Article

Exposure to ozone enhances antigen-presenting activity concentration dependently in rats

May 2004
Toxicology 197(1):37-46

DOI:10.1016/j.tox.2003.12.007

Source
PubMed

Authors:

The effect of ozone (O(3)) on the symptoms of allergic asthma and the mechanisms underlying have not yet been fully elucidated. Antigen presentation is one of the factors contributing to the allergic reaction. Therefore, we investigated the effects of repeated exposure to O(3) on antigen-presenting (AP) activity, on the expression of cell-surface molecules associated with antigen presentation (Ia, B7.1, B7.2 and CD11b/c) in bronchoalveolar lavage cells (BAL cells), and on allergic asthma-like symptoms. Rats were exposed to 0.3, 0.56, 1ppm O(3) or filtered air for a 3-day period every 2 weeks, this was replicated three times. AP activity was assessed by measuring antigen-specific T-cell proliferation; and the expression of cell-surface molecules, by flow cytometry. Rats were also made to inhale aerosolized 1% ovalbumin (OVA) or saline for 10min post-exposure to O(3), and allergic asthma-like symptoms were measured by determining the increase in enhanced pause (Penh), which correlates well with lung resistance. O(3) increased both AP activity and expression of Ia and costimulatory molecules in BAL cells concentration dependently. It also increased lung resistance, and the increase in lung resistance after O(3) exposure was significantly higher in the OVA-inhaled group than in the saline-inhaled group. The present results show that O(3) increased AP activity concentration dependently and suggest that O(3) might aggravate allergy symptoms by enhancing AP activity.

Epithelial, dendritic, and CD4(+) T cell regulation of and by reactive oxygen and nitrogen species in allergic sensitization

Article

Mar 2011
Biochim Biophys Acta

While many of the contributing cell types and mediators of allergic asthma are known, less well understood are the factors that induce allergy in the first place. Amongst the mediators speculated to affect initial allergen sensitization and the development of pathogenic allergic responses to innocuous inhaled antigens and allergens are exogenously or endogenously generated reactive oxygen species (ROS) and reactive nitrogen species (RNS). The interactions between ROS/RNS, dendritic cells (DCs), and CD4(+) T cells, as well as their modulation by lung epithelium, are of critical importance for the genesis of allergies that later manifest in allergic asthma. Therefore, this review will primarily focus on the initiation of pulmonary allergies and the role that ROS/RNS may play in the steps therein, using examples from our own work on the roles of NO(2) exposure and airway epithelial NF-κB activation. Endogenously generated ROS/RNS and those encountered from environmental sources interact with epithelium, DCs, and CD4(+) T cells to orchestrate allergic sensitization through modulation of the activities of each of these cell types, which quantitiatively and qualitatively dictate the degree and type of the allergic asthma phenotype. Knowledge of the effects of ROS/RNS at the molecular and cellular levels has the potential to provide powerful insight into the balance between inhalational tolerance (the typical immunologic response to an innocuous inhaled antigen) and allergy, as well as to potentially provide mechanistic targets for the prevention and treatment of asthma.

Bayram H-Tub Toraks-rev'06

Data

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Jun 2017

Hava kirliliği ve solunum sağlığına etkileri

Article

Full-text available

Air pollution, which started to become a serious health concern with industrial revolution, has been threatening human health. Epidemiological studies have reported a close relation between air pollution and respiratory morbidity and mortality. Studies investigating the mechanisms underlying respiratory effects of air pollution have reported that pollutants lead to increased respiratory symptoms, decreased respiratory function and induce inflammatory changes in airways. In vitro studies have demonstrated that air pollutants exert their effects by causing cellular injury directly, and indirectly activating intracellular oxidative pathways. Air way epithelial cells, which form the first line of defence against air pollutants, may play an active role in this pathophysiological course.

Site Specific Dynamics of CD11b+ and CD103+ Dendritic Cell Accumulations Following Ozone Exposure.

Article

Full-text available

Oct 2012
AM J PHYSIOL-LUNG C

Pulmonary dendritic cells (DCs) are among the first responders to inhaled environmental stimuli such as ozone (O(3)) which has been shown to activate these cells. O(3) reacts with epithelial lining fluid (ELF) components in an anatomically site-specific manner dictated by O(3) concentration, airway flow patterns, and ELF substrate concentration. Accordingly, the anatomical distribution of ELF reaction products and airway injury are hypothesized to produce selective DC maturation differentially within the airways. To investigate how O(3) affects regional airway DC populations, we utilized a model of O(3)-induced pulmonary inflammation wherein C57Bl/6 mice were exposed to 0.8 ppm O(3) 8 h/day for 1, 3, and 5 days. This model induced mild inflammation and no remarkable epithelial injury. Tracheal, but not more distant airway sites, and mediastinal lymph node (MLN), DC numbers were increased significantly after the third exposure day. The largest increase in each tissue was of the CD103(+) DC phenotype. After 3 days of exposure, less DCs expressed CD80, CD40, and CCR7 and at this same time point, total MLN T cell numbers increased. Together these data demonstrate O(3) exposure induced site-specific and phenotype changes in the pulmonary and regional lymph node DC populations. Possibly contributing to ozone mediated asthma perturbation, the phenotypic changes to DCs within pulmonary regions may alter responses to antigenic stimuli. Decreased co-stimulatory molecule expression within the MLN suggests induction of tolerance mechanisms; increased tracheal DC number may raise the potential for allergic sensitization and asthmatic exacerbation, thus overcoming O(3) induced decrements in co-stimulatory molecule expression.

Article

Full-text available

Feb 2006

Pollen cytoplasmic granules (PCG) are loaded with allergens. They are released from grass pollen grains following contact with water and can form a respirable allergenic aerosol. On the other hand, the traffic-related air pollutants NO2 and O3 are known to be involved in the current increase in the prevalence of allergic diseases via their adjuvant effects. Our objective was to determine the effects of air pollutants on the release of PCG from Phleum pratense (timothy grass) pollen. P. pratense pollen was exposed to several concentrations of NO2 and O3. The induced morphological damages were observed by environmental scanning electron microscopy, and the amount of PCG released from the pollen upon contact with water was measured. The percentages of damaged grain were 6.4% in air-treated controls, 15% after treatment with the highest NO2 dose (50 ppm) and 13.5% after exposure to 0.5 ppm O3. In treated samples, a fraction of the grains spontaneously released their PCG. Upon subsequent contact with water, the remaining intact grains released more PCG than pollen exposed to air only. Traffic-related pollutants can trigger the release of allergen-containing granules from grass pollen, and increase the bioavailability of airborne pollen allergens. This is a new mechanism by which air pollution concurs with the current increase in the prevalence of allergic diseases.

Effects of air pollution on respiratory health

Article

Full-text available

Feb 2006

Ozone enhances markers of innate immunity and antigen presentation on airway monocytes in healthy individuals

Article

Oct 2007
J ALLERGY CLIN IMMUN

Stress axis variability is associated with differential ozone-induced lung inflammatory signaling and injury biomarker response

Article

Full-text available

Sep 2018

Ozone (O3), a ubiquitous urban air pollutant, causes adverse pulmonary and extrapulmonary effects. A large variability in acute O3-induced effects has been observed; however, the basis for interindividual differences in susceptibility is unclear. We previously demonstrated a role for the hypothalamic-pituitary-adrenal (HPA) stress axis and glucocorticoid response in acute O3 toxicity. Glucocorticoids have important anti-inflammatory actions, and have been shown to regulate lung inflammatory responses. We hypothesised that a hyporesponsive HPA axis would be associated with greater O3-dependent lung inflammatory signaling. Two genetically-related rat strains with known differences in stress axis reactivity, highly-stress responsive Fischer (F344) and less responsive Lewis (LEW), were exposed for 4 h by nose-only inhalation to clean air or 0.8 ppm O3, and euthanized immediately after exposure. As expected, baseline (air-exposed) plasma corticosterone was significantly lower in the hypo-stress responsive LEW. Although O3 exposure increased plasma corticosterone in both strains, corticosterone remained significantly lower in LEW when compared to F334. LEW exhibited greater O3-induced inflammatory cytokine/chemokine signaling compared to F344, consistent with the lower corticosterone levels. Since we observed strain-specific differences in inflammatory signaling, we further investigated injury biomarkers (total protein, albumin and lactate dehydrogenase). Although the hyper-responsive F344 exhibited lower inflammatory signaling in response to O3 compared with LEW, they had greater levels of lung injury biomarkers. Our results indicate that stress axis variability is associated with differential O3-induced lung toxicity. Given the large variability in stress axis reactivity among humans, stress axis regulation could potentially be a determining factor underlying O3 sensitivity.

