Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis

• Published in: JCI insight Vol. 4; no. 24
• Main Authors: Wiley, Christopher D, Brumwell, Alexis N, 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, Jourdan Le Saux, Claude
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 19-12-2019
• Subjects: Animals; Arachidonate 5-Lipoxygenase - metabolism; Bleomycin - toxicity; Bronchoalveolar Lavage Fluid - chemistry; Cell Line; Cellular Senescence; Culture Media, Conditioned - metabolism; Disease Models, Animal; Disease Progression; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Profiling; Gene Expression Regulation - drug effects; Humans; Idiopathic Pulmonary Fibrosis - diagnosis; Idiopathic Pulmonary Fibrosis - pathology; Leukotrienes - analysis; Leukotrienes - metabolism; Lipoxygenase Inhibitors - pharmacology; Lung - cytology; Lung - pathology; Male; Mice; Primary Cell Culture; Prostaglandins - metabolism; Signal Transduction - drug effects; Pulmonology; Eicosanoids; Cellular senescence; Fibrosis; Cell Biology
• ISSN: 2379-3708
• DOI: 10.1172/jci.insight.130056

Accumulation of senescent cells is associated with the progression of pulmonary fibrosis, but mechanisms accounting for this linkage are not well understood. To explore this issue, we investigated whether a class of biologically active profibrotic lipids, the leukotrienes (LT), is part of the senescence-associated secretory phenotype. The analysis of conditioned medium (CM), lipid extracts, and gene expression of LT biosynthesis enzymes revealed that senescent cells secreted LT, regardless of the origin of the cells or the modality of senescence induction. The synthesis of LT was biphasic and followed by antifibrotic prostaglandin (PG) secretion. The LT-rich CM of senescent lung fibroblasts (IMR-90) induced profibrotic signaling in naive fibroblasts, which were abrogated by inhibitors of ALOX5, the principal enzyme in LT biosynthesis. The bleomycin-induced expression of genes encoding LT and PG synthases, level of cysteinyl LT in the bronchoalveolar lavage, and overall fibrosis were reduced upon senescent cell removal either in a genetic mouse model or after senolytic treatment. Quantification of ALOX5+ cells in lung explants obtained from idiopathic pulmonary fibrosis (IPF) patients indicated that half of these cells were also senescent (p16Ink4a+). Unlike human fibroblasts from unused donor lungs made senescent by irradiation, senescent IPF fibroblasts secreted LTs but failed to synthesize PGs. This study demonstrates for the first time to our knowledge that senescent cells secrete functional LTs, significantly contributing to the LT pool known to cause or exacerbate IPF.