Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis

Wiley, Christopher D.; Brumwell, Alexis; Davis, Sonnet S.; Jackson, Julia R.; Valdovinos, Alexis; Calhoun, Cheresa; Alimirah, Fatouma; Castellanos, Carlos A.; Ruan, Richard; Wei, Ying; Chapman, Harold A.; Ramanathan, Arvind; Campisi, Judith; Saux, Claude Jourdan Le

doi:10.1172/jci.insight.130056

Cited by 90 publications

(74 citation statements)

References 55 publications

(77 reference statements)

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“…Accumulation of senescent cells in the fibrotic tissue has been linked to the severity of IPF, and earlier studies have shown that modulation of 5-LO and COX-2 in senescent fibroblasts [93,94]. In vitro, induction of senescence in human lung fibroblasts (IMR-90) using irradiation increased expression of phospho-5-LO/total 5-LO ratio and secretion of cysLTs [95]. Further, the cysLT-rich conditional medium of senescent IMR-90 fibroblasts induced pro-fibrotic signaling in naïve fibroblasts, which was abrogated by inhibition of 5-LO.…”

Section: Cellular Senescence and Leukotriene Metabolism In Pulmonary mentioning

confidence: 99%

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Suryadevara

Ramchandran

Kamp

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.

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Section: Cellular Senescence and Leukotriene Metabolism In Pulmonary mentioning

confidence: 99%

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Suryadevara

Ramchandran

Kamp

et al. 2020

IJMS

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“…The expression of p16 INK4a in macrophages can suppress M1 polarization and hence the secretion of inflammatory factors by these cells [61]. On the other hand, the SASP secreted by senescent thyroid cells skews macrophage polarization to M2 caused by prostaglandin E2 [62], a prominent SASP factor [63].…”

Section: Interaction Of Senescent Cells With Macrophagesmentioning

confidence: 99%

Role of immune cells in the removal of deleterious senescent cells

et al. 2020

Self Cite

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Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescenceassociated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.

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“…We reported the presence of cellular senescence markers, such as p21, p53, γ-H2AX and SA-βgal staining, which along with the expression of SASP components represent a source of chronic profibrotic signaling through the activation of Il-6, Mcp1, TNF-α, and IL-1α. The presence of this secretory phenotype has already been confirmed in AE2 cells and lung fibroblasts of IPF patients (2,54). We previously demonstrated that chronic activation of the mTOR/PGC-1β pathway induces lung epithelial cells into a senescence phenotype, possibly due to augmented ROS-induced molecular damage (51).…”

Section: Discussionmentioning

confidence: 68%

“…Growing evidence indicates that aging and cellular senescence are tightly interrelated to mitochondrial dysfunction (16,54). Accumulation of dysmorphic/dysfunctional mitochondria has been described in several aged tissues, including AE2 cells of IPF lungs.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

Roque

Cuevas-Mora²,

Sales³

et al. 2020

Preprint

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The current hypothesis suggests that Idiopathic pulmonary fibrosis (IPF) arises as a result of chronic injury to alveolar epithelial cells and aberrant activation of multiple signaling pathways. Dysfunctional IPF lung epithelium manifests many hallmarks of aging tissues, including cellular senescence, mitochondrial dysfunction, metabolic dysregulation, and loss of proteostasis. Unfortunately, this disease is often fatal within 3-5 years from diagnosis, and there is no effective treatment. One of the major limitations to the development of novel treatments in IPF is that current models of the disease fail to resemble several features seen in elderly IPF patients. In this study, we sought to develop an in vitro epithelial injury model using repeated low levels of bleomycin to mimic the phenotypic and functional characteristics of the IPF lung epithelium. Consistent with the hallmarks of the aging lung epithelium, we found that chronic-injured epithelial cells exhibited features of senescence cells, including an increase in β-galactosidase staining, induction of p53 and p21, mitochondrial dysfunction, excessive ROS production, and proteostasis alteration. Next, combined RNA sequencing, untargeted metabolomics, and lipidomics were performed to investigate the dynamic transcriptional, metabolic, and lipidomic profiling of our in vitro model. We identified that a total of 8,484 genes with different expression variations between the exposed group and the control group. According to our GO enrichment analysis, the down-regulated genes are involved in multiple biosynthetic and metabolic processes. In contrast, the up-regulated genes in our treated cells are responsible for epithelial cell migration and regulation of epithelial proliferation. Furthermore, metabolomics and lipidomics data revealed that overrepresented pathways were amino acid, fatty acid, and glycosphingolipid metabolism. This result suggests that by using our in vitro model, we were able to mimic the transcriptomic and metabolic alterations of those seen in the lung epithelium of IPF patients. We believe this model will be ideally suited for use in uncovering novel insights into the gene expression and molecular pathways of the IPF lung epithelium and performing screening of pharmaceutical compounds.

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Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis

Cited by 90 publications

References 55 publications

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Role of immune cells in the removal of deleterious senescent cells

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

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