The impact of nanomaterials in immune system.

As a nanotechnology has been actively applied to the overall areas of scientific fields, it is necessary to understand the characteristic features, physical behaviors and the potential effects of exposure to nanomaterials and their toxicity. In this article we review the immunological influences induced by several nanomaterials and emphasize establishment of the animal models to estimate the impact of these nanomaterials on development of immunological diseases.

INTRODUCTION

A nanotechnology which has appeared since the mid-twenties century has provided the methods by which the limitations in the industrial application of each scientific technology could be overcome. It has also brought another revolutionary change to the overall areas in the scientific technology and the related industries. A nanotechnology has become a basis of the integrated development of scientific technology which has independently been developed. It has also been actively applied to the overall areas of scientific fields. The characteristics of nanomaterials are subject to their surface property, according to which the desirable physical property can be given deliberately to them.

As described here, products manufactured using nanomaterials are characterized to overcome the areas which cannot be resolved with the previous technology. It can therefore be stated that they have a higher degree of applicability. Synchronously, there is an increasing concern that they would be new hazardous factors for both humans and nature (1). In identifying and then clarifying risks due to exposure to nanomaterials, it is extremely important to clarify the physicochemical property and physical behavior of nanomaterials and to understand the biological and physiological actions of them in an in vivo setting (2). Based on this, a systematic approach should be made to examine the possible detrimental effects on the production, environment and health. In general, methods for assessing the detrimental effects of conventional types of chemicals are divided into the definition of detrimentalness, the assessment of dose-response, that of exposure and that of detrimental characteristics. These methods can also be applied to nanomaterials. In nanomaterials, however, as their surface area is increased, their responsiveness and toxicity to viable tissues are also increased (3). It is of prime importance to clarify new physicochemical property and to evaluate the resulting toxicity of them. Accordingly in the assessment of detrimentalness of nanomaterials, it is necessary to understand the characteristic features, physical behaviors, the potential effects of exposure to nanomaterials and their toxicity (4).

IMMUNOLOGICAL EFFECTS OF NANOMATERIALS

Nanomaterials have a structure that the size of one of three surfaces is 1~100 nm according to the definition made by ISO/TC 229. As described here, based on a smaller size of <100 nm, nanomaterials have physicochemical properties which are greatly different from general types of other substances. Due to a higher degree of surface reactivity and the cell membrane permeability, an in vivo influx of nanomaterials produces the stress on a cellular level.

Until the year of 2006, 69% of total manuscripts published on a peer-reviewed journal are related to the toxicity and the remaining 31% are related to the exposure. In particular, since 2008, research articles about the toxicity have been abruptly increased. These articles have reported the pulmonary toxicity, neurotoxicity and the permeability to blood-brain-barrier. Besides, peer-reviewed articles about the immunotoxicity have also been increasingly published.

Nanomaterials are crystalline, fine particles with a large surface area, and they have a higher degree of surface charge and proton exchangeability. Besides, it is also expected that they might have a positive effect on the environment because they facilitate the synthesis and transportation of contaminants in the environment. In addition, the potential problems of nanomaterials are not limited to the environmental pollution. By various routes such as an inhalation, they are absorbed into the body and then induce the biological toxicity (5,6). This makes nanomaterials further interesting. The possible routs by which nanomaterials migrate in the human body include the following:

Endocytosis: Nanomaterials enter the cells when they are surrounded by the cell membrane without passing it.

Cell membrane penetration occurring with the action of hydrophobic particles.

Transportation of nanoparticles with a size of <5 nm across the cell membrane channel.

As described here, it has been proposed that the contactable nanoparticles might stimulate the immune system in the body. By contrast, recent studies have been conducted to examine industrial nanoparticles. Industrial nanoparticles are mainly contacted in a working place by daily commodities or pharmaceutical products in customers. The total amount of exposure may be relatively lower or the actual one occurring in the local tissue might be relatively higher. Nanoparticles produce oxygen radicals (7,8). Besides, the mitochondrial perturbation and apoptosis (9) are induced, which are followed by the cytotoxicity. With the reactions with body proteins and other biological substances, various types of hazardous reactions might occur.

One of the advantages of nanoparticles, a biological permeability makes an intracellular and intranuclear influx of nanomaterials possible. Based on these findings, it has therefore been postulated that the oxidative stress and inflammatory responses induce the occurrence of immunotoxicity directly or indirectly. It is therefore imperative that the technology for assessing the exposure be established to examine the physicochemical properties of nanomaterials and to clarify the related immunotoxic mechanisms.

Peer-reviewed articles about the toxicity of nanomaterials have been summarized based on the chemical constituents. Based on the classification system into carbon nanomaterials, metals, metal-oxide nanomaterials and other silicas, a review of the above peer-reviewed journals was made. Results were represented in Tables I, II and III. For example, of carbon nanomaterials, carbon black induces the immune responses. In particular, multi-walled carbon nanotubes (MWCNT) rather than single-walled carbon nanotubes (SWCNT) induce the activation of immune responses to a greater extent (Table I). Of metals and metal oxides, iron oxide nanoparticles strongly induce the immune responses. Besides, gold nanoparticles induce a moderate degree of the immune responses. Furthermore, TiO2 induces a lower degree of the immune responses (Table II). In addition, it has also been reported that such substances as silica, polystyrene and latex nanomaterials have an immunotoxicity (Table III).

