Inhalation of environmental stressors & chronic inflammation: autoimmunity and neurodegeneration

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.     

The stress response and immune system share,borrow, and reconfigure their physiological network elements: Evidence from the insects

The classic biomedical view is that stress hormone effects on the immune system are largely pathological, especially if the stress is chronic. However, more recent interpretations have focused on the potential adaptive function of these effects. This paper examines stress response-immune system interactions from a physiological network perspective, using insects because of their simpler physiology. For example, stress hormones can reduce disease resistance, yet activating an immune response results in the release of stress hormones in both vertebrates and invertebrates. From a network perspective, this phenomenon is consistent with the ‘sharing’ of the energy-releasing ability of stress hormones by both the stress response and the immune system. Stress-induced immunosuppression is consistent with the stress response ‘borrowing’ molecular components from the immune system to increase the capacity of stress-relevant physiological processes (i.e. a trade off). The insect stress hormones octopamine and adipokinetic hormone can also ‘reconfigure’ the immune system to help compensate for the loss of some of the immune system's molecular resources (e.g. apolipophorin III). This view helps explain seemingly maladaptive interactions between the stress response and immune system. The adaptiveness of stress hormone effects on individual immune components may be apparent only from the perspective of the whole organism. These broad principles will apply to both vertebrates and invertebrates.     

Ambient ozone primes pulmonary innate immunity in mice

Exposure to ozone in air pollution in urban environments is associated with increases in pulmonary-related hospitalizations and mortality. Because ozone also alters clearance of pulmonary bacterial pathogens, we hypothesized that inhalation of ozone modifies innate immunity in the lung. To address our hypothesis, we exposed C57BL/6J mice to either free air or ozone, and then subsequently challenged with an aerosol of Escherichia coli LPS. Pre-exposure to ozone resulted in enhanced airway hyperreactivity, higher concentrations of both total protein and proinflammatory cytokines in lung lavage fluid, enhanced LPS-mediated signaling in lung tissue, and higher concentrations of serum IL-6 following inhalation of LPS. However, pre-exposure to ozone dramatically reduced inflammatory cell accumulation to the lower airways in response to inhaled LPS. The reduced concentration of cells in the lower airways was associated with enhanced apoptosis of both lung macrophages and systemic circulating monocytes. Moreover, both flow cytometry and confocal microscopy indicate that inhaled ozone causes altered distribution of TLR4 on alveolar macrophages and enhanced functional response to endotoxin by macrophages. These observations indicate that ozone exposure increases both the pulmonary and the systemic biologic response to inhaled LPS by priming the innate immune system.     

Interactive effects of ozone and drought stress on pigments and activities of antioxidative enzymes in Pinus halepensis

The aim of this study was to investigate the interactive effects of ozone (O₃) and drought on pigments and antioxidant enzymes of Aleppo pine (Pinus halepensis). Two‐year‐old seedlings were exposed in open‐top chambers to charcoal‐filtered air or non‐filtered air plus an additional 40 nL L^?1 of ozone. After 20 months of O₃ exposure, a subset of plants was subjected to drought stress by withholding water supply for 11 d. Ozone induced higher guaiacol peroxidase, catalase and KCN‐resistant superoxide dismutase (SOD) activities in young needles, while drought stress increased glutathione reductase and CuZnSOD. One‐year‐old needles showed lower capacity to activate these enzymes in response to stress. Both ozone and drought activated the xanthophyll cycle pool and reduced chlorophyll contents in both current and 1‐year‐old needles. The combined effects of ozone and drought decreased antioxidant enzyme activities and the capacity of recovering after re‐watering. Similarly, interactive effects of O₃ and drought reduced xanthophyll‐mediated photoprotection capacity in 1‐year‐old needles but induced a higher conversion of the cycle in current‐year needles. These results showed that ozone modified the Aleppo pine response to drought stress, suggesting that this pollutant might be reducing the ability of this species to withstand other environmental stresses.     

