Importance of group X–secreted phospholipase A2 in allergen-induced airway inflammation and remodeling in a mouse asthma model

Henderson, William R.; Emil, Y.; Bollinger, James G.; Tien, Ying Tzang; Ye, Xin; Castelli, Luca; Rubtsov, Yuri P.; Singer, Alan G.; Chiang, Gertrude K S; Nevalainen, Timo J.; Rudensky, Alexander Y.; Gelb, Michael H.

doi:10.1084/jem.20070029

Cited by 174 publications

(232 citation statements)

References 59 publications

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“…blinded to the protocol design using the grading system described by Ashcroft et al (25). The sections were stained with H&E to determine inflammatory cell infiltration on a semiquantitative scale ranging from 0 to 4 (44). Lung sections from BAT-gal transgenic mice underwent X-gal staining (23).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Henderson

Emil

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a ravaging condition of progressive lung scarring and destruction. Anti-inflammatory therapies including corticosteroids have limited efficacy in this ultimately fatal disorder. An important unmet need is to identify new agents that interact with key molecular pathways involved in the pathogenesis of pulmonary fibrosis to prevent progression or reverse fibrosis in these patients. Because aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with IPF, we have targeted this pathway for intervention in pulmonary fibrosis using ICG-001, a small molecule that specifically inhibits T-cell factor/β-catenin transcription in a cyclic AMP response-element binding protein binding protein (CBP)-dependent fashion. ICG-001 selectively blocks the β-catenin/CBP interaction without interfering with the β-catenin/p300 interaction. We report here that ICG-001 (5 mg/kg per day) significantly inhibits β-catenin signaling and attenuates bleomycin-induced lung fibrosis in mice, while concurrently preserving the epithelium. Administration of ICG-001 concurrent with bleomycin prevents fibrosis, and late administration is able to reverse established fibrosis and significantly improve survival. Because no effective treatment for IPF exists, selective inhibition of Wnt/β-catenin-dependent transcription suggests a potential unique therapeutic approach for pulmonary fibrosis.

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Section: Methodsmentioning

confidence: 99%

Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Henderson

Emil

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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412

322

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“…These eicosanoids are 5-lipoxygenase and cyclooxygenase metabolites of arachidonic acids, and the cellular availability of arachidonic acid is tightly controlled by hydrolysis of membrane phospholipids via the catalytic activity of phospholipases A 2 (PLA 2 ) (5-10). Previous animal and human studies showed that PLA 2 is involved in the genesis of airway inflammation through proinflammatory eicosanoids (11)(12)(13)(14)(15).…”

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confidence: 99%

Deficiency of Phospholipase A2 Receptor Exacerbates Ovalbumin-Induced Lung Inflammation

Tamaru

Mishina

Watanabe

et al. 2013

The Journal of Immunology

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Secretory phospholipase A2 (sPLA2) plays a critical role in the genesis of lung inflammation through proinflammatory eicosanoids. A previous in vitro experiment showed a possible role of cell surface receptor for sPLA2 (PLA2R) in the clearance of extracellular sPLA2. PLA2R and groups IB and X sPLA2 are expressed in the lung. This study examined a pathogenic role of PLA2R in airway inflammation using PLA2R-deficient (PLA2R−/−) mice. Airway inflammation was induced by immunosensitization with OVA. Compared with wild-type (PLA2R+/+) mice, PLA2R−/− mice had a significantly greater infiltration of inflammatory cells around the airways, higher levels of groups IB and X sPLA2, eicosanoids, and Th2 cytokines, and higher numbers of eosinophils and neutrophils in bronchoalveolar lavage fluid after OVA treatment. In PLA2R−/− mice, intratracheally instilled [125I]-labeled sPLA2-IB was cleared much more slowly from bronchoalveolar lavage fluid compared with PLA2R+/+ mice. The degradation of the instilled [125I]-labeled sPLA2-IB, as assessed by trichloroacetic acid-soluble radioactivity in bronchoalveolar lavage fluid after instillation, was lower in PLA2R−/− mice than in PLA2R+/+ mice. In conclusion, PLA2R deficiency increased sPLA2-IB and -X levels in the lung through their impaired clearance from the lung, leading to exaggeration of lung inflammation induced by OVA treatment in a murine model.

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“…When added to intact cells, the mature enzyme effectively hydrolyzes plasma membranes to generate free fatty acids and lysophospholipids, most notably arachidonic acid (AA) and lysophosphatidylcholine (LPC). Based on its ability to generate bioactive lipid mediators, GX sPLA 2 has been implicated in diverse biological functions, including prostaglandin-mediated inflammatory responses in airway epithelial cells, mast cells, and macrophages, and LPC-induced neurite outgrowth and melanocyte pigmentation (5)(6)(7)(8). GX sPLA 2 hydrolyzes phospholipids on lipoproteins, and evidence suggests that hydrolysis of low density lipoprotein by GX sPLA 2 results in a modified particle that induces lipid accumulation in human monocyte-derived macrophages (9,10).…”

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confidence: 99%

Group X Secretory Phospholipase A2 Regulates the Expression of Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenal Glands

Shridas

Bailey

Boyanovsky

et al. 2010

Journal of Biological Chemistry

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We developed C57BL/6 mice with targeted deletion of group X secretory phospholipase A 2 (GX KO). These mice have ϳ80% higher plasma corticosterone concentrations compared with wild-type (WT) mice under both basal and adrenocorticotropic hormone (ACTH)-induced stress conditions. This increased corticosterone level was not associated with increased circulating ACTH or a defect in the hypothalamic-pituitary axis as evidenced by a normal response to dexamethasone challenge. Primary cultures of adrenal cells from GX KO mice exhibited significantly increased corticosteroid secretion compared with WT cells. Conversely, overexpression of GX secretory phospholipase A 2 (sPLA 2 ), but not a catalytically inactive mutant form of GX sPLA 2 , significantly reduced steroid production 30 -40% in Y1 mouse adrenal cell line. This effect was reversed by the sPLA 2 inhibitor, indoxam. Silencing of endogenous M-type receptor expression did not restore steroid production in GX sPLA 2 -overexpressing Y1 cells, ruling out a role for this sPLA 2 receptor in this regulatory process. Expression of steroidogenic acute regulatory protein (StAR), the rate-limiting protein in corticosteroid production, was ϳ2-fold higher in adrenal glands of GX KO mice compared with WT mice, whereas StAR expression was suppressed in Y1 cells overexpressing GX sPLA 2 . Results from StAR-promoter luciferase reporter gene assays indicated that GX sPLA 2 antagonizes StAR promoter activity and liver X receptor-mediated StAR promoter activation. In summary, GX sPLA 2 is expressed in mouse adrenal glands and functions to negatively regulate corticosteroid synthesis, most likely by negatively regulating StAR expression.

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Importance of group X–secreted phospholipase A2 in allergen-induced airway inflammation and remodeling in a mouse asthma model

Cited by 174 publications

References 59 publications

Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Deficiency of Phospholipase A2 Receptor Exacerbates Ovalbumin-Induced Lung Inflammation

Group X Secretory Phospholipase A2 Regulates the Expression of Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenal Glands

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