Intradermal air pouch leukocytosis as an in vivo test for nanoparticles

Vandooren, Jennifer; Berghmans, Nele; Dillen, Chris; Aelst, Ilse Van; Ronsse, Isabelle; Israel, L.; Rosenberger, Ina; Kreuter, J.; Lellouche, Jean‐Paul; Michaeli, Shulamit; Locatelli, Erica; Franchini, Mauro Comes; Aiertza, Miren K.; Sánchez-Abella, Laura; Loinaz, Iraida; Edwards, Dylan R.; Shenkman, Louis; Opdenakker, Ghislain

doi:10.2147/ijn.s51628

Cited by 26 publications

(31 citation statements)

References 40 publications

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“…The air pouch is well known to be a good experimental model to study the pharmacological and immunological mechanisms of drug actions (Vandooren et al 2013;Murata et al 2014). The air pouch cavity has a thin layer of fibroblasts and macrophage-like cells that resembles the normal synovia.…”

Section: Discussionmentioning

confidence: 99%

Etanercept administration prevents the inflammatory response induced by carrageenan in the murine air pouch model

Mattei

Dalmarco

Fröde

2015

Naunyn-Schmiedeberg's Arch Pharmacol

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Rheumatoid arthritis (RA) is one of several inflammatory and autoimmune diseases that affect approximately 1% of world's population. The development of TNF inhibitors in the last decade represents a great advance in the treatment of mild and severe forms of RA. Etanercept is one of these drugs that is useful for RA treatment, but the mechanism of inhibition of the signaling pathway of inflammation was not completely elucidated. This study was conducted to evaluate the anti-inflammatory effect of etanercept in comparison to reference drugs (dexamethasone and indomethacin). Inflammation was induced by subcutaneal administration of carrageenan in the Swiss albino mice using the murine air pouch model. Exudation; leukocytes; myeloperoxidase (MPO); adenosine deaminase (ADA); nitric oxide metabolites (NOx); tumor necrosis factor (TNF); interferon gamma (IFN-γ); interleukins (IL) IL-6, IL-17, IL-10, IL-4, and IL-2; nuclear transcription factor kappa B (NF-κB) activation and apoptosis were evaluated 24 h after the induction of inflammation. Treatment with etanercept significantly inhibited exudate concentrations; leukocyte count; MPO and ADA activities; NOx, TNF, IFN-γ, and IL-17 levels; and NF-kappa B activation (p < 0.05). Etanercept induced apoptosis, reducing the number of viable neutrophils without increasing necrosis (p < 0.05). Our results suggest that the anti-inflammatory mechanism of action of etanercept may be via decrease of NF-κB activation. This effect promoted the reduction of pro-inflammatory cytokines and NOx and the induction of neutrophil apoptosis. The effect of etanercept upon neutrophils apoptosis may indicate the use of this drug therapy in the early stage of rheumatoid arthritis disease.

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Section: Discussionmentioning

confidence: 99%

Etanercept administration prevents the inflammatory response induced by carrageenan in the murine air pouch model

Mattei

Dalmarco

Fröde

2015

Naunyn-Schmiedeberg's Arch Pharmacol

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“…This model has been commonly used to determine pro-inflammatory effects of molecules including the evaluation of acute proinflammatory activity of NPs. [53][54][55] As illustrated in Figure 7, administration of 10, 100, 250, 500, or 1,000 µg/mL of unloaded PLGA NPs or 10, 100, 250, 500 µg/mL of PLGA-BSA NPs did not significantly increase the total number of attracted leukocytes into the air pouch 6 hours postinjection when compared with the control mice. However, administration of 1,000 µg/mL of PLGA-BSA NPs significantly increased leukocyte infiltration into the air pouch to the same extent of theTiO 2 positive control NPs ( Figure 7B).…”

Section: Inflammatory Propertiesmentioning

confidence: 96%

Preparation, characterization, and safety evaluation of poly(lactide-co-glycolide) nanoparticles for protein delivery into macrophages

