Serum Lysophosphatidic Acid Measurement by Liquid Chromatography–Mass Spectrometry in COPD Patients

Li, Qingling; Wong, Weng Ruh; Chakrabarti, Arindam; Birnberg, Andrew; Yang, Xiaoying; Verschueren, Erik; Neighbors, Margaret; Rosenberger, Carrie M.; Grimbaldeston, Michele A.; Tew, Gaik W.; Sandoval, Wendy

doi:10.1021/jasms.0c00429

Cited by 6 publications

(6 citation statements)

References 45 publications

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“…LPA levels were not significantly associated with other baseline clinical variables in this study. Previously we reported that the majority of the LPA species, except LPA20:4, are higher in a small cohort of COPD patients compared to healthy controls [26]. It is unclear if COPD patients with low levels of LPA16 and LPA18 species in this study have significantly higher levels of these LPAs relative to healthy individuals, as samples from age-and sex-matched healthy subjects were not tested together with the COPD samples in the current study.…”

Section: Discussionmentioning

confidence: 73%

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Lysophosphatidic acid species are associated with exacerbation in chronic obstructive pulmonary disease

Li¹,

Wong²,

Birnberg³

et al. 2021

BMC Pulm Med

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Background Chronic obstructive pulmonary disease (COPD) exacerbations are heterogenous and profoundly impact the disease trajectory. Bioactive lipid lysophosphatidic acid (LPA) has been implicated in airway inflammation but the significance of LPA in COPD exacerbation is not known. The aim of the study was to investigate the utility of serum LPA species (LPA16:0, 18:0, 18:1, 18:2, 20:4) as biomarkers of COPD exacerbation. Patients and methods LPA species were measured in the baseline placebo sera of a COPD randomized controlled trial. Tertile levels of each LPA were used to assign patients into biomarker high, medium, and low subgroups. Exacerbation rate and risk were compared among the LPA subgroups. Results The levels of LPA species were intercorrelated (rho 0.29–0.91). Patients with low and medium levels of LPA (LPA16:0, 20:4) had significantly higher exacerbation rate compared to the respective LPA-high patients [estimated rate per patient per year (95% CI)]: LPA16:0-low = 1.2 (0.8–1.9) (p = 0.019), LPA16:0-medium = 1.3 (0.8–2.0) (p = 0.013), LPA16:0-high = 0.5 (0.2–0.9); LPA20:4-low = 1.4 (0.9–2.1) (p = 0.0033), LPA20:4-medium = 1.2 (0.8–1.8) (p = 0.0089), LPA20:4-high = 0.4 (0.2–0.8). These patients also had earlier time to first exacerbation (hazard ratio (95% CI): LPA16:0-low = 2.6 (1.1–6.0) (p = 0.028), LPA16:0-medium = 2.7 (1.2–6.3) (p = 0.020); LPA20.4-low = 2.8 (1.2–6.6) (p = 0.017), LPA20:4-medium = 2.7 (1.2–6.4) (p = 0.021). Accordingly, these patients had a significant increased exacerbation risk compared to the respective LPA-high subgroups [odd ratio (95% CI)]: LPA16:0-low = 3.1 (1.1–8.8) (p = 0.030), LPA16:0-medium = 3.0 (1.1–8.3) (p = 0.031); LPA20:4-low = 3.8 (1.3–10.9) (p = 0.012), LPA20:4-medium = 3.3 (1.2–9.5) (p = 0.025). For the other LPA species (LPA18:0, 18:1, 18:2), the results were mixed; patients with low and medium levels of LPA18:0 and 18:2 had increased exacerbation rate, but only LPA18:0-low patients had significant increase in exacerbation risk and earlier time to first exacerbation compared to the LPA18:0-high subgroup. Conclusions The study provided evidence of association between systemic LPA levels and exacerbation in COPD. Patients with low and medium levels of specific LPA species (LPA16:0, 20:4) had increased exacerbation rate, risk, and earlier time to first exacerbation. These non-invasive biomarkers may aid in identifying high risk patients with dysregulated LPA pathway to inform risk management and drug development.

