- Open Access
Role of lysophosphatidic acid receptor LPA2 in the development of allergic airway inflammation in a murine model of asthma
© Zhao et al. 2009
- Received: 28 May 2009
- Accepted: 20 November 2009
- Published: 20 November 2009
Lysophosphatidic acid (LPA) plays a critical role in airway inflammation through G protein-coupled LPA receptors (LPA1-3). We have demonstrated that LPA induced cytokine and lipid mediator release in human bronchial epithelial cells. Here we provide evidence for the role of LPA and LPA receptors in Th2-dominant airway inflammation.
Wild type, LPA1 heterozygous knockout mice (LPA1 +/-), and LPA2 heterozygous knockout mice (LPA2 +/-) were sensitized with inactivated Schistosoma mansoni eggs and local antigenic challenge with Schistosoma mansoni soluble egg Ag (SEA) in the lungs. Bronchoalveolar larvage (BAL) fluids and lung tissues were collected for analysis of inflammatory responses. Further, tracheal epithelial cells were isolated and challenged with LPA.
BAL fluids from Schistosoma mansoni egg-sensitized and challenged wild type mice (4 days of challenge) showed increase of LPA level (~2.8 fold), compared to control mice. LPA2 +/- mice, but not LPA1 +/- mice, exposed to Schistosoma mansoni egg revealed significantly reduced cell numbers and eosinophils in BAL fluids, compared to challenged wild type mice. Both LPA2 +/- and LPA1 +/- mice showed decreases in bronchial goblet cells. LPA2 +/- mice, but not LPA1 +/- mice showed the decreases in prostaglandin E2 (PGE2) and LPA levels in BAL fluids after SEA challenge. The PGE2 production by LPA was reduced in isolated tracheal epithelial cells from LPA2 +/- mice. These results suggest that LPA and LPA receptors are involved in Schistosoma mansoni egg-mediated inflammation and further studies are proposed to understand the role of LPA and LPA receptors in the inflammatory process.
- Wild Type Mouse
- Idiopathic Pulmonary Fibrosis
- Human Bronchial Epithelial Cell
- Schistosoma Mansoni
Lysophosphatidic acid (LPA) is a naturally occurring bioactive lysophospholipid and is a component of plasma, biological fluids, and tissues [1–3]. Many of the biological responses of LPA such as cell proliferation [4, 5], migration [6, 7], and cytokine release [8–10] are mediated by a family of G-protein coupled receptors (GPCRs). At least six LPA receptors, LPA1-6, have been cloned and described in mammals, and the biological effects of LPA are mediated by ligation to specific LPA receptors that are coupled to heterotrimeric G-protein families, the Gs, Gi, Gq, and G12/13 [11–17].
The role of LPA and LPA receptors in airway inflammatory diseases have been studied in vitro and in vivo. LPA is a potent stimulator of interleukin-8 (IL-8) secretion in primary cultured human bronchial epithelial cells (HBEpCs) [8, 10], and is a mitogen for airway smooth muscle cells [18, 19]. Intratracheal administration of LPA in mice increased MIP-2 levels at 3 h and neutrophil infiltration at 6 h . Inhalation of LPA induced histamine release and enhanced the recruitment eosinophils and neutrophils to the guinea pig lung alveolar space [21, 22]. While these studies suggest that LPA regulates airway inflammation via stimulating the release of cytokines and inflammatory mediators that modulate infiltration of neutrophils and eosinophils into the airway, others point out that LPA exhibits anti-inflammatory effects and promotes resolution of inflammation. In human bronchial epithelial cells, LPA induced IL-13 decoy receptor, IL-13Rα2 expression and release, and attenuated IL-13-induced phosphorylation of STAT6 . Further, LPA enhanced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release in HBEpCs  suggesting a protective role in the innate immunity response and tissue repair process in airway inflammation [24, 25]. Recently, Fan et al. showed that intravenous injection with LPA attenuated bacterial endotoxin-induced plasma TNF-α production and myeloperoxidase activity in mouse lung, suggesting an anti-inflammatory role of LPA in a murine model of acute lung injury . In addition to its anti-inflammatory effect, LPA regulated E-cadherin intracellular trafficking and airway epithelial barrier integrity and intratracheal post-treatment with LPA reduced neutrophil influx, protein leak, and E-cadherin shedding in bronchoalveolar lavage (BAL) fluids in a murine model of LPS-induced acute lung injury . These data suggest a protective role of administrated LPA in airway inflammatory diseases.
