Lipidomics analysis reveals signature inflammatory and specialized pro-resolving mediators at the junction of inflammation-resolution transition in mouse lungs exposed to multiwalled carbon nanotubes

Pulmonary exposure to certain multiwalled carbon nanotubes (MWCNTs) triggers significant inflammation that is regulated temporally by powerful mediators of inflammation and resolution. Among these mediators, inflammatory lipid mediators (ILMs) and specialized pro-resolving mediators (SPMs) have garnered increasing attention. In this study, lipidomics analysis revealed that fibrogenic MWCNTs stimulate the production of signature ILMs and SPMs in mouse lungs, marking a phenotypic shift from acute inflammation to resolution. Mice exposed to 40 μg MWCNTs via oropharyngeal aspiration exhibited dynamic, polarized pulmonary inflammation. By day 7 post-exposure, lung tissue showed elevated M2 macrophage markers and cytokines, with lesions characterized by moderate neutrophil infiltration and a marked increase in macrophages within alveolar sacs and interstitial spaces. These macrophages contained engulfed nanoparticles and formed clusters of varying sizes. In vitro, MWCNTs promoted nanoparticle phagocytosis and cytoplasmic phospholipid accumulation. Lipidomics profiling of lung bioactive lipids, performed using ultraperformance liquid chromatography-tandem mass spectrometry, showed significant increases in ILMs and SPMs. These included prostaglandin (PG) E2, PGD2, thromboxane B2, leukotriene B4, and lipoxin B4 from the arachidonic acid pathway; resolvin (Rv) D5, protectin DX, maresin 1, 17-hydroxydocosahexaenoic acid (HDHA), and 14S-HDHA from the docosahexaenoic acid pathway; and RvE2, 15-hydroxyeicosapentaenoic acid (HEPE), and 18-HEPE from the eicosapentaenoic acid pathway. These findings suggest that MWCNTs trigger a distinct lipid mediator signature at the junction of inflammation-resolution transition to promote the programmatic switch from acute inflammation to resolution, supporting continued particle clearance, inflammation resolution, and return to homeostasis in response to nanoparticle exposure.