Editors' ChoicePulmonary fibrosis

Leukotrienes fuel fibrosis

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Science Translational Medicine  27 Nov 2019:
Vol. 11, Issue 520, eaaz9756
DOI: 10.1126/scitranslmed.aaz9756


Senescent fibroblasts are a key source of profibrotic leukotrienes during pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by destruction of lung architecture and deposition of fibrotic tissue. Current treatments do not halt the progression of fibrotic tissue remodeling, and the disease is associated with high mortality rates. Injury to the pulmonary epithelium is attributable to repetitive cycles of inflammation, mediated by macrophages and activated epithelial and immune cells. Accumulation of senescent (aged) cells is associated with IPF progression; however, the mechanisms accounting for this are not understood.

Using mouse models and studies with human tissues and cells, Wiley et al. investigated whether leukotrienes (LTs), a family of biologically active profibrotic lipids, contribute to the senescent phenotype of IPF cells. Lung fibroblasts were irradiated to induce senescence, and senescent cells produced more LTs compared with quiescent cells. Senescence induction in nonlung cell lines also induced LT secretion, suggesting that LT production is a common feature of the senescent cell phenotype. LT-rich conditioned medium from senescent lung fibroblasts also induced profibrotic signaling in naïve fibroblasts, which was abrogated by inhibitors of the principal enzyme in LT biosynthesis.

They next used a bleomycin-induced pulmonary fibrosis mouse model to investigate if senescent cells mediated LT-driven lung disease. Removal of senescent cells reduced LT biosynthesis and collagen deposition. Bleomycin induced an early spike in LT synthesis, followed by a progressive rise in the expression of genes associated with prostaglandin D synthesis, consistent with a switch in senescent cell phenotype from profibrotic to antifibrotic. Using patient-derived cells, they showed that senescent IPF fibroblasts synthesized LT but failed to produce antifibrotic prostaglandins, thereby identifying senescent lung fibroblasts as a key source of profibrotic LT in IPF.

This study demonstrates that senescent cells secrete LTs that cause or exacerbate IPF. Disease progression may result from an altered senescence response that promotes fibrosis via LT release; fibrosis does not resolve due to the inability of senescent IPF fibroblasts to secrete antifibrotic prostaglandins. These findings have so far been limited to in vitro and murine models, but they suggest future translational potential for the development of therapies targeting LT biosynthesis for the treatment of human IPF.

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