Effect of lipid saturation and oxidation on fibrogenesis in IPF

<bold>Aims and objectives:</bold> Cellular lipids and lipid mediators play roles in inflammation and the development and resolution of ER stress. Lipid homeostasis is important in the lung as lipid makes up 90% of surfactant. We hypothesise that aberrant lipid metabolism and the consequences on lipid mediators contributes to the pro-fibrotic niche in IPF. <bold>Methods:</bold> Lung tissue from IPF and control patients were analysed for targeted quantitative measurement of >1,100 lipids. Primary human fibroblasts were exposed to lipids identified as increased on IPF tissue lipidomic analysis. Impact on proliferation genes and proteins, and ER stress genes was measured. <bold>Results:</bold> There was an increase in pulmonary lipid content from patients with IPF compared to control (23.16nmol/mg vs. 18.66nmol/mg, p=0.0317). Specific increases were noted in 16:0 and 20:4 containing lipids. ACTA2 and Col1a1 expression were upregulated in fibroblasts following exposure to saturated phosphatidylcholine 16:0 (PC 16:0) (p<0.001) and downregulated after unsaturated PC 20:4 (p<0.01). Oxidized PC 20:4,16:0 in contrast resulted in upregulation of ACTA2 and Col1a1 expression (p<0.01), and genetic markers of ER Stress (XBP1, DDIT3, HSPA5)(P<0.05). IPF fibroblasts are protected against the pro-fibrotic impact of TGFb (P<0.001) when primed with PC 20:4 but not saturated or oxidized species. <bold>Conclusions:</bold> Abnormal lipid deposition is seen in IPF on lipidomic analysis. Saturated and oxidized lipids cause increased ER stress and production of pro-fibrotic cytokines, whereas unsaturated lipid results in decreased availability of these lipids for the generation of inflammatory and resolving lipid mediators preventing the normal reparative inflammatory process.