Combined activities of secretory phospholipases and eosinophil lysophospholipases induce pulmonary surfactant dysfunction by phospholipid hydrolysis

Kwatia, Mark A.; Doyle, Christine B.; Cho, Wonwha; Enhörning, Göran; Ackerman, Steven J.

doi:10.1016/j.jaci.2006.12.614

Cited by 13 publications

(13 citation statements)

References 45 publications

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“…Eosinophils also have endogenous sPLA 2 activity that contributes to surfactant dysfunction through the cleavage of surfactant phospholipids (15,16). The gene expression of sPLA 2 group IIA (sPLA 2 -IIA, PLA2G2A ) and sPLA 2 -X ( PLA2G10 ) were previously identified in human eosinophils (16).…”

Section: Introductionmentioning

confidence: 99%

Endogenous secreted phospholipase A 2 group X regulates cysteinyl leukotrienes synthesis by human eosinophils

Hallstrand

Lü

Hooper

et al. 2016

Journal of Allergy and Clinical Immunology

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Background Phospholipase A2s mediate the rate-limiting step in the formation of eicosanoids such as cysteinyl leukotrienes (CysLT). Group IVA cytosolic PLA2 (cPLA2α) is thought to be the dominant PLA2 in eosinophils; however, eosinophils also have secreted PLA2 (sPLA2) activity that has not been fully defined. Objectives To examine the expression of sPLA2 group X (sPLA2-X) in eosinophils, the participation of sPLA2-X in CysLT formation, and the mechanism by which sPLA2-X initiates CysLT synthesis in eosinophils. Methods Peripheral blood eosinophils were obtained from volunteers with asthma and/or allergy. A rabbit polyclonal anti-sPLA2-X antibody identified sPLA2-X by western blot. We used confocal microscopy to co-localize the sPLA2-X to intracellular structures. An inhibitor of sPLA2-X (ROC-0929) that does not inhibit other mammalian sPLA2s, as well as inhibitors of the mitogen activated kinase cascade (MAPK) and cPLA2α were used to examine the mechanism of N-formyl-methionyl-leucyl-phenylalanine (fMLP)-mediated CysLT formation. Results Eosinophils express the sPLA2-X gene (PLA2G10). The sPLA2-X protein is located in the endoplasmic reticulum (ER), golgi, and granules of eosinophils and moves to the granules and lipid bodies during fMLP-mediated activation. Selective sPLA2-X inhibition attenuated the fMLP-mediated release of arachidonic acid and CysLT formation by eosinophils. Inhibitors of p38, ERK1/2, JNK and cPLA2α also attenuated the fMLP-mediated CysLT formation. The sPLA2-X inhibitor reduced the phosphorylation of p38 and ERK1/2 as well as cPLA2α during cellular activation, indicating that sPLA2-X is involved in activating the MAPK cascade leading to CysLT formation via cPLA2α. We further demonstrate that sPLA2-X is activated prior to secretion from the cell during activation. Short-term priming with IL-13 and TNF/IL-1β increased the expression of PLA2G10 by eosinophils. Conclusions These results demonstrate that sPLA2-X plays a significant role in CysLTs formation by human eosinophils. The predominant role of the enzyme is the regulation of MAPK activation that leads to phosphorylation of cPLA2α. The sPLA2-X protein is regulated by proteolytic cleavage suggesting that an inflammatory environment may promote the formation of CysLTs through this mechanism. These results have important implications for the treatment of eosinophilic disorders such as asthma.

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Section: Introductionmentioning

confidence: 99%

Endogenous secreted phospholipase A 2 group X regulates cysteinyl leukotrienes synthesis by human eosinophils

Hallstrand

Lü

Hooper

et al. 2016

Journal of Allergy and Clinical Immunology

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“…Patients with atherosclerotic diseases (73) and sepsis (74) were found to have lower levels of plasma lysoPCs. LysoPCs are metabolites transiently generated by phospholipase A2 (PLA2) during the remodeling of glycerophospholipids (75, 76), and can be further hydrolyzed to glycerophosphocholine by lysophospholipase (77). From our pathway analysis, phospholipase A2 (PLA2) was involved in the major network affected (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that PLA2 modulated the activity of menthol receptor TRPM8 and lysophospholipids altered the sensitivity of TRPM8 (78, 79). Up-regulation of lysophospholipase and decreased levels of lysoPCs have been shown upon cigarette smoke exposure in mouse model (80) and among current smokers (59), and combined activities of secreted PLA2s and eosinophil lysophospholipases were also found to cause pulmonary surfactant dysfunction (77). Consistent with our metabolomics profiling, the results from transcriptomics data of smokers in our group also showed that PLA2G15 which codes for lysophospholipase III for the hydrolysis of glycerophospholipids was among the genes found significantly up-regulated on lymphocytes of smokers treated with cigarette smoke condensate (81).…”

Section: Discussionmentioning

confidence: 99%

Menthol Smokers: Metabolomic Profiling and Smoking Behavior

Hsu

Lan

Brasky

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background The use of menthol in cigarettes and marketing is under consideration for regulation by the FDA. However, the effects of menthol on smoking behavior and carcinogen exposure have been inconclusive. We previously reported metabolomic profiling for cigarette smokers, and novelly identified a menthol-glucuronide (MG) as the most significant metabolite directly related to smoking. Here, MG is studied in relation to smoking behavior and metabolomic profiles. Methods A cross-sectional study of 105 smokers who smoked two cigarettes in the laboratory one hour apart. Blood nicotine, MG and exhaled carbon monoxide (CO) boosts were determined (the difference before and after smoking). Spearman's correlation, Chi-Square and ANCOVA adjusted for gender, race and cotinine levels for menthol smokers assessed the relationship of MG boost, smoking behavior, and metabolic profiles. Multivariate metabolite characterization using supervised Partial Least Squares-Discriminant Analysis (PLS-DA) was carried out for the classification of metabolomics profiles. Results MG boost was positively correlated with CO boost, nicotine boost, average puff volume, puff duration, and total smoke exposure. Classification using PLS-DA, MG was the top metabolite discriminating metabolome of menthol vs. non-menthol smokers. Among menthol smokers, forty-two metabolites were significantly correlated with MG boost, which linked to cellular functions such as of cell death, survival, and movement. Conclusion Plasma MG boost is a new smoking behavior biomarker that may provides novel information over self-reported use of menthol cigarettes by integrating different smoking measures for understanding smoking behavior and harm of menthol cigarettes. Impacts These results provide insight into the biological effect of menthol smoking.

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“…Additional studies of eosinophils by Kwatia et al 30 demonstrated that eosinophils might contribute to surfactant dysfunction in asthma mediated through the combined activity of secretory phospholipase A 2 and eosinophil lysophospholipases, whereas Munitz and Levi-Schaffer 31 reviewed the role of inhibitory receptors expressed by eosinophils.…”

Section: Eosinophilsmentioning

confidence: 99%

New perspectives on mechanisms underlying chronic allergic inflammation and asthma in 2007

Broide

2008

Journal of Allergy and Clinical Immunology

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Combined activities of secretory phospholipases and eosinophil lysophospholipases induce pulmonary surfactant dysfunction by phospholipid hydrolysis

Cited by 13 publications

References 45 publications

Endogenous secreted phospholipase A 2 group X regulates cysteinyl leukotrienes synthesis by human eosinophils

Endogenous secreted phospholipase A 2 group X regulates cysteinyl leukotrienes synthesis by human eosinophils

Menthol Smokers: Metabolomic Profiling and Smoking Behavior

New perspectives on mechanisms underlying chronic allergic inflammation and asthma in 2007

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