臭氧分布及对呼吸系统的影响

臭氧是氧气的同素异形体,在常温条件下它是一种有特殊臭味的淡蓝色气体。臭氧现已成为我国主要的一种环境污染物。臭氧的分布存在着明显的时间特异性和地区特异性,与气象条件、污染物的输送与扩散以及局地光化学反应强度等因素有着重要的关系。同时在人群流行病学和动物实验中发现了臭氧可以提高慢性阻塞性肺疾病、哮喘等呼吸系统疾病的发病率和病死率,同时提示了老年人、有呼吸系统疾病病史的人群和儿童都是易受臭氧影响的高危人群。国内外学者也对臭氧对机体损伤的机制进行了研究,主要集中在臭氧的致炎作用、氧化应激作用、造成机体气道高反应性和对细胞DNA的损伤等方面。本文主要就国内外对臭氧在时空分布、对机体呼吸系统影响和臭氧造成机体损伤的机制这3方面作一简要综述。     

Connecting chronic and recurrent stress to vascular dysfunction: no relaxed role for the renin-angiotensin system

The renin-angiotensin system (RAS) is classically considered to be a protective system for volume balance and is activated during states of volume depletion. Interestingly, one of the major pathways activating the system is the sympathetic nervous system, also the primary mediator of the acute stress response. When one further examines the cells mediating the immune site of the response, which is primarily an inflammatory response leading to defense at a locally injured area, these cells all express the ANG II type 1 receptor (AGTR1). Scattered throughout the literature are reports indicating that acute and chronic stress can activate renin and increase plasma levels of components of the RAS. Moreover, there are reports describing that ANG II can modulate the distribution and function of immune cells. Since the inflammatory response is also implicated to be central in the initiation and progression of vascular damage, we propose in this review that recurrent acute stress and chronic stress can induce a state with inflammation, due to ANG II-mediated activation of inflammatory cells, specifically monocytes and lymphocytes. Such a proposal would explain a lot of the observations regarding RAS components in inflammatory cells. Despite its attractiveness, substantial research in this area would be required to substantiate this hypothesis.     

Air pollutant effects on fetal and early postnatal development

Numerical research on the health effects of air pollution has been published in the last decade. Epidemiological studies have shown that children's exposure to air pollutants during fetal development and early postnatal life is associated with many types of health problems including abnormal development (low birth weight [LBW], very low birth weight [VLBW], preterm birth [PTB], intrauterine growth restriction [IUGR], congenital defects, and intrauterine and infant mortality), decreased lung growth, increased rates of respiratory tract infections, childhood asthma, behavioral problems, and neurocognitive decrements. This review focuses on the health effects of major outdoor air pollutants including particulates, carbon monoxide (CO), sulfur and nitrogen oxides (SO(2), NOx), ozone, and one common indoor air pollutant, environmental tobacco smoke (ETS). Animal data is presented that demonstrate perinatal windows of susceptibility to sidestream smoke, a surrogate for ETS, resulting in altered airway sensitivity and cell type frequency. A study of neonatal monkeys exposed to sidestream smoke during the perinatal period and/or early postnatal period that resulted in an altered balance of Th1-/Th2-cytokine secretion, skewing the immune response toward the allergy-associated Th2 cytokine phenotype, is also discussed.     

A hassle a day may keep the pathogens away: The fight-or-flight stress response and the augmentation of immune function

