Cholesteryl-palmitate/Dipalmitoylphosphatidylcholine

Background: Acinetobacter baumannii-mediated bacterial pneumonia is a common disease that is harmful to human health. Dipalmitoylphosphatidylcholine (DPPC) is the major lipid component of the pulmonary surfactant (PS) found in the alveolar space; the PS helps to keep surface tension low, which allows for improved oxygen delivery. Resveratrol (RE) is a phytoalexin found in plants that is released in response to injury or infection. The therapeutic effect of Re is limited due to its low solubility and bioavailability. In this study, we report pulmonary delivery of Re-loaded DPPC liposomal large porous microparticles (RDLPMs) for treatment of A. baumannii-induced pneumonia. Methods: Novel RDLPMs were prepared by rotary evaporation and a freeze-drying method in this study. RDLPMs were evaluated by the particle size, electric potential, in vitro release, and particle size distribution. A rat model of A. baumannii-mediated pneumonia was established and used for pharmacodynamic evaluations. Results: The Re-loaded DPPC liposomes (RDLs) consisted of Re/DPPC (1:3, mol/mol) and DPPC/cholesterol (3:1, w/w), with a hydration time of 15 minutes. The RDLs had a high encapsulation efficiency of 69.8% ± 1.6%, a mean size of 191.5 ± 4.5 nm, and a high zeta potential of 12.4 ± 1.5 mV. The RDLPMs were composed of mannitol/large porous microparticles/RDLs (1:4:2, w/w/w) and had a loading efficiency of 2.20% ± 0.24%. The RDLPMs had an aerodynamic diameter (2.73 ± 0.65 μm), a good fluidity (28.30° ± 6.13°), and demonstrated high lung deposition (fine particle fraction = 43.33%). Surprisingly, while penicillin showed better microbial inhibition than the RDLPMs and Re groups in vitro, the RDLPMs were more effective in vivo. Conclusion: The RDLPMs showed good powder properties for pulmonary delivery. The RDLPMs may inhibit the nuclear factor kappa-B pathway and downregulate the expression of cytokines downstream of tumor necrosis factor-α and interleukin-1β. As well as, RDLPMs demonstrated some antibacterial properties against A. baumannii bacteria. Re, when delivered in RDLPMs as a dry powder inhaler, is a promising substitute for antibiotics in the treatment of A. baumannii pneumonia.

Chronic obstructive pulmonary disease (COPD) is primarily caused by inhalation of cigarette smoke and is the third leading cause of death worldwide. Pulmonary surfactant, a complex of phospholipids and proteins, plays an essential role in respiration by reducing the surface tension in the alveoli. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is an enzyme that catalyzes the biosynthesis of surfactant lipids and is expressed in type 2 alveolar epithelial cells. Its dysfunction is suggested to be involved in various lung diseases; however, the relationship between LPCAT1 and COPD remains unclear. To investigate the role of LPCAT1 in the pathology of COPD, we analyzed an elastase-induced emphysema model using Lpcat1 knockout (KO) mice. In Lpcat1 KO mice, elastase-induced emphysema was significantly exacerbated with increased apoptotic cells, which was not ameliorated by supplementation with dipalmitoylphosphatidylcholine, which is a major component of the surfactant synthesized by LPCAT1. We subsequently evaluated the effects of cigarette smoking on primary human type 2 alveolar epithelial cells (hAEC2s) and found that cigarette smoke extract (CSE) downregulated the expression of Lpcat1. Furthermore, RNA sequencing analysis revealed that the apoptosis pathway was significantly enriched in CSE-treated primary hAEC2s. Finally, we downregulated the expression of Lpcat1 using small interfering RNA, which resulted in enhanced CSE-induced apoptosis in A549 cells. Taken together, cigarette smoke-induced downregulation of LPCAT1 can promote the exacerbation of pulmonary emphysema by increasing the susceptibility of alveolar epithelial cells to apoptosis, thereby suggesting that Lpcat1 is a novel therapeutic target for irreversible emphysema.