Critical role of Lactosylceramide‐accumulation in pathogenesis of lung injury and emphysema

Study Objective To elucidate the role of Lactosylceramide (LacCer) in pathogenesis of lung injury and emphysema. Results We recently demonstrated that ceramide (Cer) plays a crucial role in pathogenesis of lung injury and emphysema. We report here that besides Cer, its downstream metabolite LacCer accumulates in severe emphysema. Moreover, LacCer‐accumulation correlates with severity of emphysema and expression of lipid‐raft (ZO‐2) and defective‐autophagy (p62) markers. Pa ‐LPS treatment and cigarette smoke (CS) induces LacCer‐accumulation in murine lungs that correlates with increased p62 expression and NFκB mediated neutrophil (NIMP‐R14) chemotaxis. We verified that LacCer‐inhibitors significantly (p<0.05) decrease NFκB, p62 and NIMP‐R14 expression in the murine lungs and IL‐6, caspase‐3/7 and MPO activities in BALFs of Pa ‐LPS/CS exposed mice. The CS extract treated in vitro (Raw264.7/Beas2b) model was used to further confirm that CS induces LacCer‐accumulation that plays a critical role in triggering aberrant‐autophagy (p62), apoptosis (caspase‐3/7) and inflammation (NFκB), hence emphysema pathogenesis, that can be controlled by LacCer inhibitors (p<0.001). Conclusions We demonstrate both the critical role of LacCer in pathogenesis of lung injury and emphysema and therapeutic potential of selective LacCer‐inhibition in treating chronic lung disease. Contact: nvij1@jhmi.edu Research Support: NIH & FAMRI