The Development of a New Patient-Reported Outcome Measure in Recessive Ataxias: The Person-Reported Ataxia Impact Scale.

Autosomal recessive cerebellar ataxias (ARCAs) are inherited neurological disorders that can affect both the central and peripheral nervous systems. To assess the effects of interventions according to the perception of people affected, patient-reported outcome measures (PROMs) must be available. This paper presents the development process of the Person-Reported Ataxia Impact Scale (PRAIS), a new PROM in recessive ataxias, and the documentation of its content validity, interpretability, and construct validity (structural and discriminant). The development followed the PROMIS framework and the Food and Drug Administration guidelines. A mixed-method study design was used to develop the PROM. A systematic review of the literature, semistructured interviews, and discussion groups was conducted to constitute an item pool. Experts' consultation helped formulate items, and the questionnaire was sent online to be completed by people affected. Statistical analyses were performed to assess the structural and discriminant validity. A total of 125 people affected by recessive ataxia completed the questionnaire. The factor analysis confirmed the three components: physical functions and activities, mental functions, and social functions. The statistical analysis showed that it can discriminate between stages of mobility and level of autonomy. It showed very good levels of internal consistency (0.79 to 0.89). The Person-Reported Ataxia Impact Scale (PRAIS) is a 38-item questionnaire that assesses the manifestations and impacts of the disease according to the perception of people affected by recessive ataxia. It can be used in clinical and research settings.

Impact of gold nanoparticles (AuNPs) on eosinophils isolated from male and female individuals.

It is well established that some differences exist between the male and female immune systems. Despites this, a sex-based analysis is not frequently performed in most scientific published reports. Knowing that inflammation is a common undesired effect observed resulting from nanoparticle (NP) exposure, we investigate here how in vitro treatment of gold NPs with a primary size of 20 and 70 nm (AuNP20 and AuNP70, respectively) will alter the biology of human eosinophils isolated from men and women blood. We found that treatment of AuNP70, but not AuNP20, significantly delay apoptosis only in eosinophils isolated from women. AuNPs were found to decrease eosinophil phagocytosis, however, significance was only observed in AuNP20-induced eosinophils isolated from women. The production of IL-8 was significantly increased in response to both AuNPs but only in eosinophils isolated from men and the production of IL-1ß was increased in AuNPs-induced eosinophils, although significance was observed only in AuNP70-induced eosinophils isolated from women. We conclude that future studies investigating the toxicity of AuNPs (or other NPs) should include a sex-based analysis, especially if the tested NPs have potential medical applications knowing the increased interest in the development of personalized precision medicine.

Impact of gold nanoparticles (AuNPs) in human neutrophils in vitro and in leukocytes attraction in vivo: A sex-based analysis.

Some differences exist between the male and female immune systems. Despite this, a sex-based analysis is not frequently performed in most studies. Knowing that inflammation is a common undesired effect observed resulting from nanoparticle (NP) exposure, we investigate here how gold NPs with a primary size of 20 (AuNP20) and 70 nm (AuNP70) will alter the biology of polymorphonuclear neutrophil cells (PMNs) isolated from men and women as well as their potential pro-inflammatory effect in vivo in male and female mice. We found that AuNP20 significantly delay apoptosis only in PMN isolated from men. The production of interleukin (IL)- 8 by PMNs was increased by both AuNPs regardless of sex although significance was only observed in AuNP20-induced PMNs. Using the murine air pouch model of inflammation, AuNPs did not induce a neutrophilic infiltration regardless of sex. In conclusion, AuNPs could differently alter the biology of PMNs according to sex.

Drug Self-Aggregation into Nano-Entities Has the Potential to Induce Immune Responses.

The free-state solution behaviors of small molecules profoundly affect their respective properties. It is becoming more obvious that compounds can adopt a three-phase equilibrium when placed in an aqueous solution, among soluble-lone molecule form, self-assembled aggregate form (nano-entities), and solid precipitate form. Recently, correlations have emerged between the existence of self-assemblies into drug nano-entities and unintended side effects. This report describes our pilot study involving a selection of drugs and dyes to explore if there may be a correlation between the existence of drug nano-entities and immune responses. We first implement practical strategies for detecting the drug self-assemblies using a combination of nuclear magnetic resonance (NMR), dynamic light scattering (DLS), transmission electron microscopy (TEM), and confocal microscopy. We then used enzyme-linked immunosorbent assays (ELISA) to monitor the modulation of immune responses on two cellular models, murine macrophage and human neutrophils, upon exposure to the drugs and dyes. The results suggest that exposure to some aggregates correlated with an increase in IL-8 and TNF-α in these model systems. Given this pilot study, further correlations merit pursuing on a larger scale given the importance and potential impact of drug-induced immune-related side effects.