WAO Special Committee on Climate Change and Allergy Climate change, migration, and allergic respiratory diseases: An update for the allergist

Article

Full-text available

Jan 2011

Meteorological conditions, climate change, new emerging factors, and asthma and related allergic disorders. A statement of the World Allergy Organization

Article

Full-text available

Dec 2015

The prevalence of allergic airway diseases such as asthma and rhinitis has increased dramatically to epidemic proportions worldwide. Besides air pollution from industry derived emissions and motor vehicles, the rising trend can only be explained by gross changes in the environments where we live. The world economy has been transformed over the last 25 years with developing countries being at the core of these changes. Around the planet, in both developed and developing countries, environments are undergoing profound changes. Many of these changes are considered to have negative effects on respiratory health and to enhance the frequency and severity of respiratory diseases such as asthma in the general population. Increased concentrations of greenhouse gases, and especially carbon dioxide (CO2), in the atmosphere have already warmed the planet substantially, causing more severe and prolonged heat waves, variability in temperature, increased air pollution, forest fires, droughts, and floods – all of which can put the respiratory health of the public at risk. These changes in climate and air quality have a measurable impact not only on the morbidity but also the mortality of patients with asthma and other respiratory diseases. The massive increase in emissions of air pollutants due to economic and industrial growth in the last century has made air quality an environmental problem of the first order in a large number of regions of the world. A body of evidence suggests that major changes to our world are occurring and involve the atmosphere and its associated climate. These changes, including global warming induced by human activity, have an impact on the biosphere, biodiversity, and the human environment. Mitigating this huge health impact and reversing the effects of these changes are major challenges. This statement of the World Allergy Organization (WAO) raises the importance of this health hazard and highlights the facts on climate-related health impacts, including: deaths and acute morbidity due to heat waves and extreme meteorological events; increased frequency of acute cardio-respiratory events due to higher concentrations of ground level ozone; changes in the frequency of respiratory diseases due to trans-boundary particle pollution; altered spatial and temporal distribution of allergens (pollens, molds, and mites); and some infectious disease vectors. According to this report, these impacts will not only affect those with current asthma but also increase the incidence and prevalence of allergic respiratory conditions and of asthma. The effects of climate change on respiratory allergy are still not well defined, and more studies addressing this topic are needed. Global warming is expected to affect the start, duration, and intensity of the pollen season on the one hand, and the rate of asthma exacerbations due to air pollution, respiratory infections, and/or cold air inhalation, and other conditions on the other hand.

Airway Epithelial Regulation of Allergic Sensitization in Asthma

Article

May 2012
PULM PHARMACOL THER

Matthew E Poynter

While many of the contributing cell types and mediators of allergic asthma are known, less well understood are the factors that influence the development of allergic responses that lead to the development of allergic asthma. As the first airway cell type to respond to inhaled factors, the epithelium orchestrates downstream interactions between dendritic cells (DCs) and CD4(+) T cells that quantitatively and qualitatively dictate the degree and type of the allergic asthma phenotype, making the epithelium of critical importance for the genesis of allergies that later manifest in allergic asthma. Amongst the molecular processes of critical importance in airway epithelium is the transcription factor, nuclear factor-kappaB (NF-κB). This review will focus primarily on the genesis of pulmonary allergies and the participation of airway epithelial NF-κB activation therein, using examples from our own work on nitrogen dioxide (NO(2)) exposure and genetic modulation of airway epithelial NF-κB activation. In addition, the mechanisms through which Serum Amyloid A (SAA), an NF-κB-regulated, epithelial-derived mediator, influences allergic sensitization and asthma severity will be presented. Knowledge of the molecular and cellular processes regulating allergic sensitization in the airways has the potential to provide powerful insight into the pathogenesis of allergy, as well as targets for the prevention and treatment of asthma.

Ambient ozone and pulmonary innate immunity

Article

Dec 2010

Ambient ozone is a criteria air pollutant that impacts both human morbidity and mortality. The effect of ozone inhalation includes both toxicity to lung tissue and alteration of the host immunologic response. The innate immune system facilitates immediate recognition of both foreign pathogens and tissue damage. Emerging evidence supports that ozone can modify the host innate immune response and that this response to inhaled ozone is dependent on genes of innate immunity. Improved understanding of the complex interaction between environmental ozone and host innate immunity will provide fundamental insight into the pathogenesis of inflammatory airways disease. We review the current evidence supporting that environmental ozone inhalation: (1) modifies cell types required for intact innate immunity, (2) is partially dependent on genes of innate immunity, (3) primes pulmonary innate immune responses to LPS, and (4) contributes to innate-adaptive immune system cross-talk.

Airway Epithelial NF-??B Activation Promotes Allergic Sensitization to an Innocuous Inhaled Antigen

Article

Full-text available

May 2011
AM J RESP CELL MOL

Activation of NF-κB in airway epithelium is observed in allergic asthma and is induced by inhalation of numerous infectious and reactive substances. Many of the substances that activate NF-κB in the airway epithelium are also capable of acting as adjuvants to elicit antigen-specific sensitization to concomitantly inhaled protein, thereby circumventing the inherent bias of the lung to promote tolerance to innocuous antigens. We have used a transgenic mouse inducibly expressing a constitutively active mutant of the inhibitor of nuclear factor κB (IκB) kinase β ((CA)IKKβ) that activates NF-κB only in nonciliated airway epithelial cells to test whether activation of this intracellular signaling pathway in this specific cell type is sufficient to establish a pulmonary environment permissive to the development of allergic sensitization to inhaled protein. When airway epithelial (CA)IKKβ was transiently expressed in antigen-naive mice only during initial inhalation of ovalbumin, the mice became allergically sensitized to the antigen. As a consequence, subsequent inhalation of ovalbumin alone led to an allergic asthma-like response that included airway hyperresponsiveness to methacholine, eosinophilia, mucus expression, elevated serum levels of antigen-specific IgE and IgG1, and splenic CD4(+) T cells that secreted T helper type 2 and type 17 cytokines in response to in vitro antigen restimulation. Furthermore, CD11c(+) cells in the mediastinal lymph nodes (MLN) of (CA)IKKβ-expressing mice displayed significantly elevated levels of activation markers. These data implicate airway epithelial NF-κB activation as a critical modulator of the adaptive immune response to inhaled antigens via the secretion of soluble mediators that affect the capacity of CD11c(+) cells to undergo maturation and promote antigen-specific allergic responses.

Ozone inhalation induces exacerbation of eosinophilic airway inflammation and hyperresponsiveness in allergen-sensitized mice

Article

Full-text available

May 2008
ALLERGY

Ozone (O(3)) exposure evokes asthma exacerbations by mechanisms that are poorly understood. We used a murine model to characterize the effects of O(3) on allergic airway inflammation and hyperresponsiveness and to identify factors that might contribute to the O(3)-induced exacerbation of asthma. BALB/c mice were sensitized and challenged with Aspergillus fumigatus (Af). A group of sensitized and challenged mice was exposed to 3.0 ppm of O(3) for 2 h and studied 12 h later (96 h after Af challenge). Naive mice and mice exposed to O(3) alone were used as controls. Bronchoalveolar lavage (BAL) cellular and cytokine content, lung function [enhanced pause (P(enh))], isometric force generation by tracheal rings and gene and protein expression of Fas and FasL were assessed. Apoptosis of eosinophils was quantified by FACS. In sensitized mice allergen challenge induced a significant increase of P(enh) and contractile force in tracheal rings that peaked 24 h after challenge and resolved by 96 h. O(3) inhalation induced an exacerbation of airway hyperresponsiveness accompanied by recurrence of neutrophils and enhancement of eosinophils 96 h after allergen challenge. The combination of allergen and O(3) exposure inhibited Fas and FasL gene and protein expression and eosinophil apoptosis and increased interleukin-5 (IL-5), granulocyte-macrophage-colony stimulating factor (GM-CSF) and G-CSF protein levels. O(3) affects airway responsiveness of allergen-primed airways indirectly by increasing viability of eosinophils and eosinophil-mediated pathological changes.

Air Pollution in Asia and Its Effect on Human Health

Chapter

Full-text available

May 2018

is still prevalent in most countries in the world. Major contributors include fossil fuel exhaust in metropolitan cities from industrial facilities and vehicular emissions. Use of renewable energy and natural gas have played a part in reducing air pollution; however, increasing populations, rampant urbanization, and industrialization, especially during winter months, have given rise to spikes in air pollution levels. Research shows that there is a close relationship between air pollution and mortality rates depending on respiration inadequacy. Studies show that contaminants increase respiratory afflictions in humans. Discontinuing use of fossil fuels, using appropriate burning techniques, and efficiency emission controls on vehicles have been proven to reduce air pollution levels.

Air Pollution and Immune Function

Chapter

Jan 2015

Air pollution has clear impacts on human health and is associated with both cardiopulmonary complications as well as exacerbating chronic disease. As a principal site of exposure to air pollution, the lung is central to the health effects of air pollution. One of the potential mechanisms that air pollution could adversely impact health is dysregulation of host immune response. Evolving scientific evidence support that air pollution has myriad effects on pulmonary immune responses. In this chapter, we provide an overview of the impact of air pollution on immune function. We focus on the three major environmental pollutants: particulate matter; vehicle/diesel exhaust; and ambient ozone and the impact of exposure on both innate and adaptive immunological responses. Improved understanding of the impact of air pollution on immunological function could provide novel insight into the pathogenesis of common human disease.