In contrast to several in vitro studies on the role of LPA as a pro- or anti-inflammatory mediator in airway epithelial and smooth muscle cells [8, 10, 18–20], there are a few reports linking LPA levels and LPA receptors to airway or lung inflammation and injury. We have recently shown that LPA was constitutively present in BAL fluids from normal and asthmatic subjects and segmental allergen challenge increased LPA levels in BAL fluids significantly . However, the source of LPA and the pathophysiological relevance of increased LPA after segmental allergen challenge to allergic inflammation remain to be elucidated. Similarly, LPA levels in BAL fluids from individuals with idiopathic pulmonary fibrosis were significantly higher compared to normal controls . Further, an increase in LPA levels in BAL fluid following lung injury was observed in the bleomycin model of pulmonary fibrosis, and mice lacking LPA1 were protected from fibrosis and mortality . These studies suggest a role for LPA receptors in linking lung injury in the murine bleomycin model of pulmonary fibrosis.
Asthma is a chronic inflammatory disease of the airways involving T-lymphocytes and eosinophils infiltration, mucus overproduction and airway hyper-responsiveness. Inflammatory mediators including lipid mediators play a critical role in the pathogenesis of chronic airway diseases and facilitate the recruitment, activation, and trafficking of inflammatory cells in the airways. Very little is known on the physiological consequences of increased LPA levels and role of LPA receptors in asthma. To address the role of LPA receptors in Th2-mediated inflammation, we have used a well described Schistosoma mansoni eggs-sensitized murine model of allergic airway inflammation [30–32]. Control wild type, LPA 1 +/- and LPA 2 +/- mice were sensitized and challenged with Schistosoma mansoni eggs. LPA2 +/- challenged mice compared to wild type showed decrease in cell numbers, eosinophils, and positive PAS staining. Interestingly, only Schistosoma mansoni eggs sensitized and challenged LPA 2 +/-, but not LPA 1 +/-, mice showed reduced PGE2 levels in BAL fluids which correlated with diminished COX-2 expression in LPA2 +/- mice. Furthermore, airway epithelial cells isolated from LPA 2 +/- mice exhibited reduced COX-2 expression and PGE2 release compared to cells from wild type mice. These results show for the first time a role for LPA2 in the development of airway inflammation and pathogenesis of asthma.
All the mice were bred and housed in a specific pathogen-free barrier facility maintained by the University of Chicago Animal Resources Center. The studies reported here conform to the principles outlined by the Animal Welfare Act and the National Institutes of Health guidelines for the care and use of animals in biomedical research.
PCR genotyping of LPA1 +/- and LPA2 +/- mice
Extract-N-Amp Tissue PCR kit (Sigma Aldrich, S. Louis) was utilized for isolating genomic DNA from mouse tail and amplifying DNA fragments. The primers for LPA1 and LPA2 knockout mice were described as previous studies [33, 34].
Schistosoma mansoni eggs sensitization and challenge
Schistosoma mansoni eggs sensitization and challenge to induce murine allergic airway disease were described before . In brief, at day 0, mice (6-8 weeks) were immunized by i.p. injection of 5,000 inactivated Schistosoma mansoni eggs. At day 7, the mice were challenged with 10 μg of SEA by intratracheal aspiration. The mice were studied at day 11.
Analyses of BAL fluids
BAL fluids were performed by an intratracheal injection of 1 ml of PBS solution followed by gentle aspiration. The lavage was repeated twice to recover a total volume of 1.8-2.0 ml. The lavage was centrifuged and supernatant was processed for PGE2 or LPA measurement. The percentages of cell types in BAL fluids were determined by FACS analysis with cell type-specific markers.