Interaction between iron oxide nanoparticles (IONs) and primary human immune cells: An up-to-date review of the literature.

Nanotechnology has been gaining more and more momentum lately and the potential use of nanomaterials such as nanoparticles (NPs) continues to grow in a variety of activity sectors. Among the NPs, iron oxide nanoparticles (IONs) have retained an increasing interest from the scientific community and industrials due to their superparamagnetic properties allowing their use in many fields, including medicine. However, some undesired effects of IONs and potential risk for human health are becoming increasingly reported in several studies. Although many in vivo studies reported that IONs induce immunotoxicity in different animal models, it is not clear how IONs can alter the biology of primary human immune cells. In this article, we will review the works that have been done regarding the interaction between IONs and primary immune cells. This review also outlines the importance of using primary immune cells in risk assessment of NPs as a reliable strategy for encouraging non-animal studies approaches, to determine risks that might affect the human immune system following different exposure scenarios. Taken all together, the reported observations help to get a more global picture on how IONs alter the human immune system especially the fact that inflammation, known to involve several immune cell types, is frequently reported as an undesired effect of IONs.

Impact of ultra-small silver nanoparticles of 2 nm (AgNP2) on neutrophil biology: AgNP2 alter the actin cytoskeleton and induce karyorrhexis by a mitogen-activated protein kinase-dependent mechanism in vitro and transitorily attract neutrophils in vivo.

Silver (Ag) is known as an antibacterial agent and there is a growing interest to use silver nanoparticles (AgNPs) in a variety of medical applications and other sectors. Some studies reported that one of the undesired effects of AgNPs is inflammation and that these NPs can alter the biology of neutrophils. Since it is commonly accepted that the more NPs are small, the more toxic they are the aim of this study was to determine the impact of ultra-small silver nanoparticles of 2 nm (AgNP2) on the biology of neutrophils, key player cells in inflammation. We report that AgNP2 are potent neutrophil activators as they rapidly induce actin polymerization and dismantling the actin network. Although AgNP2 are not necrotic for neutrophils and do not induce ROS production, kinetic studies reveal that AgNP2 are rapid inducer of apoptosis. Pyknosis (mainly 1-2 large nuclear dots) was observed after only 1h of treatment followed by karyorrhexis (several small dots) and by a complete nuclear dissolution leading to anuclear neutrophils after 6h. These observations are not associated with the release of silver ions since treatment of neutrophils with 1-50 µg/ml AgNO3 (as a source of Ag+) did not induce any apparent changes. AgNP2 induce p38 and Erk-1/2 mitogen-activated protein kinase (MAPK) and although karyorrhexis was markedly reversed by MAPK inhibitors, the cell nuclei remain with a pyknotic-like phenotype but do not return to the characteristic polylobed nucleus. Using the murine air pouch model of inflammation AgNP2 were found to induce a neutrophil influx. Our data indicate that AgNP2 are potent neutrophil activators targeting the actin cytoskeleton and the mechanism involved for inducing apoptosis is rapid, complex, and partially includes MAPK pathways. Therefore, the ultra-small AgNP2 are more potent than larger ones for inducing apoptosis and they can transitorily attract neutrophils in vivo.

Interaction between iron oxide nanoparticles (Fe3O4 NPs) and human neutrophils: Evidence that Fe3O4 NPs possess some pro-inflammatory activities.