Bronchial hyperresponsiveness and lung inflammation induced by allergic immune response and oxidative stress: Role of innate and adaptive immune responses

Article

Jul 2011

Airway response to the external environment forms the basis for many airway/lung diseases such as asthma and chronic obstructive airways disease (COPD) which are characterized by chronic airflow obstruction, chronic airway inflammation and tissue remodeling. Allergic inflammation and oxidative stress contribute to airways dysfunction and direct effects of these processes have been demonstrated in human and animal models. Airway responses to allergens and to environmental pollution such as ozone represent a mixture of innate and adaptive immune responses. Through the release of inflammatory cytokines and expression of co-stimulatory molecules, and antigen presentation, innate immune cells such as dendritic cells can interact with CD4 T-cells and direct their maturation program. The oxidant, ozone, can also utilize innate immune recognition pathways through toll-like receptors and activate a range of innate immune cells including dendritic cells (DCs), macrophages, and immune responses. Crosstalk between these two responses is likely to be common occurrence as exposure to oxidants is unavoidable in urban environments with high levels of pollution and allergic inflammation is a potential source of oxidants. The interaction of ozone and allergen offers interesting perspectives in unraveling further the interactions of innate and adaptive responses that could form the basis of chronic airway diseases of chronic airflow obstruction and inflammation.

Vetenskapligt Underlag för Hygieniska Gränsvärden 24 Kriteriegruppen för hygieniska gränsvärden

Article

Johan Montelius

Low-level ozone exposure induces airways inflammation and modifies cell surface phenotypes in healthy humans

Article

Full-text available

Apr 2010
INHAL TOXICOL

The effects of low-level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known; however, much less is known about the inflammatory and immunomodulatory effects of low-level ozone in the airways. Techniques such as induced sputum and flow cytometry make it possible to examine airways inflammatory responses and changes in immune cell surface phenotypes following low-level ozone exposure. The purpose of this study was to determine if exposure to 0.08 parts per million ozone for 6.6 h induces inflammation and modifies immune cell surface phenotypes in the airways of healthy adult subjects. Fifteen normal volunteers underwent an established 0.08 part per million ozone exposure protocol to characterize the effect of ozone on airways inflammation and immune cell surface phenotypes. Induced sputum and flow cytometry were used to assess these endpoints 24 h before and 18 h after exposure. The results showed that exposure to 0.08 ppm ozone for 6.6 h induced increased airway neutrophils, monocytes, and dendritic cells and modified the expression of CD14, HLA-DR, CD80, and CD86 on monocytes 18 h following exposure. Exposure to 0.08 parts per million ozone is associated with increased airways inflammation and promotion of antigen-presenting cell phenotypes 18 hours following exposure. These findings need to be replicated in a similar experiment that includes a control air exposure.

The Proceedings of the Panel “Effects of Air Pollution on Human Health, Air Pollution Problem in the World, Turkey and Our Region” (The Conference Hall of Dicle University, Diyarbakır 24.12.2004)

Article

Full-text available

Jan 2006

Air pollution still exceeds safe limits worldwide, particularly in big metropolitans, despite regular monitoring facilities and measures taken. It is usually originated from industrial activities, fossil fuel use in domestic settings and vehicle exhaust emission. Although there is a decrease in air pollution in big cities of Turkey due to use of natural gas, it is still a serious health concern. In Diyarbakır, because of a rapid increase in its population recently, wrong urbanisation and a relative increase in industrialisation, air pollution leads to dangerous levels, particularly in the winter. Epidemiological studies from all over the world, and Turkey have reported a close relation between air pollution and respiratory morbidity and mortality. Studies investigating the mechanisms underlying respiratory effects of air pollution demonstrated that pollutants lead to increased respiratory symptoms, decreased respiratory function and induce inflammatory changes in airways. In vitro studies have shown that air pollutants exert their effects by causing cellular injury directly, and by activating intracellular oxidative pathways indirectly. The attempts to reduce air pollution levels have been implemented in Turkey and worldwide. In order to solve the problem in Diyarbakır, several measures such as prevention the use of out standardized fuel, use of reliable burning techniques, and a close car emission monitoring system need to be implemented.

Organic extract of diesel exhaust particles stimulates expression of Ia and costimulatory molecules associated with antigen presentation in rat peripheral blood monocytes but not in alveolar macrophages

Article

Jan 2006

We hypothesized that diesel exhaust particles (DEP) induce the activation of antigen-presenting cells (APC) in lung. The present study was designed to clarify the following about DEP: (1) whether it affects the expression of Ia and B7 molecules in alveolar macrophages (AM) as a mature cell or in peripheral blood monocytes (PBM) as an immature cell, (2) if it affects the antigen-presenting (AP) activity of PBM, (3) what component of DEP is responsible for the effects, and (4) whether the effect of DEP is related to oxidative stress. DEP was extracted with methylene chloride. Cells were exposed to whole DEP, organic extract, or residual particles for 24 h. Cell-surface molecules were measured by flow cytometry. AP activity was assessed by antigen-specific T cell proliferation. Whole DEP or organic extract significantly increased the expression of Ia and B7 molecules on PBM but not on AM. No significant effect of residual particles was observed. A low concentration of organic extract also increased the AP activity of PBM. When the induction of an antioxidative enzyme was assessed, heme oxygenase-1 protein was found to be significantly increased by exposure to whole DEP, and the organic extract was more effective than the residual particles. Furthermore, the organic extract-induced expression of Ia antigen on PBM was reduced by the addition of an antioxidative agent. These results suggest that DEP may act on immature APC and enhance their AP activity and that the action contributing to oxidative stress may be mediated by organic compounds of DEP.

Effects of Ambient Air Pollutants on Asthma Medication Use and Wheezing among Fourth-Grade School Children from 12 Southern California Communities Enrolled in The Children's Health Study

Article

Nov 2004
Arch Environ Health

To investigate the effects of 12 monthly average air pollution levels on monthly prevalence of respiratory morbidity, the authors examined retrospective questionnaire data on 2034 4th-grade children from 12 Southern California communities that were enrolled in The Children's Health Study. Wheezing during the spring and summer months was associated with community levels of airborne particulate matter with a diameter < or = 10 microm (PM10) (odds ratio (OR) = 2.91; 95% confidence interval (CI) = 1.46-5.80), but was not associated with community levels of ozone, nitrogen dioxide, PM2.5 (diameter < or = 2.5), nitric acid, or formic acid. Logistic regression was performed on data stratified into two seasonal groups, spring/summer and fall/winter. Among asthmatics, the monthly prevalence of asthma medication use was associated with monthly levels of ozone, nitric acid, and acetic acid (OR = 1.80 [95%CI = 1.19-2.70]; OR = 1.80 [95%CI = 1.23-2.65]; OR = 1.57 [95% CI = 1.11-2.21]; respectively). Asthma medication use was more prevalent among children who spent more time outdoors--with consequential exposure to ozone--than among children who spent more time indoors (OR = 3.07 [95%CI = 1.61-5.86]; OR = 1.31 [95%CI = 0.47-2.71]; respectively). The authors concluded that monthly variations in some ambient air pollutants were associated with monthly respiratory morbidity among school children.

Effect of Ozone Exposure on Alveolar Macrophage-Mediated Immunosuppressive Activity in Rats

Article

Full-text available

Feb 1998

Effect of Ozone Exposure on Alveolar Macrophage-Mediated Immunosuppressive Activity in Rats, Koike, E., Kobayashi, T., Nelson, D.J., McWilliam, A.S., and Holt, P.G. (1998). ToxicoL Sci. 41, 217-223. Ozone (O3), a major component of photochemical air pollution, is a strong oxidizing agent and highly toxic Resident alveolar macrophages (AM) play an important immunomodulatory role in the lung via suppression of lymphocyte proliferation, thus limiting the magnitude and duration of local immune responses. Nitric oxide (NO) plays a crucial role in the immunosuppressive activity of AM. However, during inununoinflammatory responses, microenvironmental changes within the alveoli inhibit this AM function, permitting full expression of local T-cell-mediated immune responses. We hypothesize that similar changes in AM function may occur during inflammation induced by exposure to inorganic air pollutants, such as O3. In order to test this hypothesis, in the present study, we investigated (1) whether O3 exposure of rats might affect the immunosuppressive activity and NO production of bronchoalveolar lavage cells (BAL cells) and (2) whether changes in the microenvironment of the alveoli induced by O3 exposure can affect the immunosuppressive activity and NO production of AM. AM-mediated immunosuppressive activity was measured as inhibition of concanavalin A (Con A>induced proliferation of lymph node cells (LNC). Bronchoalveolar lavage was used to sample the alveolar microenvironment, and the resulting fluid (BALF) was tested for capacity to modulate AM activity in the cultures. BALF and BAL cells from rats exposed to 1 ppm O3 or filtered air for 3 days were used. The present results demonstrate that BAL cells isolated from O3-exposed rats suppressed Con A-induced LNC proliferation and produced NO in the same manner as BAL cells (AM) from air-exposed rats. AM-mediated suppressive activity of LNC proliferation and NO production were markedly inhibited by BALF from 03-exposed but not from air-exposed rats. These results suggested that AM-mediated immunosuppressive activity in vivo may be inhibited by the O3-induced release of soluble factors which inhibit NO production by AM.

