Abstract Air Pollution has been associated with significant adverse health effects leading to increased morbidity and mortality. Cumulative epidemiological and experimental data have shown that exposure to air pollutants lead to increased cardiovascular ischemic events and enhanced atherosclerosis. It appears that these associations are much stronger with the air particulate matter (PM) component and that in urban areas, the smaller particles could be more pathogenic, as a result of their greater propensity to induce systemic prooxidant and proinflammatory effects. Much is still unknown about the toxicology of ambient particulates as well as the pathogenic mechanisms responsible for the induction of adverse cardiovascular health effects. It is expected that better understanding of these effects will have large implications and may lead to the formulation and implementation of new regulatory policies. Indeed, we have found that ultrafine particles (<0.18 μm) enhance early atherosclerosis, partly due to their high content in redox cycling chemicals and their ability to synergize with known proatherogenic mediators in the promotion of tissue oxidative stress. These changes take place in parallel with increased evidence of phase 2 enzymes expression, via the electrophile-sensitive transcription factor, p45-NFE2 related transcription factor 2 (Nrf2). Exposure to ultrafine particles also results in alterations of the plasma HDL anti-inflammatory function that could be indicative of systemic proatherogenic effects. This article reviews the epidemiological, clinical and experimental animal evidence that support the association of particulate matter with atherogenesis. It also discusses the possible pathogenic mechanisms involved, the physicochemical variables that may be of importance in the greater toxicity exhibited by a small particle size, interaction with genes and other proatherogenic factors as well as important elements to consider in the design of future mechanistic studies. Extensive epidemiological evidence supports the association of air pollution with adverse health effects 123. It is increasingly being recognized that such effects lead to enhanced morbidity and mortality, mostly due to exacerbation of cardiovascular diseases and predominantly those of ischemic character 4. Indeed, in addition to the classical risk factors such as serum lipids, smoking, hypertension, aging, gender, family history, physical inactivity and diet, recent data have implicated air pollution as an important additional risk factor for atherosclerosis. This has been the subject of extensive reviews 56 and a consensus statement from the American Heart Association 7. This article reviews the supporting epidemiological and animal data, possible pathogenic mechanisms and future perspectives.

The purpose of this paper is to present a method for estimating particle doses that may be used to reconcile particle deposition doses used in in vitro toxicology studies with in vivo exposure levels. The focus is on the tracheobronchial (TB) tree of heavily exposed individuals. A review of the factors that influence inhaled particle deposition doses in environmental exposures leads to the identification of cases in which greater than average TB tree doses are received. Exercising individuals and those with chronic obstructive pulmonary disease not only inhale increased volumes of air but they also may have uneven ventilation that leads to greater than average particle deposition doses per unit of TB tree surface area. In addition, deposition hot spots, as occur at airway bifurcations, will greatly increase the particle exposures of target cells in the TB tree. Three particle exposure scenarios are proposed, and the average and local doses to the TB epithelium are calculated. When various factors that enhance particle doses (enhancement factors, or EFs) in vivo are considered, substantial particle doses may be justified for in vitro tissue culture studies that use TB target cells, such as epithelial cell cultures. The use of such EFs is intended to improve in vitro dosing with particles. Although the exposure of cells in vitro cannot fully replicate the complexity of in vivo exposures, it is possible to calculate toxicologically relevant doses that may define adverse health effects in potentially sensitive human populations. Local groups of TB cells in high-dose individuals are predicted to receive particle doses that are 3000-25,000 times higher than the doses averaged over the entire TB region.

We demonstrated that activated transcytosis is a major mechanism to complement the classic enhanced permeability and retention effect in pancreatic cancer. This was achieved by using an iRGD peptide that triggers transcytosis pathway at the tumor site. Co-administration of unconjugated iRGD substantially improved the effect of the chemotherapeutics delivering nanocarrier, and resulted in survival improvement in mice. Since the iRGD effect is commensurate with neuropilin-1 expression on tumor vasculature, it is necessary to contemplate a personalized approach to implement this technology.

Despite the formidable treatment challenges of pancreatic ductal adenocarcinoma (PDAC), considerable progress has been made in improving drug delivery via pioneering nanocarriers. These innovations are geared towards overcoming the obstacles presented by dysplastic stroma and fostering anti-PDAC immune reactions. We are currently conducting research aimed at enhancing chemotherapy to stimulate anti-tumor immunity by inducing immunogenic cell death (ICD). This is accomplished using lipid bilayer-coated nanocarriers, which enable the attainment of synergistic results. Noteworthy examples include liposomes and lipid-coated mesoporous silica nanoparticles known as silicasomes. These nanocarriers facilitate remote chemotherapy loading, as well as the seamless integration of immunomodulators into the lipid bilayer. In this communication, we elucidate innovative ways for further improving chemo-immunotherapy. The first is the development of a liposome platform engineered by the remote loading of irinotecan while incorporating a pro-resolving lipoxin in the lipid bilayer. This carrier interfered in stromal collagen deposition, as well as boosting the irinotecan-induced ICD response. The second approach was to synthesize polymer nanoparticles for the delivery of mutated KRAS peptides in conjunction with a TLR7/8 agonist. The dual delivery vaccine particle boosted the generation of antigen-specific cytotoxic T-cells that are recruited to lymphoid structures at the cancer site, with a view to strengthening the endogenous vaccination response achieved by chemo-immunotherapy.