Guedj¹,

Kell²,

Barnes³

et al. 2015

IJN

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Following infection, HIV establishes reservoirs within tissues that are inaccessible to optimal levels of antiviral drugs or within cells where HIV lies latent, thus escaping the action of anti-HIV drugs. Macrophages are a persistent reservoir for HIV and may contribute to the rebound viremia observed after antiretroviral treatment is stopped. In this study, we further investigate the potential of poly(lactic- co -glycolic) acid (PLGA)-based nanocarriers as a new strategy to enhance penetration of therapeutic molecules into macrophages. We have prepared stable PLGA nanoparticles (NPs) and evaluated their capacity to transport an active molecule into the human monocyte/macrophage cell line THP-1 using bovine serum albumin (BSA) as a proof-of-concept compound. Intracellular localization of fluorescent BSA molecules encapsulated into PLGA NPs was monitored in live cells using confocal microscopy, and cellular uptake was quantified by flow cytometry. In vitro and in vivo toxicological studies were performed to further determine the safety profile of PLGA NPs including inflammatory effects. The size of the PLGA NPs carrying BSA (PLGA-BSA) in culture medium containing 10% serum was ~126 nm in diameter, and they were negatively charged at their surface (zeta potential =−5.6 mV). Our confocal microscopy studies and flow cytometry data showed that these PLGA-BSA NPs are rapidly and efficiently taken up by THP-1 monocyte-derived macrophages (MDMs) at low doses. We found that PLGA-BSA NPs increased cellular uptake and internalization of the protein in vitro. PLGA NPs were not cytotoxic for THP-1 MDM cells, did not modulate neutrophil apoptosis in vitro, and did not show inflammatory effect in vivo in the murine air pouch model of acute inflammation. In contrast to BSA alone, BSA encapsulated into PLGA NPs increased leukocyte infiltration in vivo, suggesting the in vivo enhanced delivery and protection of the protein by the polymer nanocarrier. We demonstrated that PLGA-based nanopolymer carriers are good candidates to efficiently and safely enhance the transport of active molecules into human MDMs. In addition, we further investigated their inflammatory profile and showed that PLGA NPs have low inflammatory effects in vitro and in vivo. Thus, PLGA nanocarriers are promising as a drug delivery strategy in macrophages for prevention and eradication of intracellular pathogens such as HIV and Mycobacterium tuberculosis .

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“…Finally, the gels were stained with the PhastGel Blue R-350 Staining Kit (GE Healthcare) and the densities of the bands were analyzed with the ImageQuant TL software (GE Healthcare; ref. 25). The concentrations of MMP-9 and MMP-2 were calculated on the basis of the density of the bands, the recovery of the internal reference after co-prepurification, and a dilution series of recombinant wild-type MMP-9 of known concentration.…”

Section: Zymography Analysismentioning

confidence: 99%

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

Grünwald

Vandooren

Gerg

et al. 2016

Molecular Cancer Research

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Matrix metalloproteinase 9 (MMP-9/Gelatinase B) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and plays a central role in tumor cell invasion and metastasis. Here we complemented mechanistic insights in the cancer biology of MMP-9 and investigated the effects of specific long-term lossof-function, by genetic ablation, of MMP-9 on PDAC initiation and progression in the well-established KPC mouse model of spontaneous PDAC. Tumor growth and progression were analyzed by histopathology and IHC. Invasive growth of PDAC cells was analyzed by both in vitro (proliferation, survival, migration, invasion assays) and in vivo (experimental metastasis assays) methods. Retroviral shRNAi was used to knockdown target genes (MMP-9, IL6R). Gene expression was analyzed by qRT-PCR, immunoblot, ELISA, in situ hybridization, and zymography. PDAC tumors from MMP-9-deficient mice were dramatically larger, more invasive, and contained more stroma.Yet, ablation of MMP-9 in PDAC cells did not directly promote invasive growth. Interestingly, systemic ablation of MMP-9 led to increased IL6 levels resulting from abrogation of MMP-9-dependent SCF signaling in the bone marrow. IL6 levels in MMP-9 À/À mice were sufficient to induce invasive growth and STAT3 activation in PDAC cells via IL6 receptor (IL6R). Interference with IL6R blocked the increased invasion and metastasis of PDAC cells in MMP-9-deficient hosts. In conclusion, ablation of systemic MMP-9 initiated fatal communication between maintenance of physiological functions of MMP-9 in the bone marrow and invasive growth of PDAC via the IL6/ IL6R/STAT3 axis.Implications: Thus, the beneficial effects of host MMP-9 on PDAC are an important caveat for the use of systemic MMP-9 inhibitors in cancer.

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Intradermal air pouch leukocytosis as an in vivo test for nanoparticles

Cited by 26 publications

References 40 publications

Etanercept administration prevents the inflammatory response induced by carrageenan in the murine air pouch model

Etanercept administration prevents the inflammatory response induced by carrageenan in the murine air pouch model

Preparation, characterization, and safety evaluation of poly(lactide-co-glycolide) nanoparticles for protein delivery into macrophages

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

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