Open Access12-Lipoxygenase is a Critical Mediator of Type II Pneumocyte Senescence, Macrophage Polarization and Pulmonary Fibrosis after Irradiation
Author(s) -
Eun Joo Chung,
Jessica L. Reedy,
So Mee Kwon,
Shilpa Patil,
Luca Valle,
Ayla O. White,
Deborah E. Citrin
Publication year - 2019
Publication title -
radiation research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 124
eISSN - 1938-5404
pISSN - 0033-7587
DOI - 10.1667/rr15356.1
Subject(s) - senescence , pulmonary fibrosis , proinflammatory cytokine , nox4 , lung , reactive oxygen species , macrophage polarization , biology , fibrosis , nadph oxidase , inflammation , chemistry , cancer research , pathology , macrophage , microbiology and biotechnology , immunology , medicine , biochemistry , in vitro
Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive complication of therapeutic irradiation of the thorax. It has been suggested that senescence of type II pneumocytes (AECIIs), an alveolar stem cell, plays a role in the development of RIPF through loss of replicative reserve and via senescent AECII-driven release of proinflammatory and profibrotic cytokines. Within this context, we hypothesized that arachidonate 12-lipoxygenase (12-LOX) is a critical mediator of AECII senescence and RIPF. Treatment of wild-type AECIIs with 12S-hydroxyeicosateraenoic acid (12S-HETE), a downstream product of 12-LOX, was sufficient to induce senescence in a NADPH oxidase 4 (NOX4)-dependent manner. Mice deficient in 12-LOX exhibited reduced AECII senescence, pulmonary collagen accumulation and accumulation of alternatively activated (M2) macrophages after thoracic irradiation (5 × 6 Gy) compared to wild-type mice. Conditioned media from irradiated or 12S-HETE-treated primary pneumocytes contained elevated levels of IL-4 and IL-13 compared to untreated pneumocytes. Primary macrophages treated with conditioned media from irradiated AECII demonstrated preferential M2 type polarization when AECIIs were derived from wild-type mice compared to 12-LOX-deficient mice. Together, these data identified 12-LOX as a critical component of RIPF and a therapeutic target for radiation-induced lung injury.