Lungs were removed from mice and lobes were sectioned sagitally, embedded in paraffin, cut into 5-μm sections. Periodic Acid Schiff (PAS) staining were performed by Pathology Core Facility in The University of Chicago.
Antibodies and flow cytometry
Antibody to mouse CCR3 (clone 831101.111) was obtained from R&D Systems (Minneapolis, MN). Cells were fixed with 4% paraformaldehyde for 10 min and incubated with staining antibodies for 30 min at 4°C. The samples were washed and analyzed on a FACS LSR-II (Becton Dickinson).
Isolation of tracheal epithelial cells
Briefly, mice were euthanized and their tracheas were isolated and digested with 0.1% protease (Type XIV, Sigma) overnight at 4°C. The tracheal cell suspension were transferred to 15 ml tube and spun at 1500 rpm for 3 min at 4°C and were pooled in BEGM medium (Lonza, Walkersville, MD).
LPA measurement by mass spectrometry
Lipids in BAL were extracted as described before . In brief, LPA levels were determined using liquid chromatography and tandem mass spectrometry (LC) with ABI-4000 Q-TRAP hybrid triple quadrupole/ion trap mass spectrometer (MS) coupled with an Agilent 1100 liquid chromatography system. Lipids were separated using methanol/water/HCOOH, 79/20/0.5, v/v, with 5 mM NH4COOH as solvent A and methanol/acetonitrile/HCOOH, 59/40/0.5, v/v, with 5 mM NH4COOH as Solvent B. LPA molecular species were analyzed in negative ionization mode with declustering potential and collision energy optimized for LPA.
Mouse tracheal epithelial cells grown on 6-well plates were challenged with LPA for 3 h, medium were collected and centrifuged at 5,000 × g for 10 min at 4°C. The supernatant or BAL fluid supernatant were transferred to new 2.0 ml-eppendorf tubes and frozen in -80°C for later analysis. Measurement of PGE2 levels, as 13, 14-dihydro-15-keto PGE2, was carried out using a commercial ELISA kit according to manufacture's instruction.
RNA isolation and Real-time RT-PCR
Primers for mouse LPA receptors and COX-2
Equal amounts of protein (20 μg) were subjected to 10% SDS/PAGE gels, transferred to polyvinylidene difluoride membranes, blocked with 5% (w/v) BSA in TBST (25 mM Tris-HCl, pH 7.4, 137 mM NaCl and 0.1% Tween-20) for 1 h and incubated with anti-COX-2 antibody in 5% (w/v) BSA in TBST for 1-2 h at room temperature. The membranes were washed at least three times with TBST at 15 min intervals and then incubated with a rabbit horseradish peroxidase-conjugated secondary antibody (1: 3,000) for 1 h at room temperature. The membrane was developed with enhanced chemiluminescence detection system according to Manufacturer's instructions.
All results were subjected to statistical analysis using one-way ANOVA and, whenever appropriate, analyzed by Student-Newman-Keuls test. Data are expressed as means ± S.D. of triplicate samples from at least three independent experiments and level of significance was taken to P < 0.05.
