Metabolomics reveals pro-inflammatory effects of 12R-HETE and ALOX12B in maternal allergic asthma

Approximately 10% of pregnant women worldwide suffer from asthma, significantly increasing risks like preterm birth, low birth weight, and gestational hypertension. Current diagnostic methods are limited in early detection, underscoring the need for more effective diagnostic tools and treatment strategies to improve maternal and fetal health. In this study, following house dust mites (HDM) stimulation, significant changes were observed in lung tissue morphology, lung function, and inflammation in both pregnant rats and their offspring. Hydrophilic interaction chromatography-mass spectrometry (HILIC-MS) analysis revealed substantial differences in metabolite levels between the parent groups in both positive and negative ion modes. Additionally, significant variations in metabolite levels were observed between the offspring groups. Notably, targeted metabolomic analysis showed elevated levels of 12R-hydroxy-5,8,10,14-eicosatetraenoic acid (12R-HETE) in plasma and lung tissue of both the parental and offspring HDM model groups. Concurrently, arachidonate 12-lipoxygenase, 12R type (ALOX12B) expression was significantly increased in the lung tissue, particularly in bronchial epithelium, as indicated by immunohistochemistry (IHC). In bronchial epithelial cells (16HBE), overexpression of ALOX12B raised mRNA and protein levels of IL-33, IL-6, MUC5AC, and GM-CSF, while ALOX12B knockdown reduced these inflammatory factors. This indicates that the ALOX12B pathway plays a crucial role in the type 2 inflammatory response in asthma. In summary, HDM induces the accumulation of 12R-HETE by promoting ALOX12B expression, thereby exacerbating type 2 inflammatory reactions and contributing to the development of allergic asthma. Consequently, 12R-HETE or ALOX12B may serve as potential biomarkers for diagnosing pregnancy-related allergic asthma or as novel therapeutic targets.