Stress is known to suppress or dysregulate immune function and increase susceptibility to disease. Paradoxically, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that galvanizes the neuroendocrine, cardiovascular, and musculoskeletal systems into action to enable survival. Therefore, it is unlikely that short-term stress would suppress immune function at a time when it may be critically required for survival (e.g., in response to wounding and infection by a predator or aggressor). In fact, studies have shown that stress can enhance immune function under certain conditions. Several factors influence the direction (enhancing versus suppressive) of the effects of stress on immune function: (1) Duration: acute or short-term stress experienced at the time of activation of an immune response enhances innate and adaptive immune responses. Chronic or long-term stress can suppress or dysregulate immune function. (2) Leukocyte distribution: compartments (e.g., skin), that are enriched with immune cells during acute stress show immuno-enhancement, while those that are depleted of leukocytes (e.g., blood), show immuno-suppression. (3) The differential effects of physiologic versus pharmacologic stress hormones: Endogenous hormones in physiological concentrations can have immuno-enhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immuno-suppressive. (4) Timing: immuno-enhancement is observed when acute stress is experienced during the early stages of an immune response while immuno-suppression may be observed at late stages. The type of immune response (protective, regulatory/inhibitory, or pathological) that is affected determines whether the effects of stress are ultimately beneficial or harmful for the organism. Arguments based on conservation of energy have been invoked to explain potential adaptive benefits of stress-induced immuno-suppression, but generally do not hold true because most mechanisms for immuno-suppression expend, rather than conserve, energy. We propose that it is important to study, and if possible, to clinically harness, the immuno-enhancing effects of the acute stress response that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve.     

The effect of air pollutants on physiological processes in plants

Abstract. Important physiological processes, photosynthesis, respiration, carbon allocation and stomatal function are known to be affected by air pollutants. A wide range in sensitivity of photosynthesis both within and between species is evident from the literature for the pollutants sulphur dioxide, ozone, nitrogen oxide and hydrogen fluoride. Some of this variation is clearly due to genetic factors, but much is in response to differences in environmental conditions both prior to and during fumigation. Exposure of plants to mixtures of pollutants generally reduced the threshold at which effects were first detected and increased the level of inhibitory responses. In the majority of studies on stomatal responses to air pollutants, opening occurs at low concentrations, below the threshold for effects on photosynthesis, and closure occurs at injurious concentrations; this latter response often following the inhibition of photosynthesis. Effects on carbon allocation have been reported in response to air pollutants. Changes usually favour leaf development over root growth, which can compensate for a decline in net assimilation rate up to a certain point but may limit water uptake from soils with low moisture content. Future research into physiological effects of air pollutants should incorporate an integrated approach in which both key physiological parameters and growth parameters are measured together with estimates of the effective dose of pollutant. In this way, the underlying mechanisms to changes in growth and development will be more fully understood.     

Chronic stress influences the immune system through the thyroid axis

The aim of the present work was to analyze the effect of chronic stress on thyroid axis and its influence on the immune response. For this purpose a murine model of chronic stress was developed to evaluate and to correlate thyroid hormone levels with humoral alloimmune response. Results show a reduction in serum levels of thyroid hormones, specially a significant decrease in serum levels of triiodotyronine (T3) in stressed animals. On the other hand, alloimmunization was not able to induce an early increment in T3 and thyroxine (T4) levels as it was previously reported in normal animals. In addition, lower titers of alloantibodies were obtained in animals under stress conditions as compared to normal mice. The sustitutive T4 treatment in stressed animals increased significantly alloantibody production as well as the early increment in thyroid hormones after antigenic challenge. These findings suggest that chronic stress induces an alteration of the function of thyroid axis that alters the immune response.     

Nutritional Modulation of Somatotropic Axis-cytokine Relationships in Cattle: A Brief Review

The objective of this review is to summarize data on the interrelationships that exist between nutrition, the endocrine system and their modulation of plasma tumor necrosis factor-α responses to endotoxin in cattle. During stress, intake of nutrients often is compromised and a percentage of available nutrients are diverted away from growth processes to stabilize other physiological processes of a higher survival priority. Management practices that minimize the magnitude and duration of disease stress will aid in speeding the return to homeostatic equilibrium. However, the shift away from growth during stress is almost inevitable as a mechanism to survive. Some degree of control and management of the metabolic cost of disease stress involves understanding the integration of nutritional, endocrine and immune signals by cells and working with the natural homeostatic processes. Endocrine hormones and immune system cytokine signals participate in redirecting nutrient use during disease stress. In an intricate interplay, hormones and cytokines regulate, modify and modulate each other's production and tissue interactions to alter metabolic priorities. Levels of dietary protein and energy intake affect patterns of hormones and cytokines in the blood after endotoxin challenge and further modulate the biological actions of many of these regulatory effectors. In vivo, administration of growth hormone to young calves has significant effects to decrease the many specific physiological responses to endotoxemia. Many aspects of nutrition can attenuate or facilitate this effect.     

