Growing international exploitation of rare earth oxides (REOs) for commercial and biological use has increased the possibility of human exposure and adverse health effects. Occupational exposure to rare earth materials in miners and polishers leads to a severe form of pneumoconiosis, while gadolinium-containing MRI contrast agents cause nephrogenic systemic fibrosis in patients with renal impairment. The mechanisms for inducing these adverse pro-fibrogenic effects are of considerable importance for the safety assessment of REO particles as well as presenting opportunities for safer design. In this study, using a well-prepared REO library, we obtained a mechanistic understanding of how REOs induce cellular and pulmonary damage by a compartmentalized intracellular biotransformation process in lysosomes that results in pro-fibrogenic growth factor production and lung fibrosis. We demonstrate that rare earth oxide ion shedding in acidifying macrophage lysosomes leads to biotic phosphate complexation that results in organelle damage due to stripping of phosphates from the surrounding lipid bilayer. This results in nanoparticle biotransformation into urchin shaped structures and setting in motion a series of events that trigger NLRP3 inflammasome activation, IL-1β release, TGF-β1 and PDGF-AA production. However, pretreatment of REO nanoparticles with phosphate in a neutral pH environment prevents biological transformation and pro-fibrogenic effects. This can be used as a safer design principle for producing rare earth nanoparticles for biological use.

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Lysophosphatidylcholines (lysoPCs) are a class of compounds that have a constant polar head, and fatty acyls of different chain lengths, position, degrees of saturation, and double bond location in human plasma. LysoPCs levels can be a clinical diagnostic indicator that reveals pathophysiological changes. In this work, a method was developed to discriminate between different types of lysoPCs using reversed phase ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry, using mass spectrometry MS E . Isomeric lysoPCs were distinguished based on retention time and the peak intensity ratio of product ions, and 14 pairs of lysoPCs regioisomers were identified in human plasma. The plasma samples of 12 lung cancer patients and 12 healthy persons were collected and analyzed by principal component analysis to generate metabolic profiles of the identified lysoPCs. Both electrospray ionization ESI? and ESIresults showed that all lung cancer patients had the same five lysoPC metabolic abnormalities, specifically in sn-1 lyso16:0, sn-2 lysoPC 16:0, sn-1 lysoPC 18:0, sn-1 lysoPC 18:1 and sn-1 lysoPC 18:2. Thus, the function of isomers with different fatty acyl positions may be related to lung cancer, and this may help elucidate the mechanism of the disease.