Gulino Giulia Rossana, Magnetto Chiara, Khadjavi Amina, Panariti Alice, Rivolta Ilaria, Soster Marco, Argenziano Monica, Cavalli Roberta, Giribaldi Giuliana, Guiot Caterina, Prato Mauro
Dipartimento di Oncologia, Università di Torino, 10126 Torino, Italy.
Istituto Nazionale di Ricerca Metrologica (INRIM), 10135 Torino, Italy.
Mediators Inflamm. 2015;2015:964838. doi: 10.1155/2015/964838. Epub 2015 Mar 23.
Monocytes play a key role in the inflammatory stage of the healing process. To allow monocyte migration to injured tissues, the balances between secreted matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) must be finely modulated. However, a reduction of blood supply and local oxygen tension can modify the phenotype of immune cells. Intriguingly, hypoxia might be targeted by new effective oxygenating devices such as 2H,3H-decafluoropentane- (DFP-) based oxygen-loaded nanodroplets (OLNs). Here, hypoxia effects on gelatinase/TIMP release from human peripheral monocytes were investigated, and the therapeutic potential of dextran-shelled OLNs was evaluated. Normoxic monocytes constitutively released ~500 ng/mL MMP-9, ~1.3 ng/mL TIMP-1, and ~0.6 ng/mL TIMP-2 proteins. MMP-2 was not detected. After 24 hours, hypoxia significantly altered MMP-9/TIMP-1 balance by reducing MMP-9 and increasing TIMP-1, without affecting TIMP-2 secretion. Interestingly OLNs, not displaying toxicity to human monocytes after cell internalization, effectively counteracted hypoxia, restoring a normoxia-like MMP-9/TIMP-1 ratio. The action of OLNs was specifically dependent on time-sustained oxygen diffusion up to 24 h from their DFP-based core. Therefore, OLNs appear as innovative, nonconventional, cost-effective, and nontoxic therapeutic tools, to be potentially employed to restore the physiological invasive phenotype of immune cells in hypoxia-associated inflammation.
单核细胞在愈合过程的炎症阶段起着关键作用。为使单核细胞迁移至受损组织，分泌的基质金属蛋白酶（MMPs）与其抑制剂（TIMPs）之间的平衡必须得到精细调节。然而，血液供应减少和局部氧张力降低会改变免疫细胞的表型。有趣的是，缺氧可能是新型有效充氧装置的作用靶点，如基于2H,3H-十氟戊烷（DFP）的载氧纳米液滴（OLNs）。在此，研究了缺氧对人外周血单核细胞明胶酶/TIMP释放的影响，并评估了葡聚糖包被的OLNs的治疗潜力。常氧条件下的单核细胞持续释放约500 ng/mL的MMP-9、约1.3 ng/mL的TIMP-1和约0.6 ng/mL的TIMP-2蛋白。未检测到MMP-2。24小时后，缺氧通过降低MMP-9和增加TIMP-1显著改变了MMP-9/TIMP-1的平衡，而不影响TIMP-2的分泌。有趣的是，OLNs在细胞内化后对人单核细胞无毒性，能有效对抗缺氧，恢复类似常氧的MMP-9/TIMP-1比值。OLNs的作用具体取决于从其基于DFP的核心持续24小时的氧扩散。因此，OLNs似乎是创新的、非常规的、具有成本效益且无毒的治疗工具，有望用于恢复缺氧相关炎症中免疫细胞的生理侵袭表型。