Conserved features of chronic stress across phyla: the effects of long-term stress on behavior and the concentration of the neurohormone octopamine in the cricket, Gryllus texensis

Many of the deleterious effects of chronic stress in vertebrates are caused by the long-term elevation of stress hormones. These negative effects are thought to be unavoidable by-products of sustained activation of the stress response, but the details remain unclear. A comparative perspective may help in understanding chronic stress. We exposed crickets (Gryllus texensis) to a mock predator. A single exposure to a mock predator induced a transient increase in the hemolymph (blood) concentration of the insect stress neurohormone, octopamine. Repeated exposure to the mock predator increased basal levels of octopamine, similar to the effects of chronic stress on the basal levels of vertebrate stress hormones. This study is the first to report an increase in the basal levels of an invertebrate stress hormone in response to repeated flight-or-fight stress. Chronic stress reduced weight gain, and decreased feeding and enhanced weight loss after food deprivation in adult female crickets. However, chronic stress also increased the tendency of crickets to produce sustained flight. Therefore, this study supports the hypothesis that increasing basal levels of stress hormones may be a phylogenetically common response to chronically stressful conditions. It also demonstrates that chronic stress has both positive and negative effects in insects.     

Pulmonary expression of preproET-1 and preproET-3 mRNAs is altered reciprocally in rats after inhalation of air pollutants

Perturbation of vascular homeostasis is an important mechanism related to the acute health effects of inhaled pollutants. Inhalation of urban particulate matter and ozone by rats has been shown to result in increased synthesis of the potent vasoactive peptide endothelin (ET)-1 in the lungs, with spillover into the circulation. In the present work, we have analyzed the interrelationships between responses of the three major endothelin isoforms, ET-1[1-21], ET-2[1-21], and ET-3[1-21], to inhaled pollutants at the peptide and gene expression levels. Fisher-344 rats were exposed for 4 hrs by nose-only route to clean air, urban particles EHC-93 (0, 50 mg/m3), ozone (0, 0.8 ppm), or ozone and particles together. Circulating levels of both the ET-1 [1-21] and ET-3[1-21] peptides were increased immediately after exposure to particulate matter or ozone. While expression of preproET-1 mRNA in the lungs increased, expression of preproET-3 mRNA decreased immediately after exposure. PreproET-2 mRNA was not detected in the lungs, and exposure to either pollutant did not affect plasma ET-2 levels. Co-exposure to ozone and particles, while altering lung preproET-1 and preproET-3 mRNA levels in a fashion similar to ozone alone, did not cause changes in the circulating levels of the two corresponding peptides. Thus, de novo synthesis of ET-3 in the lungs is not responsible for the increase of circulating plasma ET-3 after inhalation of pollutants, which implies regulation of preproET-3 at a remote site and, hence, systemic impacts of the pollutants. Upregulation of preproET-1 coupled with down-regulation of preproET-3 in the lungs of animals exposed to air pollutants implies a mismatch of local ET-1/ET(A) receptor-mediated vasoconstriction and ET-3/ET(B) receptor-mediated vasodilation.     

Ghrelin modulates brain activity in areas that control appetitive behavior

Feeding behavior is often separated into homeostatic and hedonic components. Hedonic feeding, which can be triggered by visual or olfactory food cues, involves brain regions that play a role in reward and motivation, while homeostatic feeding is thought to be under the control of circulating hormones acting primarily on the hypothalamus. Ghrelin is a peptide hormone secreted by the gut that causes hunger and food consumption. Here, we show that ghrelin administered intravenously to healthy volunteers during functional magnetic resonance imaging increased the neural response to food pictures in regions of the brain, including the amygdala, orbitofrontal cortex, anterior insula, and striatum, implicated in encoding the incentive value of food cues. The effects of ghrelin on the amygdala and OFC response were correlated with self-rated hunger ratings. This demonstrates that metabolic signals such as ghrelin may favor food consumption by enhancing the hedonic and incentive responses to food-related cues.     