Ozone-induced Inflammation in the Lower Airways of Human Subjects

Article

Full-text available

Mar 1989
Am J Respir Crit Care Med

Although ozone (O3) has been shown to induce inflammation in the lungs of animals, very little is known about its inflammatory effects on humans. In this study, 11 healthy nonsmoking men, 18 to 35 yr of age (mean, 25.4 +/- 3.5), were exposed once to 0.4 ppm O3 and once to filtered air for 2 h with intermittent exercise. Eighteen hours later, bronchoalveolar lavage (BAL) was performed and the cells and fluid were analyzed for various indicators of inflammation. There was an 8.2-fold increase in the percentage of polymorphonuclear leukocytes (PMN) in the total cell population, and a small but significant decrease in the percentage of macrophages after exposure to O3. Immunoreactive neutrophil elastase often associated with inflammation and lung damage increased by 3.8-fold in the fluid while its activity increased 20.6-fold in the lavaged cells. A 2-fold increase in the levels of protein, albumin, and IgG suggested increased vascular permeability of the lung. Several biochemical markers that could act as chemotactic or regulatory factors in an inflammatory response were examined in the BAL fluid (BALF). The level of complement fragment C3 alpha was increased by 1.7-fold. The chemotactic leukotriene B4 was unchanged while prostaglandin E2 increased 2-fold. In contrast, three enzyme systems of phagocytes with potentially damaging effects on tissues and microbes, namely, NADPH-oxidase and the lysosomal enzymes acid phosphatase and beta-glucuronidase, were increased neither in the lavaged fluid nor cells. In addition, the amounts of fibrogenic-related molecules were assessed in BALF.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of Impairment of the Airway Epithelium for Ozone-Induced Airway Hyperresponsiveness in Guinea Pigs

Article

Full-text available

May 1995

We examined the relationship between ozone (O3)-induced airway hyperresponsiveness (AHR) and inflammation in guinea pigs. Inhalation of methacholine (MCh) was adopted in the time course study of AHR that was assessed by measuring pulmonary inflation pressure after O3 exposure (3 ppm, for 2 hr) because the degree of AHR detected by inhalation of MCh was greater than that detected by i.v. administration. AHR was detected up to 5 hr after O3 exposure and was not observed at 24 and 48 hr. In the bronchoalveolar lavage (BAL) study, the numbers of neutrophils, eosinophils, lymphocytes and macrophages in BAL fluid (BALF) reached maximum at 24 hr or later. On the other hand, the number of airway epithelial cells in the BALF significantly increased at 2 and 5 hr. In the histological study, disorder and impairment of the airway epithelium in the trachea and lung were observed at 2 and 5 hr. Changes in the airway epithelium were recovered at 48 hr, although an increase in leukocytes was observed in the lung. These results indicate that O3-induced AHR in guinea pigs is most probably associated with impairment of the epithelium rather than with infiltration of inflammatory cells in the airway.

The Role of Ozone Exposure in the Epidemiology of Asthma

Article

Full-text available

Jan 1994

John Balmes

Asthma is a clinical condition characterized by intermittent respiratory symptoms, nonspecific airway hyperresponsiveness, and reversible airway obstruction. Although the pathogenesis of asthma is incompletely understood, it is clear that airway inflammation is a paramount feature of the condition. Because inhalation of ozone by normal, healthy subjects causes increased airway responsiveness and inflammation, it is somewhat surprising that most controlled human exposure studies that have involved asthmatic subjects have not shown them to be especially sensitive to ozone. The acute decrement in lung function that is the end point traditionally used to define sensitivity to ozone in these studies may be due more to neuromuscular mechanisms limiting deep inspiration than to bronchoconstriction. The frequency of asthma attacks following ozone exposures may be a more relevant end point. Epidemiologic studies, rather than controlled human exposure studies, are required to determine whether ozone pollution increases the risk of asthma exacerbations. Asthma affects approximately 10 million people in the United States and, thus, the answer to this question is of considerable public health importance. Both the prevalence and severity of asthma appear to be increasing in many countries. Although increased asthma morbidity and mortality are probably of multifactorial etiology, a contributory role of urban air pollution is plausible. The epidemiologic database to support an association between asthma and ozone exposure is limited, but the results of several studies suggest such an association. Some potential approaches to further investigation of the relationship between asthma and ozone, including those that would link controlled human exposures to population-based studies, are considered.

Regulation of alveolar macrophage-T cell interactions during Th1-type sarcoid inflammatory process

Article

Full-text available

Sep 1999
Am J Physiol

The accessory function of antigen-presenting cells depends on the presence of a number of costimulatory molecules, including members of the B7 family (CD80 and CD86) and the CD5 coligand CD72. The aim of this study was to evaluate the regulation of T cell-antigen-presenting cell costimulatory pathways in the lung of patients with a typical Th1-type reaction, i.e., sarcoidosis. Although normal alveolar macrophages (AMs) did not bear or bore low levels of costimulatory molecules, AMs from sarcoid patients with CD4 T-cell alveolitis upmodulated CD80, CD86, and CD72 and expressed high levels of interleukin (IL)-15; lymphocytes accounting for T-cell alveolitis expressed Th1-type cytokines [interferon (IFN)-gamma and/or IL-2] and bore high levels of CD5 and CD28 but not of CD152 molecules. In vitro stimulation of AMs with Th1-related cytokines (IL-15 and IFN-gamma) upregulated the expression of CD80 and CD86 molecules. However, stimulation with IL-15 induced the expression of Th1-type cytokines (IFN-gamma) and CD28 on sarcoid T cells, suggesting a role for this macrophage-derived cytokine in the activation of the sarcoid T-cell pool. The hypothesis that CD80 and CD86 molecules regulate the sarcoid T-cell response was confirmed by the evidence that AMs induced a strong proliferation of T cells that was inhibited by pretreatment with CD80 and CD86 monoclonal antibodies. To account for these data, it is proposed that locally released cytokines provide AMs with accessory properties that contribute to the development of sarcoid T-cell alveolitis.

Ozone Exposure Enhances Expression of Cell-Surface Molecules Associated with Antigen-Presenting Activity on Bronchoalveolar Lavage Cells in Rats

Article

Sep 2001
TOXICOL SCI

Eiko Koike

In this study, we investigated the effects of ozone (O3) exposure on expression of cell-surface molecules associated with antigen presentation and on accessory activity of bronchoalveolar lavage cells (BAL cells). Rats were exposed to 1 ppm O3 for 3 days. Expression of cell-surface molecules was measured by flow cytometry. Accessory activity of BAL cells was assessed by the allogeneic mixed lymphocyte reaction (MLR) and specific antigen-presenting activity. O3 exposure increased the expression of Ia, B7.1, B7.2, and CD11b/c on BAL cells. Morphological and immunological studies showed the Ia-positive cells to have monocyte-like features. Peripheral blood monocytes expressed Ia, B7.1, B7.2, and CD11b/c. The Ia expression on the monocytes was further increased by treatment of them with BAL fluid from O3-exposed rats (O3-BALF). Resident alveolar macrophages, however, did not express Ia antigen, and the Ia expression was not increased by O3-BALF. Neutrophils, which also infiltrated in response to O3 exposure, did not express Ia, B7.1, and B7.2. Therefore, infiltrating monocytes may have caused the increased expression of Ia and B7 molecules on BAL cells exposed to O3. The accessory activity of BAL cells in terms of MLR and specific antigen-presenting activity was also enhanced by O3 exposure. The present study suggests that monocytes infiltrating in response to O3 exposure caused enhancements of the expression of Ia and costimulatory molecules on and the accessory activity of BAL cells.

Increased expression of the CD80 accessory molecule by alveolar macrophages in asthmatic subjects and its functional involvement in allergen presentation to autologous TH2 lymphocytes

Article

Jun 1999
J ALLERGY CLIN IMMUN

Background: Alveolar macrophages (AMs) are more efficient antigen-presenting cells in allergic individuals than in nonatopic subjects. Objective: We studied whether this difference may be correlated to increased expression of membrane costimulatory molecules, such as the B7 molecules (CD80 and CD86). Methods: Eleven subjects with allergic asthma sensitized to Dermatophagoides pteronyssinus and 5 healthy nonatopic volunteers underwent bronchoalveolar lavage, and the costimulatory molecule expression on AMs was evaluated. Peripheral blood T cells, either freshly isolated or as established D pteronyssinus -specific cell lines, were cultured with autologous monocytes or AMs as antigen-presenting cells. In vitro allergen-induced proliferation and cytokine production were evaluated in the presence of B7-blocking reagents. Results: Allergic individuals had a significantly higher proportion of AMs expressing the CD80 molecule than control subjects (28.5% +/- 14.8% vs 1.4% +/- 1.2%; P <.001), whereas no difference was observed in CD86 expression (2.0% +/- 2.3% vs 1.1% +/- 0.6; P >.1). In a large proportion of the asthmatic subjects we studied, AMs were presenting soluble antigens (tetanus toxoid and streptolysin-O) to freshly isolated T cells more efficiently than AMs from nonatopic control subjects. Finally, both T-cell proliferation and cytokine production of D pteronyssinus- specific established T-cell lines were inhibited by a CD80-blocking antibody in a dose-dependent manner. Conclusion: Costimulation by means of CD80 expressed by AMs is probably involved in the amplification of the allergen-specific T-lymphocyte response in the airways of asthmatic subjects.

