细胞外囊泡包裹的 CC16 作为治疗急性肺损伤的新型纳米治疗药物。

Extracellular vesicle-encapsulated CC16 as novel nanotherapeutics for treatment of acute lung injury.

机构信息

Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.

Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; Department of Clinical Pharmacy, College of Pharmacy, University of Hail, Hail 55473, Saudi Arabia.

出版信息

Mol Ther. 2023 May 3;31(5):1346-1364. doi: 10.1016/j.ymthe.2023.01.009. Epub 2023 Jan 11.

Acute lung injury (ALI) is still associated with high mortality. Growing evidence suggests that Club Cell Protein 16 (CC16) plays a protective role against ALI. However, the doses of recombinant CC16 (rCC16) used in preclinical studies are supraphysiological for clinical applications. Extracellular vesicles (EVs) are nanovesicles endogenously generated by mammalian cells. Our study demonstrated that CC16 is released via small EVs and EV-encapsulated CC16 (sEV-CC16) and has anti-inflammatory activities, which protect mice from lipopolysaccharide (LPS) or bacteria-induced ALI. Additionally, sEV-CC16 can activate the DNA damage repair signaling pathways. Consistent with this activity, we observed more severe DNA damage in lungs from Cc16 knockout (KO) than wild-type (WT) mice. Mechanistically, we elucidated that CC16 suppresses nuclear factor κB (NF-κB) signaling activation by binding to heat shock protein 60 (HSP60). We concluded that sEV-CC16 could be a potential therapeutic agent for ALI by inhibiting the inflammatory and DNA damage responses by reducing NF-κB signaling.

急性肺损伤（ALI）仍然与高死亡率相关。越来越多的证据表明，克拉细胞蛋白 16（CC16）在对抗 ALI 方面发挥保护作用。然而，在临床应用中，用于临床前研究的重组 CC16（rCC16）的剂量对于生理状态来说是过高的。细胞外囊泡（EVs）是哺乳动物细胞内源性产生的纳米囊泡。我们的研究表明，CC16 通过小细胞外囊泡（sEV）和囊封 CC16（sEV-CC16）释放，并具有抗炎活性，可保护小鼠免受脂多糖（LPS）或细菌诱导的 ALI。此外，sEV-CC16 可以激活 DNA 损伤修复信号通路。与这一活性一致，我们观察到 Cc16 敲除（KO）小鼠的肺部比野生型（WT）小鼠的 DNA 损伤更严重。从机制上讲，我们阐明了 CC16 通过与热休克蛋白 60（HSP60）结合来抑制核因子 κB（NF-κB）信号激活。我们的结论是，sEV-CC16 通过减少 NF-κB 信号，抑制炎症和 DNA 损伤反应，可能成为治疗 ALI 的潜在治疗剂。