Table I

Immunotoxicity of carbon-based nanomaterials

Table II

Immunotoxicity of metal-based nanomaterials

Table III

Immunotoxicity related of silica or polystyrene-based nanomaterials

THE NECESSITY FOR CONDUCTING STUDIES ABOUT THE RELATEDNESS TO DISEASE THROUGH AN ANIMAL EXPERIMENTAL MODEL OF PULMONARY DISEASES IN AN IN VIVO SETTING

Relatedness of nanomaterials to diseases can be presumed based on studies about the particulate matter (PM) associated with air pollution and the diseases (10-12). A long-term exposure to particulate matter (PM) increases the incidence of complications associated with pulmonary (13,14) and cardiovascular diseases (15) and the resulting mortality. The occurrence of malignant mesothelioma due to an inhalation of asbestos fiber (16,17), which has become a socially issue in recent years, well illustrates the hazardousness of microparticles. Particulate matters (PM10) of <10 µm in size are associated with respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute/chronic bronchitis and lower respiratory tract diseases and cardiovascular diseases such as myocardial infarction, arrhythmias and arteriosclerosis. Besides, particulate matters (PM2.5) of <2.5 µm in size have a poorer effect on the respiratory system and cardiovascular one as compared with PM10 and they also raise the mortality. An analysis was performed for the correlation between the concentration of PM2.5 and the mortality in the USA, according to which 100,000 people are found to die directly or indirectly due to PM2.5 every year.

The number of particulate matters in the atmosphere has been reported to be associated with the occurrence of respiratory diseases. Since then, it has been proposed that nanoparticles inhaled through a mathematical model of the expansion of human lungs might be deposited in an area ranging from the trachea to terminal bronchioles. The surface area of particles rather the amount of particles are associated with the occurrence of inflammatory responses. At the present, no studies have provided the possibility that carbon nanotubes, nano-fibers and nano-wire products might induce the detrimentalness to such an equivalent extent to asbestos. Nevertheless, to rule out this possibility, it is imperative that the safety following a long-term exposure to above materials be audited. An experimental animal model of a long-term exposure would therefore be mandatory.

Nanoparticles contained in particulate matter are known as a strong inducer of oxidative stress in macrophages and epithelial cells lining the airway tract. They increase the activity such molecules as MAP kinase, NF-κB and AP-1 and also promotes the synthesis of oxygen radicals (18,19). This phenomenon is explained as one of the key pathophysiologic mechanisms by which COPD occurs, one of the representative chronic inflammatory respiratory tract diseases. It has been hypothesized that COPD might be a type of dust-induced diseases. In this regard, the use of particulate matters and biomass fuel which has recently been of increasing interest has been considered as a pathogenesis of COPD. Nanoparticles contained in the atmosphere have a possibility for aggravating the respiratory diseases.

In a murine model of asthma, one of the respiratory diseases, particulate matter of 0.2~10 µm in size was experimentally administered. According to this experiment, as the size of particles was relatively smaller, the deposition to the lower respiratory tracts was increased. Following the administration of microparticles into the airway tract in the above experimental model, the concentration of protein in the bronchoalveolar lavage is increased (20) and this is also accompanied by the increased occurrence of eosinophilic and neutrophilic inflammations occurring in the airway tract and the elevated levels of TH2 cytokines (IL-4, IL-5 and eotaxin) (21,22) as well as TH1 cytokines (IFN-γ, IL-6 and TNF-α) (23). Besides, following an intranasal administration of oil flash ash, a key substance for pathological phenomena due to particulate matters in a murine model of asthma, the occurrence of respiratory hypersensitivity and eosinophilic inflammation was further increased (24).

In regard to the effects of nanoparticles on the asthma, a murine model of albumin-induced asthma has shown that the inflammatory responses and the production of immunoglobluins were increased by nanoparticles in the respiratory tract (Fig. 1). These inflammatory phenomena are explained by the expression of IL-5 and eotaxin which was induced in the early stage of inflammation. Subsequently, with the induced expression of such cytokines as IL-13, RANTES and MCP-1, the degree of inflammation was further increased. Moreover, based on the reports that TiO2 which has frequently been used for cosmetic products aggravates the atopic dermatitis, it has been proposed that nanoparticles might aggravate the immune diseases.

Figure 1

Potential contribution of nanomaterials on asthma pathophysiology.

In conclusion, with the development of nanotechnology, a great deal of nanoproducts and the related materials have been produced. Due to a lack of the clarification of the potential hazard of technical development, however, demand and supply of the products have not been activated up to present. At the present, therefore, if guidelines or landmarks should be provided for safety assessment or data about the safety range including the immune toxicity of nanomaterials, this would greatly contribute to the activation of nanoindustry.