The Lysophosphatidic Acid Receptor LPA<sub>1</sub> Promotes Epithelial Cell Apoptosis after Lung Injury

Funke, Manuela; Zhao, Zhenwen; Xu, Yan; Chun, Jerold; Tager, Andrew M.

doi:10.1165/rcmb.2010-0155oc

Cited by 119 publications

(106 citation statements)

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“…Fibrosis and acute lung injury were induced by a single intratracheal injection of bleomycin (Fresenius Kabi, Lake Zurich, IL) or 4 mg/kg LPS (Escherichia coli 026:B6; Sigma, St. Louis, MO), respectively, to anesthetized 6-to 8-week-old male C57Bl/6 mice (NCI-Frederick, Frederick, MD), as previously described (12)(13)(14)(15)(16). All animal protocols were approved by the Massachusetts General Hospital Subcommittee on Research Animal Care (Massachusetts General Hospital, Boston, MA), and all mice were maintained in a specific pathogen-free environment certified by the American Association for Accreditation of Laboratory Animal Care.…”

Section: Bleomycin and Lps Mouse Modelsmentioning

confidence: 99%

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Ahluwalia

Grasberger

Mugo

et al. 2016

Am J Respir Cell Mol Biol

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Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-b, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.Keywords: idiopathic pulmonary fibrosis; pathogenesis; fibroblast; invasion; migration Idiopathic pulmonary fibrosis (IPF) is a disease of great unmet medical need. Aberrant or overexuberant wound healing responses to chronic lung injury are now thought to be responsible for the excessive fibroblast accumulation and extracellular matrix deposition that distort the lung's architecture and compromise its function in IPF (1, 2). Better characterization of these abnormal responses to lung injury should provide a rich set of therapeutic targets for novel IPF therapies.The abnormal accumulation of fibroblasts is a central hallmark of fibrotic tissues, including the lung in IPF. In addition to fibroblast proliferation, fibroblast accumulation in pulmonary fibrosis appears to fundamentally depend on: (1) the migration of these cells to sites of tissue injury; and (2) their ability to invade extracellular matrix. Although migration

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Section: Bleomycin and Lps Mouse Modelsmentioning

confidence: 99%

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Ahluwalia

Grasberger

Mugo

et al. 2016

Am J Respir Cell Mol Biol

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“…An intratracheal administration of bleomycin induces the rapid apoptosis of bronchial and alveolar epithelial cells (20). To determine whether LPA 2 deficiency also suppressed epithelial cell apoptosis during pulmonary fibrogenesis, we compared the amounts of bleomycin-induced alveolar and bronchial epithelial cell apoptosis in WT and Lpar2 2/2 mouse lung parenchyma.…”

Section: Bleomycin-induced Lung Epithelium Apoptosis Is Decreased In mentioning

confidence: 99%

“…Lipid profiling indicates that LPA levels were dramatically higher in bronchoalveolar lavage (BAL) fluid collected from patients with IPF, compared with their normal counterparts (16). In the bleomycin-induced pulmonary fibrosis model, LPA 1 deficiency conferred significant protection against bleomycin-induced fibrosis and mortality (16,20). Furthermore, LPA-induced fibroblast recruitment, vascular leakage, and epithelial cell apoptosis were also markedly reduced in Lpar1 2/2 mice (16,20).…”

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confidence: 99%

“…In the bleomycin-induced pulmonary fibrosis model, LPA 1 deficiency conferred significant protection against bleomycin-induced fibrosis and mortality (16,20). Furthermore, LPA-induced fibroblast recruitment, vascular leakage, and epithelial cell apoptosis were also markedly reduced in Lpar1 2/2 mice (16,20). In vivo, the oral administration of an LPA 1 antagonist dramatically prevented bleomycin-induced pulmonary fibrosis in mice (16,21), and the intraperitoneal injection of an LPA 1/3 antagonist ameliorated irradiation-induced lung fibrosis (22).…”

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Lysophosphatidic Acid Receptor–2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice

Huang¹,

Patel

et al. 2013

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis is a devastating disease characterized by alveolar epithelial cell injury, the accumulation of fibroblasts/ myofibroblasts, and the deposition of extracellular matrix proteins. Lysophosphatidic acid (LPA) signaling through its G proteincoupled receptors is critical for its various biological functions. Recently, LPA and LPA receptor 1 were implicated in lung fibrogenesis. However, the role of other LPA receptors in fibrosis remains unclear. Here, we use a bleomycin-induced pulmonary fibrosis model to investigate the roles of LPA 2 in pulmonary fibrogenesis. In the present study, we found that LPA 2 knockout (Lpar2 2/2 ) mice were protected against bleomycin-induced lung injury, fibrosis, and mortality, compared with wild-type control mice. Furthermore, LPA 2 deficiency attenuated the bleomycin-induced expression of fibronectin (FN), a-smooth muscle actin (a-SMA), and collagen in lung tissue, as well as levels of IL-6, transforming growth factor-b (TGF-b), and total protein in bronchoalveolar lavage fluid. In human lung fibroblasts, the knockdown of LPA 2 attenuated the LPA-induced expression of TGF-b1 and the differentiation of lung fibroblasts to myofibroblasts, resulting in the decreased expression of FN, a-SMA, and collagen, as well as decreased activation of extracellular regulated kinase 1/2, Akt, Smad3, and p38 mitogen-activated protein kinase. Moreover, the knockdown of LPA 2 with small interfering RNA also mitigated the TGF-b1-induced differentiation of lung fibroblasts. In addition, LPA 2 deficiency significantly attenuated the bleomycin-induced apoptosis of alveolar and bronchial epithelial cells in the mouse lung. Together, our data indicate that the knockdown of LPA 2 attenuated bleomycin-induced lung injury and pulmonary fibrosis, and this may be related to an inhibition of the LPA-induced expression of TGF-b and the activation and differentiation of fibroblasts.

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“…By signaling through these receptors, LPA mediates multiple fundamental responses to tissue injury, including responses that may be aberrant or aberrantly excessive when injury leads to fibrosis rather than to repair. LPA signaling specifically through LPA 1 has pro-fibrotic effects on epithelial cells, endothelial cells, and fibroblasts: genetic deletion of this receptor reduces epithelial cell apoptosis, vascular leak, and fibroblast accumulation in the bleomycin model of lung fibrosis (1,8). LPA 1 -deficient mice are consequently dramatically protected from fibrosis and mortality in this model (1).…”

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Autotaxin Emerges as a Therapeutic Target for Idiopathic Pulmonary Fibrosis

Tager

2012

Am J Respir Cell Mol Biol

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The Lysophosphatidic Acid Receptor LPA₁ Promotes Epithelial Cell Apoptosis after Lung Injury

Cited by 119 publications

References 48 publications

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Lysophosphatidic Acid Receptor–2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice

Autotaxin Emerges as a Therapeutic Target for Idiopathic Pulmonary Fibrosis

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The Lysophosphatidic Acid Receptor LPA1 Promotes Epithelial Cell Apoptosis after Lung Injury

Cited by 119 publications

References 48 publications

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Lysophosphatidic Acid Receptor–2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice

Autotaxin Emerges as a Therapeutic Target for Idiopathic Pulmonary Fibrosis

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The Lysophosphatidic Acid Receptor LPA₁ Promotes Epithelial Cell Apoptosis after Lung Injury