title: Oxygen-Loaded Nanodroplets Effectively Abrogate Hypoxia Dysregulating Effects on Secretion of MMP-9 and TIMP-1 by Human Monocytes.
abstract: 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.
authors: Dipartimento di Oncologia, Università di Torino, 10126 Torino, Italy.
authors: Giulia Rossana
authors: GR
authors: Gulino
authors: Istituto Nazionale di Ricerca Metrologica (INRIM), 10135 Torino, Italy.
authors: Chiara
authors: C
authors: Magnetto
authors: Dipartimento di Neuroscienze, Università di Torino, 10125 Torino, Italy.
authors: Amina
authors: A
authors: Khadjavi
authors: Dipartimento di Scienze della Salute, Università di Milano Bicocca, 20900 Monza, Italy.
authors: Alice
authors: A
authors: Panariti
authors: Dipartimento di Scienze della Salute, Università di Milano Bicocca, 20900 Monza, Italy.
authors: Ilaria
authors: I
authors: Rivolta
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, 10125 Torino, Italy.
authors: Marco
authors: M
authors: Soster
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, 10125 Torino, Italy.
authors: Monica
authors: M
authors: Argenziano
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, 10125 Torino, Italy.
authors: Roberta
authors: R
authors: Cavalli
authors: Dipartimento di Oncologia, Università di Torino, 10126 Torino, Italy.
authors: Giuliana
authors: G
authors: Giribaldi
authors: Dipartimento di Neuroscienze, Università di Torino, 10125 Torino, Italy.
authors: Caterina
authors: C
authors: Guiot
authors: Dipartimento di Neuroscienze, Università di Torino, 10125 Torino, Italy ; Dipartimento di Scienze della Sanità Pubblica e Pediatriche, Università di Torino, 10126 Torino, Italy.
authors: Mauro
authors: M
authors: Prato
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage*; D010100:Oxygen / Q000008:administration & dosage*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
chemical_list: C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D010100:Oxygen