Iron oxide nanoparticles (Fe3O4 NPs) are important for different medical applications. However, potential toxicity has been reported and several parameters must still be studied to reach highest therapeutic efficacy with minimal undesired effects. Inflammation is one of the most reported undesired effects of NP exposure in a variety of inflammatory models and conflicting data exist regarding whether Fe3O4 NPs possess pro- or anti-inflammatory activities. The aim of this study was to determine the direct effect of Fe3O4 NPs on the biology of neutrophil, a key player cell in inflammation. Freshly isolated human neutrophils were incubated in vitro with Fe3O4 NPs, and several functions have been studied. Using transmission electronic microscopy, Fe3O4 NPs were found to be ingested by neutrophils. These NPs do not induce a respiratory burst by themselves, but they increase the ability of neutrophils to adhere onto human endothelial cells as well as enhance phagocytosis. An antibody array approach revealed that Fe3O4 NPs induce the production of some cytokines, including the chemokine IL-8 (CXCL8), which was confirmed by ELISA. Fe3O4NPs were found to delay spontaneous neutrophil apoptosis regardless of sex of the donor. Using a pharmacological approach, we demonstrate that Fe3O4 NPs delay apoptosis by a de novo protein synthesis-dependent mechanism and via different cell signalling pathways. The data indicate that Fe3O4 NPs can alter the biology of human neutrophils and that they possess some pro-inflammatory effects, particularly based on their capacity to delay apoptosis and to induce the production of pro-inflammatory cytokines. Therefore, Fe3O4 NPs can regulate inflammation by targeting human neutrophil functions.

Evaluating the Apoptotic Cell Death Modulatory Activity of Nanoparticles in Men and Women Neutrophils and Eosinophils.

Apoptosis is an important cell death mechanism for the resolution of inflammation. Neutrophil spontaneous apoptosis rates were reported to be slightly different in men and women and to be modulated by female sex hormones. The aim of this study was to determine whether different nanoparticles (NPs) will alter the neutrophil and eosinophil apoptotic rates differently in men and women. Using the antiapoptotic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) and the proapoptotic plant lectin Viscum album agglutinin-I (VAA-I) as controls, we found that these factors respectively delay and induce apoptosis in both neutrophils and eosinophils with apoptotic rates remarkably similar in both sexes. The polyamidoamine (PAMAM) dendrimers of generation 0 (G0) and G3 slightly, but not significantly, accelerate neutrophil apoptosis regardless of sex. Zinc oxide (ZnO), titanium dioxide (TiO2), cerium dioxide (CeO2), and palladium (Pd) but not platinum (Pt) NPs were found to significantly delay neutrophil apoptosis. When results were compared between men and women, only ZnO and Pd NPs were found to significantly delay neutrophil apoptosis in men while ZnO, TiO2, CeO2, and Pt NPs inhibit apoptosis in women neutrophils. In eosinophils, G3, but not G0 NPs, significantly accelerate apoptosis in women. ZnO, Pt, and Pd NPs significantly delay eosinophil apoptosis but only in women. Unlike neutrophils, TiO2 and CeO2 NPs did not significantly delay eosinophil apoptosis. We propose that future studies aiming at determining potential effect NPs on cellular biological processes should incorporate a sex-based analysis based on the differences reported here studying the impact of NPs on human granulocyte apoptosis.

Activation of Human Eosinophils with Nanoparticles: a New Area of Research.

It is becoming increasingly clear that nanoparticles (NPs) possess many potential applications in both clinical medicine and research. Potential utilization of NPs in nanomedicine for the treatment of respiratory diseases where eosinophils exert pathogenic roles is gaining increasing attention. Even though several NPs were found to possess pro-inflammatory activities in in vivo models based on an increased number of eosinophils in rodent airways, it is not clear how NPs could directly activate eosinophils themselves and how they can alter their biology. In this review, we discuss the most recent data in this new area of research demonstrating that NPs could now be added as new eosinophils modulators. Indeed, activation of eosinophils with NPs could lead to modulation of spontaneous apoptosis, caspase activation, and cytoskeleton breakdown when apoptosis is induced; cytokine production, de novo protein synthesis, cellular adhesion onto a cell substratum, and cell signalling events such as activation of the phosphoinositide 3-kinase/Akt pathway and actin re-localization are involved in NP-induced adhesion. Therefore, future development of therapeutic strategies with NPs aiming at targeting diseases where eosinophils are involved should now consider the capacity of NPs to modulate human eosinophil biology.

Biological activities of interleukin (IL)-21 in human monocytes and macrophages.

The biological roles of interleukin (IL)-21 in human monocytes and macrophages have been neglected. We previously demonstrated that IL-21 induce phagocytosis and established that Syk is a new molecular target of IL-21. Herein, we found that IL-21 is not chemoattractant for immature THP-1 and primary monocytes but can increase the capacity of THP-1 cells (not primary monocytes) to adhere onto a cell substratum by a Syk-dependent mechanism without altering the expression of a panel of cell surface molecules. Unlike THP- 1 and monocytes, IL-21 can increase metalloproteinase (MMP)-9 secretion and activity in monocyte-derived macrophages (HMDM), as assessed by western blot and zymography experiments, respectively. We reported that IL-21 did not increase the production of IL-6 and the chemokines MIP-1α and GRO-α in HMDM. Therefore, IL-21 can increase functions other that phagocytosis, but this cytokine does not have a large spectrum of biological activities in monocytes and macrophages.