Postnatal episodic ozone results in persistent attenuation of pulmonary and peripheral blood responses to LPS challenge

Early life is a dynamic period of growth for the lung and immune system. We hypothesized that ambient ozone exposure during postnatal development can affect the innate immune response to other environmental challenges in a persistent fashion. To test this hypothesis, we exposed infant rhesus macaque monkeys to a regimen of 11 ozone cycles between 30 days and 6 mo of age; each cycle consisted of ozone for 5 days (0.5 parts per million at 8 h/day) followed by 9 days of filtered air. Animals were subsequently housed in filtered air conditions and challenged with a single dose of inhaled LPS at 1 yr of age. After completion of the ozone exposure regimen at 6 mo of age, total peripheral blood leukocyte and polymorphonuclear leukocyte (PMN) numbers were reduced, whereas eosinophil counts increased. In lavage, total cell numbers at 6 mo were not affected by ozone, however, there was a significant reduction in lymphocytes and increased eosinophils. Following an additional 6 mo of filtered air housing, only monocytes were increased in blood and lavage in previously exposed animals. In response to LPS challenge, animals with a prior history of ozone showed an attenuated peripheral blood and lavage PMN response compared with controls. In vitro stimulation of peripheral blood mononuclear cells with LPS resulted in reduced secretion of IL-6 and IL-8 protein in association with prior ozone exposure. Collectively, our findings suggest that ozone exposure during infancy can result in a persistent effect on both pulmonary and systemic innate immune responses later in life.     

Conserved features of chronic stress across phyla: The effects of long-term stress on behavior and the concentration of the neurohormone octopamine in the cricket,Gryllus texensis

Many of the deleterious effects of chronic stress in vertebrates are caused by the long-term elevation of stress hormones. These negative effects are thought to be unavoidable by-products of sustained activation of the stress response, but the details remain unclear. A comparative perspective may help in understanding chronic stress. We exposed crickets (Gryllus texensis) to a mock predator. A single exposure to a mock predator induced a transient increase in the hemolymph (blood) concentration of the insect stress neurohormone, octopamine. Repeated exposure to the mock predator increased basal levels of octopamine, similar to the effects of chronic stress on the basal levels of vertebrate stress hormones. This study is the first to report an increase in the basal levels of an invertebrate stress hormone in response to repeated flight-or-fight stress. Chronic stress reduced weight gain, and decreased feeding and enhanced weight loss after food deprivation in adult female crickets. However, chronic stress also increased the tendency of crickets to produce sustained flight. Therefore, this study supports the hypothesis that increasing basal levels of stress hormones may be a phylogenetically common response to chronically stressful conditions. It also demonstrates that chronic stress has both positive and negative effects in insects.     

Association between Air Pollution and Suicide in South Korea: A Nationwide Study

Suggestive associations of suicide with air pollutant concentrations have been reported. Recognizing regional and temporal variability of pollutant concentrations and of suicide, we undertook a detailed meta-analysis of completed suicides in relation to 5 major pollutants over 6 years in the 16 administrative regions of the Republic of Korea, while also controlling for other established influences on suicide rates. Of the 5 major pollutants examined, ozone concentrations had a powerful association with suicide rate, extending back to 4 weeks. Over the range of 2 standard deviations (SD) around the annual mean ozone concentration, the adjusted suicide rate increased by an estimated 7.8% of the annual mean rate. Particulate matter pollution also had a significant effect, strongest with a 4-week lag, equivalent to 3.6% of the annual mean rate over the same 2 SD range that approximated the half of annual observed range. These results strongly suggest deleterious effects of ozone and particulate matter pollution on the major public health problem of suicide.