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Inhalation of environmental stressors & chronic inflammation: Autoimmunity and neurodegeneration

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Abstract

Human life expectancy and welfare has decreased because of the increase in environmental stressors in the air. An environmental stressor is a natural or human-made component present in our environment that upon reaching an organic system produces a coordinated response. This response usually involves a modification of the metabolism and physiology of the system. Inhaled environmental stressors damage the airways and lung parenchyma, producing irritation, recruitment of inflammatory cells, and oxidative modification of biomolecules. Oxidatively modified biomolecules, their degradation products, and adducts with other biomolecules can reach the systemic circulation, and when found in higher concentrations than normal they are considered to be biomarkers of systemic oxidative stress and inflammation. We classify them as metabolic stressors because they are not inert compounds; indeed, they amplify the inflammatory response by inducing inflammation in the lung and other organs. Thus the lung is not only the target for environmental stressors, but it is also the source of a number of metabolic stressors that can induce and worsen pre-existing chronic inflammation. Metabolic stressors produced in the lung have a number of effects in tissues other than the lung, such as the brain, and they can also abrogate the mechanisms of immunotolerance. In this review, we discuss recent published evidence that suggests that inflammation in the lung is an important connection between air pollution and chronic inflammatory diseases such as autoimmunity and neurodegeneration, and we highlight the critical role of metabolic stressors produced in the lung. The understanding of this relationship between inhaled environmental pollutants and systemic inflammation will help us to: (1) understand the molecular mechanism of environment-associated diseases, and (2) find new biomarkers that will help us prevent the exposure of susceptible individuals and/or design novel therapies.

Introduction

Biological systems are continuously exposed to oxidants, which may be generated either endogenously (e.g., from mitochondrial electron transport during respiration or during activation of phagocytes) or exogenously (e.g., pollutants, nanoparticles, dust microorganisms, ozone or cigarette smoke) [1], [2]. When these oxidants are inhaled, their main target is the lung, where they may cause chronic inflammation. However, the link between our environment, the lung, and chronic inflammation has not received the attention it deserves. During the past few years, it has become clear that inhaled pollutants also cause adverse effects outside the respiratory tract, and these effects may in some cases become more important than the respiratory effects [3].

One of the most important topics of environmental research in recent years is the genetic–environment interplay as a determinant of disease susceptibility, progression, and outcome [4], [5], [6]. Although the social and economic impact of chronic inflammatory diseases in our societies is great, the role of the lung in worsening or inducing disease is poorly appreciated, particularly in connection with environmental–genetic interactions. However, there is a clear and parallel increase in chronic inflammatory disease (for example, cardiovascular diseases, autoimmunity, neurodegeneration, and cancer) associated with an increase in air pollution [1], [6], [7], [8]. Air pollution and the concomitant inhalation of environmental stressors have now been associated with the worsening of pre-existing chronic inflammatory diseases such as type II diabetes [8], rheumatic autoimmune diseases [6] and neurodegenerative disorders [9], [10]. In this regard, the indirect effect of inhaled stressors on cell metabolism and genetic and epigenetic factors has gained importance, and there have been several mechanisms presented explaining this complex interaction between our environment, the lung, and diseases (Fig. 1). For example, a link has been established between lipid peroxidation products and genetic (mutagenesis) [11], [12], [13] and epigenetic changes (e.g., changes in DNA conformation by histone modification) [5], [14].

In this review we discuss recent epidemiological and experimental evidence suggesting that systemic oxidative stress and inflammation are key hallmarks of inhalation exposure mediated by metabolic stressors (Fig. 1). Metabolic stressors (bioactive mediators) induced by inhalation of environmental stressors may play a key pathogenic role by inducing or worsening chronic inflammatory diseases in genetically susceptible populations. Along with an increase in our understanding of the key role of lung-generated systemic inflammation and the ability to detect such a process earlier, we may be able to protect susceptible populations and find novel diagnostic strategies and therapies to prevent these diseases.

Section snippets

The lung as a target of inhaled environmental stressors

The lung has the largest surface area exposed to the environment in the human body. It is one of the most vascularized tissues in the body; it is a source of oxygen for loading hemoglobin and a way to eliminate the main product of metabolism (i.e., carbon dioxide) and other volatile metabolites in the exhaled breath [15]. Among the most common environmental stressors that reach our body through the lung (Table 1) are particulate matter comprising insect and microbial components, along with

The lung as a source of metabolic stressors

Oxidized biomolecules, their products of degradation, adducts with proteins, advanced glycoxidation end products (AGEs), and lipid peroxidation end products (ALEs) are generated [23] and eliminated in the breath [15] and/or transported to different tissues in the body [38], [48], [49], [50] (Fig. 1). When detected in the exhaled breath condensate [15] and/or in blood [38], these oxidation products are biomarkers of oxidative stress and inflammation. From an analytical point of view these

Genetic determinants of lung susceptibility to environmental and metabolic stressors

Humans do not generate adaptive immune responses to pollutants per se. Thus, the issue facing immunologists is how, when, and for whom environmental stressors can abrogate immunotolerance and produce autoimmunity [62]. It is known that inflammatory cells are attracted to a site of irritation to mount an immune response. Irritation, and the danger signals it produces, attracts cells from the adaptive and innate immune system. Activation of inflammatory cells can generate a number of ROS (see

Inhalation of environmental stressors and autoimmunity

It has been suggested that immunopathologies per se are due to a combination of genetic and environmental factors. For example, DEPs can both induce and exacerbate in vivo allergic responses in the human upper respiratory tract [65]. In atopic patients, while allergen alone produces a two-to three-fold increase in allergen-specific IgE, a challenge of allergen combined with DEP enhances local allergen-specific IgE production 20–50-fold [62]. The study suggests that ROS and oxidatively modified

Inhalation of environmental stressors and neuro-degeneration

If environmental toxins can induce neuro-degeneration, then it is likely that inhalation ought to be a significant contributing route of exposure to environmental neuro-toxicants. Surprisingly, the literature in this area is rather sparse. A search of the PubMed database (http://www.ncbi.nlm.nih.gov) using the query terms “neuro-degeneration” and “inhalation” yielded only 84 references; nonetheless, there are compelling reasons to explore this issue. Volatile organic hydrocarbons or hydrophobic

Concluding remarks and future directions

As environmental health scientists, we work towards identifying mechanisms by which non-respiratory health effects occur and, by extension, facilitating the appropriate management of relationships between air quality and health [16]. Investigation of these mechanisms has spawned a new field of research: human exposure science, which studies human exposure to chemical, physical or biological agents occurring in our environment, and aims at advancing the knowledge of the mechanisms and dynamics

Conflict of interest

None.

Acknowledgements

The project described was supported by Award Number R00ES015415 from the National Institute of Environmental Health Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences or the National Institutes of Health. DCR also acknowledge the start-up grant from the Presbyterian Health Foundation (PHF) to OMRF. We thank Dr. Ann Motten for editing and Drs. Luke Szweda and Maria S.

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