Titanium dioxide nanoparticles induce human eosinophil adhesion onto endothelial EA.hy926 cells via activation of phosphoinositide 3-kinase/Akt cell signalling pathway.

The use of nanoparticles (NPs) for developing new therapeutic strategies in a variety of diseases is gaining increasing attention. However, NPs could possess undesired effects, including pro-inflammatory activities. Despite the fact that several studies reported that NPs may induce or exacerbate eosinophilic inflammation in vivo in rodents, the information regarding the direct interaction between NPs and human eosinophils is lacking. In the present study, we test the possibility that NPs could alter the capacity of human eosinophils to adhere onto a cellular substratum. Using a panel of NPs, we found that several were able to increase the adhesion of human eosinophil onto endothelial EA.hy926 cells. Among them, TiO2 NPs were the most potent and we therefore pursue this study with these NPs. TiO2 NPs were found to increase the adhesion of eosinophils in a concentration dependent fashion. TiO2 NPs did not alter the cell surface expression of a panel of cellular adhesion molecules, but CD29. Indeed, a weak to moderate, but significant, decrease of CD29 was observed after 30min but returned to normal levels after 90min. TiO2 NPs were found to activate Akt, one important target of phosphoinositide 3-kinase (PI3K). However, despite the fact that cells were fully responsive to the cytokine GM-CSF activating both Akt and Erk-1/2, TiO2 NPs did not activate Erk-1/2. Using a pharmacological approach with the PI3K/Akt inhibitor, wortmannin, the ability of TiO2 NPs to activate Akt was drastically inhibited and, further, their capacity to increase adhesion of eosinophils was reversed. This study provides insights into the effects of NPs on the biology of human eosinophils indicating that as other agents, NPs, namely TiO2 NPs, can induce intracellular events associated with a cellular function, adhesion.

WITHDRAWN: Titanium dioxide nanoparticles induce human eosinophil adhesion onto endothelial EA.hy926 cells via activation of phosphoinositide 3-kinase/Akt cell signalling pathway.

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Evaluation of the in vitro and in vivo proinflammatory activities of gold (+) and gold (-) nanoparticles.

OBJECTIVE AND DESIGN: The aim of this study was to determine potential effects of gold (+) and gold (-) nanoparticles, AuNP(+) and AuNP(-), on neutrophil biology. MATERIAL OR SUBJECTS: Freshly isolated human neutrophils were used for the in vitro aspects and CD-1 mice were used in the in vivo murine air pouch model of acute neutrophilic inflammation. TREATMENT: Human neutrophils were treated with the indicated concentrations of AuNP(+) or AuNP(-) in vitro and mice received 100 or 500 µg/ml AuNP(+) or AuNP(-) into air pouches. METHODS: Cellular uptake of AuNP by neutrophils was confirmed by transmission electron microscopy and the ability of the NP to modulate apoptosis, gelatinase activity, and chemokine production and chemotaxis was determined by cytology, zymography, ELISArray, antibody array, and ELISA and by a micro-chemotaxis chamber, respectively. In vivo, exudates were harvested after 6 h to determine the leukocyte infiltration to detect the production of several cytokines by an antibody array approach and ELISA. One-way analysis of variance was used for statistical analysis. RESULTS: AuNP possess proinflammatory activities in vitro and induce mainly a neutrophil influx in vivo, albeit at different degrees. CONCLUSIONS: AuNP(+) and AuNP(-) should be added as new candidates into a growing list of NP having proinflammatory activities by themselves.

Cytotoxicity assessment, inflammatory properties, and cellular uptake of Neutraplex lipid-based nanoparticles in THP-1 monocyte-derived macrophages.

