

What then are the possible mechanism(s) by which LPA attenuates the inflammatory response and as a result protects the organs against injury? We have shown that the rise in plasma levels of IL-1β associated with endotoxemia is attenuated with LPA 18:0, indicating a possible anti-inflammatory role for LPA 18:0 in endotoxemia. This beneficial effect was blocked by Ki16425, indicating that LPA 18:0 either directly or indirectly (by reducing tissue injury or other pathways prior to IL-1β activation) attenuates the pro-inflammatory response. We have also shown that LPA 18.0 attenuates the rise in circulating levels of IL-6 associated with endotoxemia, although this was not significant. Also, previous investigation into renal ischemia-reperfusion injury has reported that LPA reduces renal apoptosis as well as release of TNF-α, neutrophil influx and complement activation (17), thus providing further possible protective mechanisms.

Limitations of the Study: Despite these findings, the identity/identities of the LPA receptors activated by LPA in this model remains elusive due to the non-selectivity of current antagonists, with Ki16425 antagonizing all LPA G-protein-coupled receptors (30). LPA1 and LPA2 have been shown to be involved in T cell proliferation and migration, respectively, and both receptors protect against T cell and macrophage apoptosis (31). The role of a putative nuclear LPA receptor showing immunomodulatory functions also remains to be established (32). Obviously, further investigation of the anti-inflammatory mechanism(s) of LPA is warranted, including the receptor subsets involved. Additionally, in this model of endotoxemia we have not provided direct evidence of PPAR-γ activation by unsaturated LPA. However, we and others have previously shown that i) ligands for PPAR-γ are protective in models of systemic inflammation (10-13, 15), ii) GW9662 has been shown to specifically antagonize PPAR-γ activation both in vitro and in vivo (7, 10, 15, 24) and iii) unsaturated LPA has previously been shown to activate PPAR-γ both in vitro and in vivo (6, 7).

In conclusion, our results show for the first time that both saturated and unsaturated LPA, given in a therapeutic regime, protects against endotoxin induced organ injury and the rise in circulating IL-1β levels. Mechanistically, this protection is dependant on acyl chain saturation, with saturated LPA activating only specific G-protein-coupled receptors but unsaturated LPA activates both G-protein-coupled receptors and PPAR-γ. We propose that LPA may be a useful strategy in the therapy of organ injury in diseases associated with shock of various aetiologies.

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ACKNOWLEDGMENTS

OM was funded by the Medical Research Council. MC was financially supported by the Helsingin Sanomat Centennial Foundation.

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Keywords:

GW9662; Ki16425; LPS; peroxisome proliferator-activated receptor-γ; sepsis

©2007The Shock Society