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Section: Discussionmentioning

confidence: 73%

“…LPA species were extracted using acidified butanol solvent as previously described [26]. Briefly, 10 µl of serum from each sample was pooled together as quality control samples.…”

Section: Mass Spectrometry Lpa Assaysmentioning

confidence: 99%

Lysophosphatidic acid species are associated with exacerbation in chronic obstructive pulmonary disease

Li¹,

Wong²,

Birnberg³

et al. 2021

BMC Pulm Med

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“…3 E) 6 , 17 . To confirm the release of LPA from these macrophages, macrophage-conditioned media was taken 30 min or 48 h after plating and various LPA species were measured by mass spectrometry 18 . We observed a significant increase in several LPA species over time.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis

Poon,

Lorrain,

Stebbins

et al. 2024

Sci Rep

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Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood–brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.

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“…By using 5% FBS in our culture media, these PLs were also introduced, but probably in much lower amounts than those added separately, although there seems to be no data available in the literature on FBS. Based on data from human serum or plasma, our serum-reduced culture medium contained the equivalent concentrations (nmol/mL) for LPC 16:0, LPC 18:0, LPC 18:1, LPA 16:0, and LPA 18:0 of approximately 3.6, 1.4, 0.9, 0.004, and 0.001 [ 41 , 42 ]. Whether the low PL concentrations added to the culture medium via 5% FBS already have an effect on FLS remains to be determined in further studies.…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Lysophospholipids by Proteomic and Lipidomic Analysis of Fibroblast-like Synoviocytes

Hild

Liebisch

Rickert

et al. 2023

Cells

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Synovial fluid (SF) from human knee joints with osteoarthritis (OA) has elevated levels of lysophosphatidylcholine (LPC) species, but their functional role is not well understood. This in vitro study was designed to test the hypothesis that various LPCs found elevated in OA SF and their metabolites, lysophosphatidic acids (LPAs), modulate the abundance of proteins and phospholipids (PLs) in human fibroblast-like synoviocytes (FLSs), with even minute chemical variations in lysophospholipids determining the extent of regulation. Cultured FLSs (n = 5–7) were treated with one of the LPC species, LPA species, IL-1β, or a vehicle. Tandem mass tag peptide labeling coupled with LC-MS/MS/MS was performed to quantify proteins. The expression of mRNA from regulated proteins was analyzed using RT-PCR. PL synthesis was determined via ESI-MS/MS, and the release of radiolabeled PLs was determined by means of liquid scintillation counting. In total, 3960 proteins were quantified using multiplexed MS, of which 119, 8, and 3 were significantly and reproducibly regulated by IL-1β, LPC 16:0, and LPC 18:0, respectively. LPC 16:0 significantly inhibited the release of PLs and the synthesis of phosphatidylcholine, LPC, and sphingomyelin. Neither LPC metabolite—LPA 16:0 nor LPA 18:0—had any reproducible effect on the levels of each protein. In conclusion, small chemical variations in LPC species can result in the significantly altered expression and secretion of proteins and PLs from FLSs. IL-1β influenced all proteins that were reproducibly regulated by LPC 16:0. LPC species are likely to modulate FLS protein expression only in more advanced OA stages with low IL-1β levels. None of the eight proteins being significantly regulated by LPC 16:0 have been previously reported in OA. However, our in vitro findings show that the CD81 antigen, calumenin, and B4E2C1 are promising candidates for further study, focusing in particular on their potential ability to modulate inflammatory and catabolic mechanisms.

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Serum Lysophosphatidic Acid Measurement by Liquid Chromatography–Mass Spectrometry in COPD Patients

Cited by 6 publications

References 45 publications

Lysophosphatidic acid species are associated with exacerbation in chronic obstructive pulmonary disease

Lysophosphatidic acid species are associated with exacerbation in chronic obstructive pulmonary disease

Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis

Functional Characterization of Lysophospholipids by Proteomic and Lipidomic Analysis of Fibroblast-like Synoviocytes

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