Current antiretroviral drugs used to prevent or treat human immunodeficiency virus type 1 (HIV-1) infection are not able to eliminate the virus within tissues or cells where HIV establishes reservoirs. Hence, there is an urgent need to develop targeted delivery systems to enhance drug concentrations in these viral sanctuary sites. Macrophages are key players in HIV infection and contribute significantly to the cellular reservoirs of HIV because the virus can survive for prolonged periods in these cells. In the present work, we investigated the potential of the lipid-based Neutraplex nanosystem to deliver anti-HIV therapeutics in human macrophages using the human monocyte/macrophage cell line THP-1. Neutraplex nanoparticles as well as cationic and anionic Neutraplex nanolipoplexes (Neutraplex/small interfering RNA) were prepared and characterized by dynamic light scattering. Neutraplex nanoparticles showed low cytotoxicity in CellTiter-Blue reduction and lactate dehydrogenase release assays and were not found to have pro-inflammatory effects. In addition, confocal studies showed that the Neutraplex nanoparticles and nanolipoplexes are rapidly internalized into THP-1 macrophages and that they can escape the late endosome/lysosome compartment allowing the delivery of small interfering RNAs in the cytoplasm. Furthermore, HIV replication was inhibited in the in vitro TZM-bl infectivity assay when small interfering RNAs targeting CXCR4 co-receptor was delivered by Neutraplex nanoparticles compared to a random small interfering RNA sequence. This study demonstrates that the Neutraplex nanosystem has potential for further development as a delivery strategy to efficiently and safely enhance the transport of therapeutic molecules into human monocyte-derived macrophages in the aim of targeting HIV-1 in this cellular reservoir.

Silver nanoparticles induce irremediable endoplasmic reticulum stress leading to unfolded protein response dependent apoptosis in breast cancer cells.

Nowadays, silver nanoparticles (AgNP) are widely used in the medical field mainly for their antibacterial properties. Although some studies report a cytotoxic activity of the particles, the mechanisms involved in AgNP-induced cell death remain to be determined. Herein, we report that AgNP of 2 (AgNP2) and 15 nm (AgNP15) induce apoptosis in human MCF-7 and T-47D breast cancer cells. Treatment with AgNP2 and AgNP15 led to accumulation and aggregation of misfolded proteins causing an endoplasmic reticulum (ER) stress and activating the unfolded protein response (UPR). The three main ER sensors, PERK, IRE-1α and ATF-6, were rapidly activated in response to AgNP2 and AgNP15. Although Grp78 levels remained unchanged, AgNP2 and AgNP15 induced upregulation of the transcription factors ATF-4 and GADD153/CHOP. Moreover, the initiating caspase-9 and the effector caspase-7 were activated in response to these NPs. The expression levels of the pro-apoptotic BIM and BAD proteins remained unchanged. In contrast, a downregulation of Mcl-1 and xIAP protein expression as well as a processing of PARP were observed. Pharmacological inhibition of PERK kinase and IRE-1 endonuclease activities, as well as inhibition of ER-stress, partially protected cells from AgNP2- and AgNP15-induced apoptosis. Of note, the non-cancerous MCF-10A cells were more resistant to both AgNP2 and AgNP15 when compared to MCF-7 and T-47D cell lines. Taken together, our results demonstrate that AgNP induce ER stress and can target the UPR-dependent apoptotic pathway in MCF-7 and T-47D, which highlights new potential strategies for the treatment of breast cancers.

Human eosinophils are direct targets to nanoparticles: Zinc oxide nanoparticles (ZnO) delay apoptosis and increase the production of the pro-inflammatory cytokines IL-1ß and IL-8.

Zinc oxide NPs (ZnO) have been recently proposed as novel candidates for the treatment of allergic inflammatory diseases. Paradoxically, recent data suggested that ZnO could cause eosinophilic airway inflammation in rodents. Despite the above observations, there are currently no studies reporting direct interaction between a given NP and human eosinophils themselves. In this study, freshly isolated human eosinophils were incubated with ZnO and several cellular functions were studied. We found that ZnO delay human eosinophil apoptosis, partially by inhibiting caspases and by preventing caspase-4 and Bcl-xL degradation. ZnO do not induce production of reactive oxygen species but increase de novo protein synthesis. In addition, ZnO were found to increase the production of the proinflammatory IL-1ß and IL-8 cytokines. Using a pharmacological approach, we demonstrated that inhibition of caspase-1 reversed the ability of ZnO to induce IL-1ß and IL-8 production, whereas inhibition of caspase-4 only reversed that of IL-8. Our results indicate the necessity of conducting studies to determine the potential of using NP as nanotherapies, particularly in diseases in which eosinophils may be involved. We conclude that, indeed, human eosinophils represent potential new direct targets to NPs, ZnO in the present case.