Schistosoma mansoni eggs sensitization and challenge increases LPA levels in BAL fluids
Quatification of LPA molecular species in BAL fluids
LPA molecular species
Wt sensitization only (pmol/ml)
Wt sensitization and SEA challenged (pmol/ml)
5.6 ± 3.1
14.6 ± 1.2
50.4 ± 37.0
160.9 ± 3.7
88.4 ± 51.7
253.6 ± 10.8
83.9 ± 54.6
274.4 ± 7.0
154.3 ± 114.7
517.6 ± 17.9
54.9 ± 27.4
153.7 ± 8.0
26.7 ± 22.0
95.7 ± 1.9
212.9 ± 168.2
739.0 ± 23.1
51.7 ± 39.8
165.2 ± 5.5
4.7 ± 3.4
14.1 ± 0.8
189.4 ± 114.4
548.9 ± 18.1
291.6 ± 166.2
576.9 ± 22.2
16.8 ± 9.5
41.1 ± 1.5
0.7 ± 0.6
1.9 ± 0.5
0.2 ± 0.1
0.2 ± 0.1
1254.3 ± 357.0
3557.9 ± 109.3
Schistosoma mansoni eggs sensitization and challenge-induced airway inflammation is dependent on LPA1 and LPA2
LPA2 +/-, but not LPA1 +/-, mice exhibit reduced LPA and PGE2 levels in BAL fluids, and COX-2 expression in lungs of Schistosoma mansoni eggs sensitized/challenged mice
LPA2 deficiency on airway epithelial cells leads to reduced LPA mediated COX-2 expression and PGE2 release
LPA receptors mRNA expression in lung tissue
Normalized to 18S
49.5 ± 23.5
235.0 ± 15.5
46.0 ± 21.2
73.5 ± 6.7
In the present study, we present several novel findings regarding LPA receptors expression, and its role in infiltration of eosinophils and lung inflammation in Schistosoma mansoni eggs sensitized and challenged murine model of asthma. We provide direct evidence for increased LPA levels in BAL fluids from Schistosoma mansoni eggs sensitized and challenged mice compared to control mice and a direct link between LPA2expression and lung inflammation mediated by Schistosoma mansoni eggs sensitization and challenge. The pro-inflammatory role of LPA2 is also evident from reduced PGE2 levels in BAL fluids and COX-2 expression in lung tissues of LPA2 +/- mice sensitized and challenged with Schistosoma mansoni eggs compared to controls. We also demonstrate that airway epithelial cells isolated from LPA2 +/- mice, compared to cells from wild type mice, exhibited reduced COX-2 expression and PGE2 release in response to LPA. To the best of our knowledge, this is the first report demonstrating a functional link between LPA, LPA2 and lung inflammation in a murine model of asthma.
Asthma is a Th2-type immune disease of the lung that is characterized by chronic inflammation, infiltration of inflammatory cells, reversible obstruction of airway hyperresponsiveness, mucus hypersecretion by goblet cells and remodeling of the bronchoalveolar structures. Th1 and Th2 cytokines play a key role in orchestrating inflammatory and structural changes of the airway in asthma by recruiting, activating and promoting inflammatory cells into the airway [38–40]. In addition to cytokines, lipid mediators such as prostaglandins, leukotrienes, platelet-activating factor, and lysophospholipids regulate immune and inflammatory responses in asthma [41–43]. Many of these lipid mediators exert their biological responses via GPCRs. Increasing sphingosine-1-phosphate (S1P) levels in circulation offers protection against lung injury in mice and S1P-receptor 1 (S1P1) heterozygous mice showed enhanced inflammation after LPS challenge suggesting an anti-inflammatory role of S1P1 . The present study demonstrates the role of LPA and LPA2, a GPCR, in the pathogenesis of allergic airway inflammation in Schistosoma mansoni eggs sensitized and challenged murine model of asthma. LPA1 -/- mice generated from LPA1 +/- colonies, as compared to LPA2 -/- from LPA2 +/-, showed 50% neonatal lethality and impaired suckling, and therefore, we decided to use LPA1 +/- and LPA2 +/- mice to investigate role of LPA receptors in airway inflammation. Although LPA1 +/- and LPA2 +/- mice exhibited less neutrophils infiltration, compared to wild type mice, after LPA challenge (Fig. 2), influx of eosinophils was lower in LPA2 +/-, but not in LPA1 +/- mice after Schistosoma mansoni eggs sensitization and challenge (Fig. 3B). Both LPA1 +/- and LPA2 +/- mice showed reduced PAS positive cells in the bronchus compared to wild type after Schistosoma mansoni eggs sensitization and challenge (Fig. 4) suggesting the potential involvement of LPA1 and LPA2 in activation of goblet cells. These results indicate that activation of goblet cells are dependent on LPA1 and LPA2, however, only LPA2 is involved in chemotaxis of eosinophils into alveolar space after Schistosoma mansoni eggs sensitization and challenge. Our current results on infiltration of eosinophils in Schistosoma mansoni eggs sensitized and challenged murine model of asthma are in good agreement with increased numbers of eosiophils, a characteristic feature of human bronchial asthma, in biopsies of human lung tissues [40, 45]. LPA is constitutively present in human BAL fluids and increased following allergic inflammation  and in patients with pulmonary fibrosis . Intratracheal administration of LPA increased eosinophil influx in guinea pigs  and treatment of human eosinophils with LPA induced calcium mobilization, actin reorganization, and chemotaxis through Gαi-dependent LPA receptors . In the present study, we found that LPA levels were increased by ~3 fold following Schistosoma mansoni eggs sensitization and challenge of wild type, which supports the notion of LPA as a chemotaxis factor of inflammatory cells in allergic inflammation.