Effect of Ozone Exposure on Alveolar Macrophage-Mediated Immunosuppressive Activity in Rats

Article

Feb 1998

Ozone (O3), a major component of photochemical air pollution, is a strong oxidizing agent and highly toxic. Resident alveolar macrophages (AM) play an important immunomodulatory role in the lung via suppression of lymphocyte proliferation, thus limiting the magnitude and duration of local immune responses. Nitric oxide (NO) plays a crucial role in the immunosuppressive activity of AM. However, during immunoinflammatory responses, microenvironmental changes within the alveoli inhibit this AM function, permitting full expression of local T-cell-mediated immune responses. We hypothesize that similar changes in AM function may occur during inflammation induced by exposure to inorganic air pollutants, such as O3. In order to test this hypothesis, in the present study, we investigated (1) whether O3 exposure of rats might affect the immunosuppressive activity and NO production of bronchoalveolar lavage cells (BAL cells) and (2) whether changes in the microenvironment of the alveoli induced by O3 exposure can affect the immunosuppressive activity and NO production of AM. AM-mediated immunosuppressive activity was measured as inhibition of concanavalin A (Con A)-induced proliferation of lymph node cells (LNC). Bronchoalveolar lavage was used to sample the alveolar microenvironment, and the resulting fluid (BALF) was tested for capacity to modulate AM activity in the cultures. BALF and BAL cells from rats exposed to 1 ppm O3 or filtered air for 3 days were used. The present results demonstrate that BAL cells isolated from O3-exposed rats suppressed Con A-induced LNC proliferation and produced NO in the same manner as BAL cells (AM) from air-exposed rats. AM-mediated suppressive activity of LNC proliferation and NO production were markedly inhibited by BALF from O3-exposed but not from air-exposed rats. These results suggested that AM-mediated immunosuppressive activity in vivo may be inhibited by the O3-induced release of soluble factors which inhibit NO production by AM.

Immunophenotypic characterisation of human peritoneal and alveolar macrophages and of human blood monocytes differentiated in the presence of either GM-CSF or M-CSF or a combination of GM-CSF/M-CSF

Article

Feb 1992

In vivo, circulating blood monocytes (Mo) migrate into the various tissues where they undergo terminal maturation into macrophages (M phi) with morphological and sometimes functional properties that are characteristic for the tissue in which they reside. This tissue-specific M phi heterogeneity results from the immediate microenvironment, but may also originate from genetically distinct Mo subpopulations. The in vitro transformation of Mo to M phi is thought to reflect the events of the in vivo maturation and thus is widely used as a model to analyse M phi development. To study the heterogeneity within the mononuclear phagocyte system, we have investigated the phenotypic characterisation of mature tissue M phi, blood Mo and Mo-derived M phi cultured in medium with either GM-CSF, M-CSF or a combination of both cytokines. Tissue peritoneal and alveolar M phi showed different antigenic specificities, particularly concerning the transferrin receptor and CD68 and CD14 antigens. M-CSF-derived M phi when compared to the other M ø populations also exhibited a significantly increased expression of transferrin receptor and CD68 antigen. In contrast, GM-CSF treated cells which exhibited a better long term survival, showed notably more positivity for CD11b and CD32 antigens. These results show that the phenotypic heterogeneity of the different M phi populations is limited and appears to result from discrepancies in the differentiation and/or activation of the cells. The location of the CD68 antigen, which is generally considered to be an intracellular protein, was investigated at the ultrastructural level and found to be exclusively situated at the outer cell membrane.

Interleukin10 (IL10) inhibits the induction of nitric oxide synthase by interferon-? in murine macrophages

Article

Mar 1992

A murine macrophage cell line, J774, expresses high levels of the enzyme nitric oxide synthase (NOS) and produces large amounts of nitric oxide (NO) when activated with recombinant interferon (IFN)-gamma and a low concentration of LPS (10 ng/ml). Both the expression of NOS and the production of NO were inhibited by recombinant IL-10 in a dose-dependent manner. The inhibition was effective only when the cells were pretreated with IL-10; addition of IL-10 at the same time or after IFN-gamma activation was without effect. These results demonstrate that IL-10, a product of Th2 (helper T lymphocyte 2) cells, can antagonise the function of IFN-gamma, a product of Th1 cells, by modulating the mechanism of synthesis of nitric oxide in the macrophages.

Immunosuppresive activity induced by nitric oxide in culture supernatant of activated rat alveolar macrophages

Article

Jun 1992

Alveolar macrophages (AM) from normal rats had immunosuppressive activity to mitogen-induced proliferative responses of splenic lymphocytes. We studied the mechanism and the implication of the nitric oxide synthetase pathway in AM-mediated suppression of concanavalin A (Con A)-induced lymphocyte proliferation. The culture supernatant from AM cultures alone did not have immunosuppressive activity to Con A-induced proliferative responses of non-adherent spleen cells (n-ad SC), but the culture supernatant from co-culture of AM and autologous n-ad SC had this activity. Con A-pulsed AM also liberated the immunosuppressive factor. When AM and autologous n-ad SC were cultured separately under the condition that medium could freely communicate, the culture supernatant did not suppress the Con A-induced proliferative response of n-ad SC. This indicated that the immunosuppressive factor was liberated when AM was activated by cell-to-cell contact with n-ad SC. Further, we examined the immunosuppressive activity of the culture supernatant of co-culture of AM and autologous n-ad SC to Con A-induced responses of allogeneic n-ad SC and xenogeneic murine n-ad SC, and allogeneic mixed leucocyte reaction, and found that this culture supernatant could suppress all these proliferative responses. Nitrate (NO2-) synthesis was markedly augmented in the culture supernatants of Con A-pulsed AM and co-culture of AM and n-ad SC. NG-monomethyl-L-arginine (MMA), a specific competitive inhibitor of the nitric oxide synthetase pathway (NOSP), extinguished both NO2- synthesis by AM and AM-mediated immunosuppressive activity. These data suggest that NOSP was important in AM-mediated suppression of Con A-induced lymphocyte proliferation.

Increased expression of class II antigens of the major histocompatibility complex on alveolar macrophages and alveolar type II cells and interleukin-1 (IL-1) secretion from alveolar macrophages in an animal model of silicosis

Article

Sep 1989

Silicosis is a chronic progressive granulomatous and fibrotic lung disease caused by inhaled silica. Although the causative agent is known, the pathogenesis, especially the immunologic response, is not well understood. We examined two important components of cell-mediated immune responses in the lungs of rats with silica-induced lung disease, i.e., class II (Ia) antigen expression and IL-1 production. The relative density of Ia was examined on isolated alveolar macrophages and type II cells with a solid-phase cellular radioimmunoassay and the percent of Ia positive cells was determined by an indirect immunofluorescent technique. There was a three-fold increase of Ia expression on the alveolar macrophages and nearly a two-fold increase on type II cells from rats with silicosis compared to normal rats. The percent of alveolar type II cells positive for Ia increased by 20%, and the alveolar macrophages increased by 40%. IL-1 in supernatants from cultured alveolar macrophage was measured by the amount of DNA synthesis in an IL-1 dependent cell line (D10). A six-fold increase in IL-1 secretion was noted in macrophage supernatants derived from silica-treated animals. We conclude that in this animal model of silicosis, a local amplification of cell-mediated immune responses may be instrumental in the pathogenesis.

Suppression of IgE Antibody Production after Exposure to Ozone in Mice

Article

Feb 1985
Int Arch Allergy Appl Immunol

The effect of ozone exposure on IgE antibody production with aerosolized ovalbumin (OA) administration was investigated in Balb/c mice. Mice were continuously exposed to 0.8 ppm ozone for 1, 2, or 4 weeks, respectively, and subsequently aerosolized OA was administered through the respiratory tract for 6 min with a nebulizer. The mice were then immunized intraperitoneally 1 week later with OA. IgE antibody production was suppressed in ozone-exposed mice. However, no significant difference in the primary IgE antibody production by intraperitoneal immunization alone with OA was observed between ozone-exposed mice and nonexposed mice. In order to elucidate the suppressive mechanism of IgE antibody production, hapten-carrier antigenic system was used. It is shown that the induction of helper T cell function was suppressed if the aerosolized carrier protein was administered before intraperitoneal immunization in the mice exposed to ozone. These results suggest that ozone exposure has the effect on the stage of administration of inhaled antigen and the quite insignificant effect on the IgE antibody production after intraperitoneal immunization with OA.

Enhanced alveolar macrophage Ia antigen expression after asbestos inhalation

Article

Jul 1984

Asbestos is a disease characterized by pleural and interstitial pulmonary fibrosis resulting from the inhalation of asbestos dust (1). Although the pathogenesis of the disease is not fully understood, immunologic mechanisms are suspected to play an important role in asbestos-mediated lung injury. There is also evidence that alveolar macrophages (AM) may be pivotal in this regard. As an extension of earlier studies, the authors have recently shown that both amphibole (crocidolite) and serpentine (chrysotile) asbestos inhalation are associated with augmented antigen-directed release of interleukin 1 (IL 1) and interleukin 2 (IL 2) during in vitro culture. Because IL 1 activity is known to be under the control of the 1 region of the major histocompatibility complex, the present study was undertaken to assess the effects of crocidolite and chrysotile asbestos inhalation on Ia antigen expression by AM. By using a defined rat model the longer-term effects of asbestos inhalation were studied in one set of animals at a time contemporaneous with the earlier interleukin study. Another set of rats was also studied to monitor the shorter-term effects of asbestos exposure. The results indicate that both amphibole and serpentine asbestos inhalation in the rat are associated with enhanced Ia expressitivity on AM.

