Autotaxin in Pathophysiology and Pulmonary Fibrosis
Lysophospholipid signaling is emerging as a druggable regulator of pathophysiological responses, and especially fibrosis, exemplified by the relative ongoing clinical trials in idiopathic pulmonary fibrosis (IPF) patients. In this review, we focus on ectonucleotide pyrophosphatase-phosphodiesterase...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-06-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmed.2018.00180/full |
| _version_ | 1818554299343437824 |
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| author | Ioanna Ninou Christiana Magkrioti Vassilis Aidinis |
| author_facet | Ioanna Ninou Christiana Magkrioti Vassilis Aidinis |
| author_sort | Ioanna Ninou |
| collection | DOAJ |
| description | Lysophospholipid signaling is emerging as a druggable regulator of pathophysiological responses, and especially fibrosis, exemplified by the relative ongoing clinical trials in idiopathic pulmonary fibrosis (IPF) patients. In this review, we focus on ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2), or as more widely known Autotaxin (ATX), a secreted lysophospholipase D (lysoPLD) largely responsible for extracellular lysophosphatidic acid (LPA) production. In turn, LPA is a bioactive phospholipid autacoid, forming locally upon increased ATX levels and acting also locally through its receptors, likely guided by ATX's structural conformation and cell surface associations. Increased ATX activity levels have been detected in many inflammatory and fibroproliferative conditions, while genetic and pharmacologic studies have confirmed a pleiotropic participation of ATX/LPA in different processes and disorders. In pulmonary fibrosis, ATX levels rise in the broncheoalveolar fluid (BALF) and stimulate LPA production. LPA engagement of its receptors activate multiple G-protein mediated signal transduction pathways leading to different responses from pulmonary cells including the production of pro-inflammatory signals from stressed epithelial cells, the modulation of endothelial physiology, the activation of TGF signaling and the stimulation of fibroblast accumulation. Genetic or pharmacologic targeting of the ATX/LPA axis attenuated disease development in animal models, thus providing the proof of principle for therapeutic interventions. |
| first_indexed | 2024-12-12T09:37:32Z |
| format | Article |
| id | doaj.art-169a8c8ffba84a04bca55f480ad23231 |
| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-12-12T09:37:32Z |
| publishDate | 2018-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Medicine |
| spelling | doaj.art-169a8c8ffba84a04bca55f480ad232312022-12-22T00:28:40ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2018-06-01510.3389/fmed.2018.00180358630Autotaxin in Pathophysiology and Pulmonary FibrosisIoanna NinouChristiana MagkriotiVassilis AidinisLysophospholipid signaling is emerging as a druggable regulator of pathophysiological responses, and especially fibrosis, exemplified by the relative ongoing clinical trials in idiopathic pulmonary fibrosis (IPF) patients. In this review, we focus on ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2), or as more widely known Autotaxin (ATX), a secreted lysophospholipase D (lysoPLD) largely responsible for extracellular lysophosphatidic acid (LPA) production. In turn, LPA is a bioactive phospholipid autacoid, forming locally upon increased ATX levels and acting also locally through its receptors, likely guided by ATX's structural conformation and cell surface associations. Increased ATX activity levels have been detected in many inflammatory and fibroproliferative conditions, while genetic and pharmacologic studies have confirmed a pleiotropic participation of ATX/LPA in different processes and disorders. In pulmonary fibrosis, ATX levels rise in the broncheoalveolar fluid (BALF) and stimulate LPA production. LPA engagement of its receptors activate multiple G-protein mediated signal transduction pathways leading to different responses from pulmonary cells including the production of pro-inflammatory signals from stressed epithelial cells, the modulation of endothelial physiology, the activation of TGF signaling and the stimulation of fibroblast accumulation. Genetic or pharmacologic targeting of the ATX/LPA axis attenuated disease development in animal models, thus providing the proof of principle for therapeutic interventions.https://www.frontiersin.org/article/10.3389/fmed.2018.00180/fullautotaxin (ATX)lysophosphatidic acid (LPA)lysophosphatidic acid receptor (LPAR)g-proteinspulmonary fibrosis |
| spellingShingle | Ioanna Ninou Christiana Magkrioti Vassilis Aidinis Autotaxin in Pathophysiology and Pulmonary Fibrosis Frontiers in Medicine autotaxin (ATX) lysophosphatidic acid (LPA) lysophosphatidic acid receptor (LPAR) g-proteins pulmonary fibrosis |
| title | Autotaxin in Pathophysiology and Pulmonary Fibrosis |
| title_full | Autotaxin in Pathophysiology and Pulmonary Fibrosis |
| title_fullStr | Autotaxin in Pathophysiology and Pulmonary Fibrosis |
| title_full_unstemmed | Autotaxin in Pathophysiology and Pulmonary Fibrosis |
| title_short | Autotaxin in Pathophysiology and Pulmonary Fibrosis |
| title_sort | autotaxin in pathophysiology and pulmonary fibrosis |
| topic | autotaxin (ATX) lysophosphatidic acid (LPA) lysophosphatidic acid receptor (LPAR) g-proteins pulmonary fibrosis |
| url | https://www.frontiersin.org/article/10.3389/fmed.2018.00180/full |
| work_keys_str_mv | AT ioannaninou autotaxininpathophysiologyandpulmonaryfibrosis AT christianamagkrioti autotaxininpathophysiologyandpulmonaryfibrosis AT vassilisaidinis autotaxininpathophysiologyandpulmonaryfibrosis |