The source of LPA accumulation and mechanism(s) of LPA generation in the lung after allergic inflammation is unclear. Our previous studies have demonstrated that acyl glycerol kinase (AGK) converts monoacylglycerol to LPA in human bronchial epithelial cells . Further, phospholipase D (PLD) can also contribute to intracellular LPA generation by providing phosphatidic acid, a substrate for PA specific phospholipase A2 [48, 49]. Interestingly, we observed that LPA levels in LPA2 +/- mice were significantly lower compared to wild type mice after Schistosoma mansoni eggs sensitization and challenge suggesting involvement of LPA2 and potentially other LPA receptors in regulation of LPA generation in the airway. The relative contributions of AGK and/or PLD pathways in LPA generation in response to Schistosoma mansoni eggs sensitization and challenge are unknown Additionally, extracellular LPA can be generated by lysoPLD (autotaxin), which converts lysophosphatidylcholine (LPC) to LPA . Not only LPC levels were increased in BAL fluids of segmental allergen challenged patients , there was an increase in lysoPLD expression in LPS-stimulated monocytes , and stimulation of lysoPLD activity in asthmatic patients . Thus, increase in LPC levels and lysoPLD expression and activity may be involved in enhanced LPA generation during lung inflammation. Further studies are needed to establish the potential source(s) of LPA in BAL fluids and mechanism(s) of LPA generation during allergic lung inflammation.
In contrast to LPA, there are only a few reports that describe the role of LPA receptors in lung inflammation, injury and remodeling. Deletion of LPA1 reduced fibroblast recruitment and vascular leak in the bleomycin model of pulmonary fibrosis  while LPA/LPA2 signaling via αvβ6 integrin-mediated activation of TGF-β has been implicated in the development of bleomycin-induced lung fibrosis in mice . Down-regulation of LPA2 by siRNA attenuated LPA-induced phosphorylation of p38 MAPK/JNK, and IL-8 secretion in human bronchial epithelial cells . Interestingly, Schistosoma mansoni eggs sensitization and challenge induced COX-2 expression and PGE2 was significantly attenuated in LPA2 +/-, but not LPA1 +/-, mice suggesting a potential link between reduced LPA2 expression and COX2/PGE2 levels. In accordance with our in vivo results on Schistosoma mansoni eggs mediated COX-2 expression and PGE2 release in mouse lungs, tracheal epithelial cells from LPA2 +/- mice exhibited decreased COX-2 expression and PGE2 release in response to LPA as compared to cells from wild type mice. Further, our results with LPA2 +/- mice suggest a role for LPA2 in the influx of eosinophils and lung inflammation induced by Schistosoma mansoni eggs sensitization and challenge suggest a role for LPA signaling via LPA2 in pro-inflammatory responses.
The present study demonstrates increased LPA levels in BAL fluids in a murine model of asthma and LPA2 heterozygous knockout mice show reduced Th-2 dominant airway inflammatory responses. These results suggest that endogenous LPA and LPA2 play a critical role in pathogenesis of airway inflammatory diseases. Therapeutic targeting of LPA2 may be beneficial in reducing allergic inflammatory responses in airway diseases.
The work was supported by National Institutes of Health grant HL091916 (to Y.Z.), HL71152 and HL79396 (to V.N.), MH51699 (to J.C.), and AI50180 (to A.I.S.)
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