Immunoglobulin E-Containing Cells in Mouse Lung Following Allergen Inhalation and Ozone Exposure

Article

Feb 1981
Int Arch Allergy Appl Immunol

Cells containing immunoglobulin E (IgE) were enumerated and their location in mouse lungs was determined by direct immunofluorescence. Lungs were studied from mice that had been immunized with aerosolized ovalbumin as well as from normal mice and from mice that were exposed to ozone (0.5 or 0.8 ppm) prior to receiving aerosolized antigen. In addition, some mice were immunized intraperitoneally with ovalbumin precipitated in alum. IgE-containing cells were primarily airway-related in normal mice and in mice immunized by the intraperitoneal route. Lungs from aerosol-immunized, and aerosol-immunized ozone-exposed mice showed a more disseminated distribution of IgE-containing cells. Fluorescent cells were counted and numbers were expressed as total cells per square millimeter of lung tissue and as airway-associated cells per millimeter of airway. Total IgE cells increased 9.4-fold in mice that received aerosolized ovalbumin as compared to normal mice. When ozone exposure was added to the effects from aerosolized ovalbumin, the increase of IgE cells over normal was 34.2-fold. IgE cell counts correlated well with anaphylactic sensitivity to intravenous challenge with ovalbumin. The observed enhancement of allergic sensitization by ozone exposure has important implications for human health.

Macrophage-mediated suppression. I. Evidence for participation of both hydrogen peroxide and prostaglandins in suppression of murine lymphocyte proliferation

Article

Mar 1980

Macrophage-mediated suppression of Con A induced proliferation of murine splenic lymphocytes was studied in vitro. Either Corynebacterium parvrum-induced peritoneal exudate cells (PEC) or thioglycollate-induced PEC could totally suppress lymphocyte proliferation at a PEC:lymphocyte ratio of 2:10, whereas a ratio of 1 to 1.5: 10 caused a partial (60 to 68%) suppression. Exogenous PGE1 and PGE2 at concentrations of 10(-8) to 10(-6) M could not totally suppress lymphocyte proliferation. Conversely, indomethacin reversed the partial suppression by macrophages but only partially protected the totally suppressed lymphocyte cultures. Macrophage-mediated cytotoxicity and cytostasis have been proposed to be mediated by hydrogen peroxide. Therefore, hydrogen peroxide was investigated as a possible additional cause for macrophage-mediated suppression, by testing the anti-inhibitory effects of catalase. Partially suppressed cultures were effectively protected from suppression by catalase. In totally suppressed cultures, catalase alone was only minimally effective, but a synergistic effect of catalase and indomethacin was obtained, which provided complete protection from maximal macrophage-mediated suppression. Catalase presumably contributes to the reversal of macrophage suppressive effects both by reducing the direct toxic effect of H2O2 and by preventing the H2O2 from generating additional prostaglandins.

Cytokine modulation of the immunosuppressive phenotype of pulmonary alveolar macrophage populations

Article

Nov 1995

Under steady-state conditions, T-cell activation in the lung is tightly controlled by lymphocytostatic signals from resident pulmonary alveolar macrophages (PAM). The present study focuses upon the mechanism of suppression in the mouse, and how it is bypassed during local inflammatory challenge. Reactive nitrogen intermediates such as nitric oxide (NO) are shown to play a central role in the process as the expression of lymphocytostatic activity by resident murine PAM was abrogated by the NO synthetase inhibitor N-monomethyl-arginine. Overnight pretreatment of resident PAM with granulocyte-macrophage colony-stimulating factor (GM-CSF) abrogated lymphocytostatic activity, with a concomitant small decrease in NO production; this effect was markedly amplified by tumour necrosis factor-alpha (TNF-alpha), but the latter was ineffective alone. The cytokines were inactive if added singly or in combination to fresh PAM:T-cell co-cultures. If GM-CSF plus TNF-alpha exposure of PAM was prolonged beyond 48 hr, both lymphocytostatic and NO-producing capacity were spontaneously re-established. Transforming growth factor-beta (TGF-beta) also inhibited both NO production and lymphocytostatic activity of PAM, but in contrast to GM-CSF and TNF-alpha, TGF-beta was only active if present throughout the PAM:T-cell coculture period. Additionally, monocytes recruited into the lung by a sterile inflammatory stimulus are shown to be initially stimulatory towards T-cell activation, and to progressively develop both T-cell suppressive- and NO synthetic-capacity as they mature into mature PAM in vivo. Thus, during acute lung inflammation, a series of overlapping mechanisms are potentially available to bypass local immunosuppression: secretion of cytokines which are capable of temporarily abrogating the immunosuppressive activity of resident PAM, and the recruitment of permissive monocytes which exhibit potent accessory cell activity, the net result being the creation of a transient 'window' for induction of local T cell-mediated immunity.

Alveolar macrophages from humans and rodents selectively inhibit T-cell proliferation but permit T-cell activation and cytokine secretion

Article

Feb 1995

Alveolar macrophages (AM) are thought to play a key role in the regulation of immune responses within the lung. While it is well established that AM inhibit T-cell proliferation in vitro, it is unclear whether other aspects of the T-cell activation process are also inhibited. The present study demonstrates that AM from rat, mouse and human differ markedly in the potency with which they inhibit mitogen-induced T-cell proliferation, although in humans the degree of inhibition approaches that observed in the animal systems, if antigen (as opposed to mitogen) is employed as the T-cell activating agent. Rodent and human AM also differ in the mechanisms employed to achieve this inhibition; rodent AM appear to utilize reactive nitrogen intermediates, while this does not appear to be the case for human AM. Despite these differences, T cells stimulated in the presence of AM display a similar phenotype in all species examined, i.e. CD3 down-modulation, up-regulation of interleukin-2 receptor (IL-2R) expression and IL-2 production, but inability to respond to IL-2. Thus, AM appear to allow T-cell activation and expression of T-cell effector function, while selectively inhibiting T-cell proliferation.

Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines

Article

Apr 1995

Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the amino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline. NO is important in the bactericidal and cytotoxic activities of macrophages. An equivalent functional role of arginase and its products is not known. We tested the induction of arginase in bone marrow-derived macrophages by endogenous mediators that are known to induce NO synthase, such as interferon-gamma (IFN-gamma), or suppress the induction of this enzyme, such as interleukin (IL)-4, IL-10, and prostaglandin E2 (PGE2). We find that PGE2 and the TH2 cytokines IL-4 and IL-10 are potent inducers of arginase. In contrast, the TH1 cytokine IFN-gamma does not induce arginase. Simultaneous application of both types of mediators leads to reduced induction of both arginase and NO synthase. Exposure of macrophage cultures to inducers of NO synthase exhausts their ability to respond subsequently to inducers of arginase. Conversely, exposure of the cells to inducers of arginase exhausts their ability to respond subsequently to inducers of NO synthase. The results are consistent with a competition of both enzymes for their substrate, L-arginine, with a reciprocal inhibition in the induction of both enzymes, or a combination of both phenomena. The enzymes NO synthase and arginase appear to define two alternate functional states of macrophages, induced by TH1 and TH2 cytokines, respectively.

Regulation of T-cell function in lung tissue by pulmonary alveolar macrophages

Article

Nov 1993

Collagenase digestion of perfused, lavaged rat lung yields a large population of CD5+ T cells, which on current evidence appear to be recently derived from the peripheral blood pool. Two-colour cytofluorographic analysis indicates that approximately 65% are CD4+ T cells, which are predominantly of the activated/memory phenotype. By limiting dilution analysis, these peripheral lung wall T cells and their airway counterparts isolated by bronchoalveolar lavage, exhibit markedly reduced capacity to proliferate by comparison to peripheral blood T cells. However, intratracheal inoculation of liposomes containing dichloro-methylene-diphosphonate at a dosage shown to eliminate the majority of resident alveolar macrophages (AM) rapidly restores the immunocompetence of these lung T-cell populations. These results are discussed in relation to recent reports that in vivo elimination of AM from rats and mice greatly amplifies immune responses to inhaled antigens, in particular T-memory cell-dependent secondary antibody responses.

Modulation of Phenotypic and Functional Properties of Normal Human Mononuclear Phagocytes by Granulocyte-Macrophage Colony-Stimulating Factor

Article

Jun 1994

In asthma, alveolar macrophages (AMs) are hyperreactive releasing large amounts of mediators and expressing high levels of surface markers. Granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulates monocytes and AMs, and may be involved in the hyperreactivity of AMs. The effects of GM-CSF were tested on monocytes and AMs from normal subjects by examining the expression of factors thought to be upregulated in asthma. After various incubation times of GM-CSF, the expression of CD23 and beta 2-integrins (CD11a, CD11b, CD11c) was studied by FACS and the release of sCD23 was measured by ELISA. The priming and stimulatory effects of GM-CSF were tested on monocytes and AMs and the release of leukotriene B4 (LTB4) was measured by ELISA. GM-CSF induced the expression of CD11c and CD23 and the release of sCD23. GM-CSF primed and stimulated monocytes and AMs to release LTB4. The effects of GM-CSF may explain partly the hyperreactivity of AMs in asthma.