Particulate matter (PM) is an important risk factor for asthma. Generation of oxidative stress by PM is a major mechanism of its health effects. Transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mediates antioxidant and phase II enzymes and is essential in protecting against oxidative stress and lung inflammation. We have previously shown that ambient ultrafine particles (UFP) could exert a potent adjuvant effect on allergic sensitization to ovalbumin (OVA) in mice. We hypothesized that Nrf2 deficiency in dendritic cells (DC) could enhance the adjuvant potential of UFP on allergic sensitization. We show that the adjuvant effect of intranasally instilled UFP is significantly enhanced in Nrf2 knockout (Nrf2(-/-)) mice compared with their wild-type (Nrf2(+/+)) counterparts. Under resting conditions, Nrf2(-/-) DC displayed an intrinsic predilection to a T helper 2-favoring cytokine profile characterized by a low level of IL-12p70 and a high level of IL-6 as compared to Nrf2(+/+) DC. Adoptive transfer of OVA/UFP-treated Nrf2(-/-) DC provoked a more severe allergic inflammation in the lung than Nrf2(+/+) DC in the same treatment group. We conclude that Nrf2 deficiency in DC may promote a constitutive immune-polarizing cytokine milieu, which we propose may have contributed to the augmented adjuvant effect of UFP on allergic sensitization.

Ultrafine particles (UFPs) are airborne particulates of less than 100 nm in aerodynamic diameter. Examples of UFPs are diesel exhaust particles, products of cooking, heating, and wood burning in indoor environments, and, more recently, products generated through the use of nanotechnology. Studies have shown that ambient UFPs have detrimental effects on both the cardiovascular and respiratory systems, including a higher incidence of atherosclerosis and exacerbation rate of asthma. UFPs have been found to alter in vitro and in vivo responses of the immune system to allergens and can also play a role in allergen sensitization. The inflammatory properties of UFPs can be mediated by a number of different mechanisms, including the ability to produce reactive oxygen species, leading to the generation of proinflammatory cytokines and airway inflammation. In addition, because of their small size, UFPs also have unique distribution characteristics in the respiratory tree and circulation and might be able to alter cellular function in ways that circumvent normal signaling pathways. Additionally, UFPs can penetrate intracellularly and potentially cause DNA damage. The recent advances in nanotechnology, although opening up new opportunities for the advancement of technology and medicine, could also lead to unforeseen adverse health effects in exposed human subjects. Further research is needed to clarify the safety of nanoscale particles, as well as the elucidation of the possible beneficial use of these particulates to treat disease.

Particulate pollutants cause adverse health effects through the generation of oxidative stress. A key question is whether these effects are mediated by the particles or their chemical compounds. In this article we show that aliphatic, aromatic, and polar organic compounds, fractionated from diesel exhaust particles (DEPs), exert differential toxic effects in RAW 264.7 cells. Cellular analyses showed that the quinone-enriched polar fraction was more potent than the polycyclic aromatic hydrocarbon (PAH)-enriched aromatic fraction in O2 .- generation, decrease of membrane potential (Delta-Psi m), loss of mitochondrial membrane mass, and induction of apoptosis. A major effect of the polar fraction was to promote cyclosporin A (CsA)-sensitive permeability transition pore (PTP) opening in isolated liver mitochondria. This opening effect is dependent on a direct effect on the PTP at low doses as well as on an effect on Delta-Psi m at high doses in calcium (Ca2+)-loaded mitochondria. The direct PTP effect was mimicked by redox-cycling DEP quinones. Although the aliphatic fraction failed to perturb mitochondrial function, the aromatic fraction increased the Ca2+ retention capacity at low doses and induced mitochondrial swelling and a decrease in Delta-Psi m at high doses. This swelling effect was mostly CsA insensitive and could be reproduced by a mixture of PAHs present in DEPs. These chemical effects on isolated mitochondria could be reproduced by intact DEPs as well as ambient ultrafine particles (UFPs). In contrast, commercial polystyrene nanoparticles failed to exert mitochondrial effects. These results suggest that DEP and UFP effects on the PTP and Delta-Psi m are mediated by adsorbed chemicals rather than the particles themselves.