Dysregulated metabolic pathways of pulmonary fibrosis and the lipids associated with the effects of nintedanib therapy
Yasuo Shimizu, Yasuhiro Horibata, Mariko Domae, Yusuke Nakamura, Tatsuya Yokoyama, Ryo Arai, Taichi Shiobara, Akihiro Takemasa, Ryosuke Koike, Nobuhiko Uchida, Meitetsu Masawa, Rinna Tei, Taiji Watanabe, Hiroko Morita, Masaaki Miyoshi, Sayo Soda, Seiji Niho, Ko Igami, Hiroyuki Sugimoto
Abstract
BACKGROUND: Pulmonary fibrosis (PF) is a disease with a poor prognosis, and its pathogenesis is not fully understood. Identifying dysregulation of lipid metabolism in PF may provide insight and promote the development of novel therapies. The present study was designed to clarify the dysregulated lipid pathways and identify lipids correlated with treatment response. METHODS: This research comprised two prospective cohort studies. Study 1 aimed to identify dysregulated metabolic pathways and lipids in the peripheral blood of PF patients, compared with healthy control (HC) subjects. Study 2 aimed to identify lipids associated with the decline in % forced vital capacity (%FVC) and survival in PF patients treated with the anti-fibrotic drug, nintedanib. As a preliminary ancillary experiment, we attempted to identify the lipids associated with endothelial cells and fibroblasts. RESULTS: In Study 1, 38 lipids were identified that differed between the PF (n = 66) and HC (n = 63) groups. Compared with the HC subjects, phosphatidylcholine (PC) 36:5 was the most up-regulated and lysophosphatidylcholine (LPC) 18:0 was the most down-regulated in PF patients. Glycerophospholipid metabolism was the most enriched pathway. Plasmenyl phosphatidylethanolamine (pPE) and plasmanyl phosphatidylcholine (pPC) were determined to be endothelial-related lipids, and phosphatidylethanolamine (PE) were fibroblast-related lipids in PF. In Study 2, 10 lipids were identified that differed between the absolute decline in %FVC < 2.5% group (6 M responders, n = 14) and the decline in %FVC > 2.5% group (6 M non-responders, n = 6) after 6 M of nintedanib therapy, and 6 lipids were identified that differed between the absolute decline in %FVC < 5% group (12 M responders, n = 15) and the decline in %FVC > 5% group (12 M non-responders, n = 5) after 12 M of nintedanib therapy. Four lipids were consistently detected at 6 M and 12 M, and among them, higher levels of pPE 18:0p/22:6 at 6 M showed a poorer prognosis for 24 M survival (p < 0.05, HR = 6.547, 95% CI = 1.471-29.13). Under nintedanib therapy, pPE species were correlated with progressive fibrosis, and pPE 18:0p/22:6 was considered an endothelial-related lipid. CONCLUSIONS: Lipidomic profiling revealed distinct pathways in PF patients. pPE species were strongly associated with the responses to nintedanib therapy. Targeting the lipids or catabolic enzymes involved in dysregulated pathways has the potential to ameliorate PF. TRIAL REGISTRATION: Registry for UMIN, Lipidomic analysis on plasma in idiopathic pulmonary fibrosis patients. Trial registry number, UMIN000020872. Registered 3 February 2016, https://center6.umin.ac.jp/cgiopenbin/ctr/index.cgi .