Bronchoalveolar Lavage Neutrophilia in Asthmatic and Healthy Volunteers After Controlled Exposure to Ozone and Filtered Purified Air

Article

Jan 1995

To characterize the pulmonary response of asthmatic and healthy nonsmoking adult men to 0.20 ppm ozone by controlled chamber exposure. A prospective, crossover study of five atopic asthmatic and five normal subjects randomly exposed to ozone and filtered purified air (FPA) for 6 h, consisting of 30-min alternating periods of rest and moderate exercise. The two exposures were separated by at least 30 days. A controlled exposure in a stainless steel chamber. Five atopic asthmatic and five normal subjects between 18 and 45 years of age. Treatment with medications was withheld from asthmatics prior to the exposures. All subjects were nonsmokers. Symptoms were assessed throughout the exposures. Pulmonary function was measured at baseline, hourly throughout an exposure, and after an exposure. Bronchoalveolar lavage (BAL) was performed 18 h after the completion of an exposure. The BAL fluid (BALF) was analyzed for cell count and differential; the cell-free supernatant was analyzed for albumin, tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6), and interleukin 8 (IL-8). There were statistically significant increases in IL-8 levels, as well as percent polymorphonuclear neutrophils (PMNs) and PMNs per milliliter of lavage in asthmatics exposed to ozone as compared with the same asthmatics exposed to FPA and the same normal subjects exposed to ozone and FPA. Interleukin 6 was also significantly increased in asthmatics exposed to ozone. The BALF albumin, TNF, and IL-1 levels were not significantly different among the four groups. There were no differences between asthmatics and healthy controls exposed to ozone or FPA in baseline to postexposure FEV1, FVC, FEV1/FVC, and sRaw. We conclude that asthmatics exposed to ozone develop a significant BALF neutrophilia and increased levels of the cytokines, IL-8 and IL-6. These BALF findings occur even though the level of ozone exposure was not significant enough to reduce pulmonary function.

Effect of Chronic Tobacco Smoke Exposure on the Function of Alveolar Macrophages in Mice

Article

Feb 1994

We evaluated the effect of chronic tobacco smoke exposure on the function of the alveolar macrophage (AM) in mice. Tumor necrosis factor-alpha production of the AM triggered by lipopolysaccharides was smaller in smoke-exposed mice as compared to control mice but did not reach statistical significance (27.3 +/- 4.0 vs. 34.8 +/- 4.9 U/ml). The percentage of AM which did not phagocytize latex particles in the smoke-exposed mice was significantly larger than that in control mice (33.9 +/- 2.3 vs. 20.8 +/- 2.1%; p < 0.05). Ia antigen expression of the AM was significantly larger in smoke-exposed mice (cytotoxicity index: 0.180 +/- 0.033 vs. 0.038 +/- 0.0118; p < 0.01). The asialo-GM1 antigen expression was similar in both groups (0.949 +/- 0.007 vs. 0.961 +/- 0.011). Although the precise mechanisms of these functional changes of the AM by tobacco smoke exposure are not clear, they may have some immunological effects on the alveolar space.

Suppressor macrophages in African Trypanosomes inhibit T cell proliferative responses by nitric oxide and prostaglandins

Article

Dec 1993

Suppression of host T cell responses is one of the hallmarks of infection with the African trypanosomes. The cellular basis for immunosuppression includes the generation of suppressor macrophages that down-regulate T cell proliferative but not necessarily cytokine responses to both mitogen and trypanosome Ag. Since macrophages from infected animals display activation characteristics, we have asked whether products of activated cells, specifically nitric oxide (NO) and PG, may mediate the suppressor cell effects and immunosuppression observed. We demonstrate that cells isolated from B10.BR mice infected with Trypanosoma brucei rhodesiense exhibited transcriptional up-regulation of inducible NO synthase and released significant amounts of NO. The levels of NO released were elevated further after stimulation of cells with T cell mitogens or specific parasite Ag; antibody blocking experiments demonstrated that this up-regulation of NO synthesis was at least partially dependent upon IFN-gamma and TNF-alpha. The addition of inducible NO synthase substrate analogues such as NG-monomethyl-L-arginine to cell cultures inhibited NO release and also partially reversed the suppressor cell activity and immunosuppression displayed by such cultures. PG levels also were elevated in cell cultures from infected mice, but the PG inhibitor indomethacin had no effect on suppressor cells or suppression when added alone to the cultures. However, the concurrent inhibition of NO and PG synthesis by the addition of both NG-monomethyl-L-arginine and indomethacin completely blocked suppressor cell activity associated with infected macrophages and also resulted in further recovery of infected cells from immunosuppression, thus revealing an epistatic effect between these two mediators. We conclude that macrophage activation in trypanosomiasis induces the release of reactive nitrogen intermediates and PG, which down-regulate proliferative responses by T cells during infection.

Comparison of Pulmonary Responses of Asthmatic and Nonasthmatic Subjects Performing Light Exercise While Exposed to a Low Level of Ozone

Article

Jul 1995

To determine if asthmatic subjects (ASTH, n = 17) experience greater O3-induced pulmonary decrements than nonasthmatic subjects (NONA, n = 13), both groups were exposed for 7.6 h to both clean air and 0.16 ppm O3. Exposures consisted of seven 50-min periods of light exercise (VE = 14.2 and 15.3 l/min/m2 for ASTH and NONA, respectively), each followed by 10 min rest. A 35-min lunch period followed the third exercise. Following O3 exposure, decrements in forced expiratory volume in one second (FEV1) and FEV1 divided by forced vital capacity (FVC), corrected for air exposure, for ASTH (-19.4 +/- 3.1% and -6.2 +/- 2%, respectively) were significantly greater (p = 0.04 and 0.02) than for NONA (-9.8 +/- 1.9% and -1 +/- 1%, respectively). There was no difference (p = 0.33) for decrements in FVC between ASTH (-11.8 +/- 1.9%) and NONA (-8.8 +/- 2.1%). Nine of 17 ASTH experienced wheezing with O3, while only one experienced wheezing with air (p = 0.004); no NONA experienced wheezing. Six of 17 ASTH requested inhaled beta-agonist bronchodilator prior to and/or during O3 exposure and experienced some temporary alleviation of decrements. At end exposure, however, ASTH who were medicated had greater O3-induced decrements than those who were not medicated. ASTH who had the larger O3-induced decrements had lower baseline FEV1/FVC and lower baseline %predicted FEV1. These data indicate that in ASTH, unlike NONA, some portion of O3-induced pulmonary decrements experienced was related to bronchoconstriction, and that O3-responsiveness for ASTH depended upon baseline airway status.

Noninvasive Measurement of Airway Responsiveness in Allergic Mice Using Barometric Plethysmography

Article

Oct 1997

To study the mechanisms and kinetics underlying the development of increased airway responsiveness (AR) after allergic sensitization, animal models have been invaluable. Using barometric whole-body plethysmography and increases in enhanced pause (Penh) as an index of airway obstruction, we measured responses to inhaled methacholine in conscious, unrestrained mice after sensitization and airway challenge with ovalbumin (OVA). Sensitized and challenged animals had significantly increased AR to aerosolized methacholine compared with control animals. AR measured as Penh was associated with increased IgE production and eosinophil lung infiltration. In a separate approach we confirmed the involvement of the lower airways in the response to aerosolized methacholine using tracheotomized mice. Increases in Penh values after methacholine challenge were also correlated with increased intrapleural pressure, measured via an esophageal tube. Lastly, mice demonstrating AR using a noninvasive technique also demonstrated increased pulmonary resistance responses to aerosolized methacholine when measured using an invasive technique the following day in the same animals. The increases in Penh values were inhibited by pretreatment of the mice with a beta 2-agonist. These data indicate that measurement of AR to inhaled methacholine by barometric whole-body plethysmography is a valid indicator of airway hyperresponsiveness after allergic sensitization in mice. The measurement of AR in unrestrained, conscious animals provides new opportunities to evaluate the mechanisms and kinetics underlying the development and maintenance of airway hyperresponsiveness and to assess various therapeutic interventions.

Expression of B7 co-stimulatory molecules and CD1a antigen by alveolar macrophages in allergic bronchial asthma

Article

Dec 1998

Lung allergen recognition that takes place in the airways of asthmatic subjects is still a controversial matter. We hypothesized that a rapid allergen recognition process requires the presence, at the mucosal surface, of professional APC, such as B7+ alveolar macrophages (AM) and/or CD1+ dendritic cells, which usually have a lower expression in the normal human lung. Studies were performed on bronchoalveolar lavage (BAL) fluid collected from 10 untreated allergic subjects and 10 adult normal volunteers. Further controls consisted of five untreated pulmonary sarcoidosis (PS) and four extrinsic allergic alveolitis (EAA) individuals. To ascertain whether T helper 2-type cytokines or allergen influence B7 and CD1 antigen expression, in vitro studies were carried out using unprimed (naive) cord blood plastic-adherent monocytes. Cytofluorymetric analysis revealed that AM from asthmatics, unlike those from normal subjects or patients with PS or EAA, overexpressed B7-2, CD1a and, to a lesser extent, B7-1 surface molecules. Immunohistochemical studies confirmed the presence of CD1+ dendritic cells in the BAL fluid from asthmatic subjects. On in vitro cultured naive cord blood monocytes both purified Dermatophagoides pteronyssinus allergen and T-cell cytokines, i.e. IL-4 and granulocyte macrophage colony-stimulating factor, induced surface expression of B7-2 and CD1a receptors, whereas they had no appreciable effect on that of B7-1 membrane molecule. Taken together, these findings support the proposal that airways of atopic individuals are equipped with professional APC that synergize with allergen-specific T cells for the recognition of intact allergens. When the recognition process takes place, asthmatic symptoms could develop in genetically susceptible individuals.