Activation of human AML14.3D10 eosinophils by nanoparticles: Modulatory activity on apoptosis and cytokine production.

Eosinophilic inflammation is frequently observed in response to nanoparticle (NP) exposure in airway rodent models of allergies where the number of eosinophils is increased in lungs. Despite this, it is surprising that the potential cytotoxic effect of NP, as well as their direct role on eosinophils is poorly documented. The present study investigated how different NP can alter the biology of the human eosinophilic cell line AML14.3D10. It was found that among NP forms of CeO2, ZnO, TiO2, and nanosilver of 20 nm (AgNP20) or 70 nm (AgNP70) diameters, only ZnO and AgNP20 induced apoptosis. Caspases-7 and -9 were not activated by the tested NP while caspase-3 was activated by AgNP20 only. However, both ZnO and AgNP20 induced cytoskeletal breakdown as evidenced by the cleavage of lamin B1. Using an ELISArray approach for the simultaneous detection of several analytes (cytokines/chemokines), it was found that only ZnO and AgNP20 increased the production of different analytes including the potent pro-inflammatory CXCL8 (IL-8) chemokine. From the data here, we conclude that toxic effects of some NP could be observed in human eosinophil-like cells and that this could be related, at least partially, by induction of apoptosis and production of cytokines and chemokines involved in inflammation. The results of this study also indicate that distinct NP do not activate similarly human eosinophils, since ZnO and AgNP20 induce apoptosis and cytokine production while others such as TiO2, CeO2, and AgNP70 do not.

In vivo proinflammatory activity of generations 0-3 (G0-G3) polyamidoamine (PAMAM) nanoparticles.

OBJECTIVE AND DESIGN: The aim of this study was to determine whether different generations (G) polyamidoamine (PAMAM) dendrimers possess proinflammatory activities in vivo. MATERIAL OR SUBJECTS: Several hundred female CD-1 mice were used to test four different PAMAM dendrimers using the murine air pouch model. TREATMENT: Mice received appropriate negative and positive controls or G0-G3 PAMAM nanoparticles at 100 and 500 µg/ml into air pouches. METHODS: Exudates were harvested after 3, 6, 24 and 48 h. Cell pellets and supernatants were used to determine the number of total leukocytes and neutrophils and to detect the production of several analytes by an antibody array approach, respectively. One-way analysis of variance was used for statistical analysis. RESULTS: PAMAM dendrimers rapidly increased a leukocyte influx after 3 h, the vast majority of cells being neutrophils. This was also observed after 6 and 24 h, and resolution of inflammation was noted after 48 h. In general, the increased production of a greater number of analytes detected in the exudates after 6 h correlated with the number of dendrimer generations (G3 > G2 > G1 > G0). CONCLUSIONS: PAMAM dendrimers devoid of any delivering molecules possess proinflammatory activities in vivo by themselves, probably via the production of different chemokines released by air pouch lining cells.

Silver nanoparticles of 70 nm and 20 nm affect differently the biology of human neutrophils.

The influence of size of nanoparticles (NP), especially in regard to pulmonary toxicity, has been widely investigated. In general, NP with smaller diameters are more pro-inflammatory in vivo, at least in terms of neutrophil influx. Nevertheless, the influence of size of NP on polymorphonuclear neutrophil (PMN) cell biology is poorly documented. In the study here, it was decided to determine if AgNP with a diameter of 70 nm (AgNP70) will alter the biology of human PMN similarly to AgNP20 previously reported to induce apoptosis and inhibit de novo protein synthesis. The results here indicated that, in contrast to AgNP20, AgNP70 delayed PMN apoptosis. However, both AgNP20 and AgNP70 inhibited de novo protein synthesis. Both forms of AgNP did not significantly increase reactive oxygen species (ROS) production, but AgNP20 significantly increased the cell production of the CXCL8 chemokine (IL-8). In addition, AgNP20, but not AgNP70, induced the release of albumin and matrix metalloproteinase-9 (MMP-9/gelatinase B) into culture supernatants. Consistent with this latter observation, gelatinase activity was increased by AgNP20, as assessed by zymography. From these outcomes, it is concluded that two NP with different initial diameters can possess similar - as well as distinct - biological properties in modulating human PMN functions. These outcomes are testimony to the complexity of the modes of action of NP at the cellular level.