Abstract Background and Purpose Exploring the targeted regulatory effect of isorhynchophylline on lipopolysaccharide (LPS)‐induced acute lung injury (ALI) by constructing a drug delivery system of GEF‐modified exosomes derived from M2 macrophages (M2‐Exos) loaded with isorhynchophylline (GEF‐M2‐Exos‐IRN; GMI). Experimental Approach GMI was constructed using an ultrasonic method with M2‐Exos and isorhynchophylline. Targeting GMI was traced using immunofluorescence of mouse lung tissue frozen sections and BEAS‐2B/A549 cells. Haematoxylin and eosin staining was used to detect pathological changes and Terminal deoxynucleotidyl transferase dUTP Nick‐End Labelling (TUNEL) was employed to detect cell apoptosis. Expression levels of α ‐SMA, iNOS and Arg1 were detected via immunohistochemistry and fluorescence. GMI intervention in acute lung injury were analysed by transcriptome sequencing and key differential genes were verified by quantitative reverse transcription polymerase chain reaction (RT‐qPCR). Key Results GMI drug lung targeting delivery system was successfully constructed. GMI reduced the percentage of apoptotic cells, down‐regulate the expression of α ‐SMA, inhibit M1 phenotype and activated M2 phenotype. Transcriptome sequencing showed that LPS promoted Th17 differentiation through the NF‐κB/MAPK/JAK–STAT pathway, causing an IL‐6/TNF‐ α inflammatory storm, inducing metabolic‐oxidative stress aggravating the injury. GMI reversed the injury inhibiting Th17/CXCL axis, activating Treg/TGF‐ β axis, restoring glycolysis/cholesterol metabolism, epigenetically regulating SOCS3 and promoting tissue barrier reconstruction. Gene interaction network identified Spib ‐ Pou2f1 ‐ Aicda / Tnfrsf4 as the core hub, mediating the immune‐inflammatory reaction. The key differential genes were consistent with the sequencing results after RT‐qPCR verification. Conclusions and Implications GMI alleviates LPS‐induced acute lung injury through a multi‐factorial network of ‘inflammation‐metabolism‐epigenetics’, providing a new strategy for lung‐targeted anti‐inflammatory treatment.
Zou et al. (Thu,) studied this question.