Ozone-induced lung inflammation and mucosal barrier disruption: Toxicology, mechanisms, and implications

Article

Jan 1999

D K Bhalla

The airway epithelial lining serves as an efficient barrier against penetration of exogenous particles and macromolecules. Disruption of this barrier following O3 exposure represents a state of compromised epithelial defenses leading to increased transmucosal permeability. Although the barrier disruption following an acute exposure is transient in nature, the brief period of disruption caused by O3, an oxidant air pollutant, provides an opportunity for facilitated entry of a potentially toxic particulate copollutant(s) across the airway epithelia. The subsequent deposition and retention of the copollutant(s) in the subepithelial compartment for prolonged periods adds the risk of injury due to chronic exposure following an acute episode. Toxicological studies from several laboratories have demonstrated alterations in epithelial permeability, suggestive of barrier disruption, in animals and humans exposed to O3. Inflammatory cells represent another important component of pulmonary defenses, but upon activation these cells can both induce and sustain injury. The recruitment of these cells into the lung following O3 exposure presents a risk of tissue damage through the release of toxic mediators by activated inflammatory cells. Several studies have reported concomitant changes in permeability and recruitment of the inflammatory cells in the lung following O3 exposure. In these studies, an inflammatory response, as detected by an increase in the number of polymorphonuclear leukocytes in the bronchoalveolar lavage (BAL) or in lung parenchyma, was accompanied by either an increased tracer transport across the airway mucosa or an elevation in the levels of total protein and/or albumin in the BAL. The magnitude of response and the time at which the permeability changes and inflammatory response peaked varied with O3 concentration, exposure duration, and the mode of analysis. The responsiveness to O3 also appeared to vary with the animal species, and increased under certain conditions such as physical activity and pregnancy. Some of the effects seen after an acute exposure to O3 were modified upon repeated exposures. The responses following repeated exposures included attenuation, persistence, or elevation of permeability and inflammation. Mechanistic studies implicate chemotactic factors, cellular mediators, and cell-surface-associated molecules in the induction of inflammation and lung injury. In discussing these studies, this review serves to introduce the mucosal barrier functions in the lung, evaluates inflammatory and permeability consequences of O3, addresses mechanisms of inflammatory reactions, and offers alternate viewpoints.

Mechanisms of ozone-induced inhibitory effect of bronchoalveolar lavage fluid on alveolar macrophage-mediated immunosuppressive activity in rats

Article

Aug 1999

Resident alveolar macrophages (AM) play an important immunomodulatory role via suppression of lymphocyte proliferation, and nitric oxide (NO) plays a crucial role in this immunosuppression of AM. Our previous report suggested that during ozone (O3)-induced lung inflammation, bronchoalveolar lavage fluid (BALF) inhibited AM-mediated immunosuppression and concanavalin A (Con A)-induced proliferation of lymph node cells (LNC) [E. Koike et al. (1998) Toxicol. Sci. 41, 217-223]. In these studies, we investigated the mechanisms of the inhibition of BALF from O3-exposed rats (O3-BALF). We investigated whether BALF might affect (1) the interferon-gamma (IFN-gamma) production by Con A-stimulated LNC and IFN-gamma-induced NO production by AM, and (2) the interleukin (IL)-2 production by Con A-stimulated LNC and IL-2-induced LNC proliferation. These results demonstrated that O3-BALF inhibited IFN-gamma production by Con A-stimulated LNC, IFN-gamma-induced NO production by AM, and IL-2-induced LNC proliferation. In addition, the major inhibitory factor against AM-mediated immunosuppression in O3-BALF may be a protein of greater than 10 kDa.

Recombinant interleukin-16 selectively modulates surface receptor expression and cytokine release in macrophages and dendritic cells

Article

Jul 1999

Interleukin-16 (IL-16), a natural ligand for the CD4 receptor, has been found to modulate T-lymphocyte function and to inhibit human immunodeficiency virus type 1 (HIV-1) replication. Antigen-presenting cells (APC), including macrophages and dendritic cells, are known to express functional surface CD4 molecules, to be susceptible to HIV-1 infection and to play a critical role in different immune processes. Therefore, we evaluated the ability of recombinant IL-16 (rIL-16) to regulate receptor expression and cytokine release in monocyte-derived macrophages (MDM) and monocyte-derived dendritic cells (MDDC). Recombinant IL-16 was found to up-regulate CD25 and CD80 but to down-regulate CD4 and CD86 surface expression in MDM cultures. However, no change could be observed on the level of CD4, CD80 and CD86 expression in IL-16-stimulated MDDC, although a significant up-regulation of CD25 and CD83 was consistently detected. Furthermore, the level of gene expression of the chemokine receptors CCR5 and CXCR4 was significantly reduced in rIL-16-treated MDM and costimulation with IL-2 did not modify the activity of the recombinant cytokine. The effects on chemokine receptor gene expression were less evident in MDDC and only a transient down-regulation of weak intensity could be detected following stimulation with rIL-16. Analysis of supernatants from rIL-16-stimulatedcultures revealed a different profile of released cytokines/chemokines among the two cell populations studied. These findings establish an important role for IL-16 in modulating the activity of APC and may have relevance regarding the protection of reservoir cells against HIV-1 infection.

Lung injury, inflammation, and inflammatory stimuli in rats exposed to ozone

Article

Mar 2000

The effects of ozone (O3) on airway epithelia, inflammation, and expression of inflammatory stimuli were investigated to delineate the mechanisms of inflammatory reactions relevant to lung injury. Because the airway responses to O3 develop gradually, this investigation included a time-sequence analysis. Rats exposed for 3 h to 1 ppm O3 were studied at 4-h intervals up to 20 h postexposure. Bronchoalveolar lavage fluid (BAL) was analyzed for albumin as an indicator of increased permeability, polymorphonuclear leukocytes (PMNs) to assess the inflammatory status, macrophage inflammatory protein-2 (MIP-2, an inflammatory chemokine), and cell adhesion molecules for their role in inflammation and PMN functions. The time-related increase in albumin was matched by a similar significant increase for PMNs, MIP-2, and intercellular adhesion molecule-1 (ICAM-1). However, no marked change occurred for beta-2 integrin (CD-18) and leukotriene B4 (LTB4). The results establish a temporal correlation of epithelial permeability with changes in inflammatory activity and stimuli responsible for PMN recruitment in the lung. The observations of elevated MIP-2 and ICAM-1 levels are consistent with their role in injury and inflammation. An early expression of MIP-2 mRNA in BAL cells, that is, immediately post O3 exposure, and the peak increase in BAL MIP-2 levels 4 h later support the chemotactic role of MIP-2 in PMN recruitment at 4- and 12-h time points. The rapid drop in MIP-2 and ICAM-1 levels appears to signal the termination of inflammatory cell recruitment, which is accompanied by an onset of recovery.

Priming of Allergic Immune Responses by Repeated Ozone Exposure in Mice

Article

Sep 2000

The effects of repeated ozone exposures on the development of immune responses toward ovalbumin (OVA) were investigated in BALB/c and C57BL/6 mice. Ozone exposures (180 to 500 microg/m(3); 4 h, three times/wk for 4 wk) were combined with a protocol of OVA-aerosol exposure (1% OVA). Immediate cutaneous hypersensitivity (ICHS) reactions and antibody titers were assessed in parallel to cytokine levels of bronchoalveolar lavage fluids. In BALB/c mice, ozone triggered a T-helper (Th)2-like response indicated by dose-dependent increases in total serum immunoglobulin (Ig) E (from 133 to 821 ng/ml), interleukin (IL)-4 (from 60 to 208 pg/ml), and IL-5 levels (from 43 to 356 pg/ml), and by the recruitment of eosinophils and lymphocytes into the airways. Ozone exposure (500 microg/m(3)) in parallel to OVA-aerosol exposure increased anti-OVA IgG(1) antibody titers by 80%, leukotrienes (C(4)/D(4)/E(4)) by 60%, and airway responsiveness (11.3 versus 7.2 mg/ml methacholine), and doubled the frequency of positive ICHS reactions. In C57BL/6 mice, only the combination of OVA and ozone exposure induced positive ICHS reactions, doubled anti-OVA IgG(1), and suppressed anti-OVA IgG(2a) (-64%) antibody titers. Ozone, therefore, shifted the immune responses to OVA toward a Th2-like pattern in both "IgE-high responder" (BALB/c) and "IgE-low responder" (C57BL/6) mice.

Exposure to ozone enhances antigen-presenting activity concentration dependently in rats

Abstract

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