scholarly journals Beta-2 Adrenergic and Glucocorticoid Receptor Agonists Modulate Ozone-Induced Pulmonary Protein Leakage and Inflammation in Healthy and Adrenalectomized Rats

2018 ◽  
Vol 166 (2) ◽  
pp. 288-305 ◽  
Author(s):  
Andres R Henriquez ◽  
Samantha J Snow ◽  
Mette C Schladweiler ◽  
Colette N Miller ◽  
Janice A Dye ◽  
...  
Keyword(s):  
Corn Oil ◽  
Stress Hormones ◽  
Lavage Fluid ◽  
Ozone Exposure ◽  
Cell Trafficking ◽  
Receptor Agonists ◽  
Protein Leakage ◽  
Chronic Pulmonary Diseases ◽  
Circulating Lymphocytes ◽  
Wistar Kyoto

Abstract We have shown that acute ozone inhalation activates sympathetic-adrenal-medullary and hypothalamus-pituitary-adrenal stress axes, and adrenalectomy (AD) inhibits ozone-induced lung injury and inflammation. Therefore, we hypothesized that stress hormone receptor agonists (β2 adrenergic-β2AR and glucocorticoid-GR) will restore the ozone injury phenotype in AD, while exacerbating effects in sham-surgery (SH) rats. Male Wistar Kyoto rats that underwent SH or AD were treated with vehicles (saline + corn oil) or β2AR agonist clenbuterol (CLEN, 0.2 mg/kg, i.p.) + GR agonist dexamethasone (DEX, 2 mg/kg, s.c.) for 1 day and immediately prior to each day of exposure to filtered air or ozone (0.8 ppm, 4 h/day for 1 or 2 days). Ozone-induced increases in PenH and peak-expiratory flow were exacerbated in CLEN+DEX-treated SH and AD rats. CLEN+DEX affected breath waveform in all rats. Ozone exposure in vehicle-treated SH rats increased bronchoalveolar lavage fluid (BALF) protein, N-acetyl glucosaminidase activity (macrophage activation), neutrophils, and lung cytokine expression while reducing circulating lymphocyte subpopulations. AD reduced these ozone effects in vehicle-treated rats. At the doses used herein, CLEN+DEX treatment reversed the protection offered by AD and exacerbated most ozone-induced lung effects while diminishing circulating lymphocytes. CLEN+DEX in air-exposed SH rats also induced marked protein leakage and reduced circulating lymphocytes but did not increase BALF neutrophils. In conclusion, circulating stress hormones and their receptors mediate ozone-induced vascular leakage and inflammatory cell trafficking to the lung. Those receiving β2AR and GR agonists for chronic pulmonary diseases, or with increased circulating stress hormones due to psychosocial stresses, might have altered sensitivity to air pollution.

scholarly journals Exacerbation of ozone-induced pulmonary and systemic effects by β2-adrenergic and/or glucocorticoid receptor agonist/s

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Andres R. Henriquez ◽  
Samantha J. Snow ◽  
Mette C. Schladweiler ◽  
Colette N. Miller ◽  
Janice A. Dye ◽  
...  
Keyword(s):  
Glucose Intolerance ◽  
Glucocorticoid Receptors ◽  
Dual Therapy ◽  
Lavage Fluid ◽  
Ozone Exposure ◽  
Systemic Effects ◽  
Dependent Manner ◽  
Pollution Effects ◽  
Circulating Lymphocytes ◽  
Wistar Kyoto

AbstractAgonists of β2 adrenergic receptors (β2AR) and glucocorticoid receptors (GR) are prescribed to treat pulmonary diseases. Since ozone effects are mediated through the activation of AR and GR, we hypothesized that the treatment of rats with relevant therapeutic doses of long acting β2AR agonist (LABA; clenbuterol; CLEN) and/or GR agonist (dexamethasone; DEX) would exacerbate ozone-induced pulmonary and systemic changes. In the first study, male 12-week-old Wistar-Kyoto rats were injected intraperitoneally with vehicle (saline), CLEN (0.004 or 0.02 mg/kg), or DEX (0.02 or 0.1 mg/kg). Since dual therapy is commonly used, in the second study, rats received either saline or combined CLEN + DEX (each at 0.005 or 0.02 mg/kg) one day prior to and on both days of exposure (air or 0.8ppm ozone, 4 hr/day x 2-days). In air-exposed rats CLEN, DEX or CLEN + DEX did not induce lung injury or inflammation, however DEX and CLEN + DEX decreased circulating lymphocytes, spleen and thymus weights, increased free fatty acids (FFA) and produced hyperglycemia and glucose intolerance. Ozone exposure of vehicle-treated rats increased bronchoalveolar lavage fluid protein, albumin, neutrophils, IL-6 and TNF-α. Ozone decreased circulating lymphocytes, increased FFA, and induced hypeerglycemia  and glucose intolerance. Drug treatment did not reverse ozone-induced ventillatory changes, however, lung effects (protein and albumin leakage, inflammation, and IL-6 increase) were exacerbated by CLEN and CLEN + DEX pre-treatment in a dose-dependent manner (CLEN > CLEN + DEX). Systemic effects induced by DEX and CLEN + DEX but not CLEN in air-exposed rats were analogous to and more pronounced than those induced by ozone. These data suggest that adverse air pollution effects might be exacerbated in people receiving LABA or LABA plus glucocorticoids.

scholarly journals Glucose dynamics during ozone exposure measured using radiotelemetry: Stress drivers and human concordance

2021 ◽  
Author(s):  
Andres R Henriquez ◽  
Samantha J Snow ◽  
John S House ◽  
Alison A Motsinger-Reif ◽  
Cavin Ward-Caviness ◽  
...  
Keyword(s):  
Real Time ◽  
Glucocorticoid Receptors ◽  
Stress Hormones ◽  
Glucose Monitoring ◽  
Air Pollutant ◽  
Ozone Exposure ◽  
Metabolic Dysfunction ◽  
Serum Samples ◽  
Glucose Levels ◽  
Wistar Kyoto

Background. Stress-related neurobehavioral and metabolic disorders are associated with altered circulating adrenal-derived hormones and hyperglycemia. Temporal assessment of glucose and these hormones is critical for insights on an individuals health. Objectives. Here we use implantable-telemetry in rats to assess real-time changes in circulating glucose during and after exposure to the air pollutant ozone, and link responses to circulating neuroendocrine stress and metabolic hormones. We also proposed to compare rodent glucose and corticosterone (cortisol in humans) responses to humans exposed to ozone. Methods. First, using a cross-over design, we monitored glucose levels during single or repeated ozone exposures (0.0, 0.2, 0.4 and 0.8-ppm) and non-exposure periods in male Wistar-Kyoto-rats implanted with glucose-telemeters. A second cohort of un-implanted rats was exposed to ozone (0.0, 0.4 or 0.8-ppm) for 30-min, 1-hour, 2-hour, or 4-hour with hormones measured immediately after exposure. Then we assessed glucose metabolism in sham and adrenalectomized rats with or without pharmacological interventions of adrenergic and glucocorticoid receptors. Finally, we assessed glucose and cortisol in serum samples form a clinical study involving exposure of human volunteers to air or 0.3 ppm ozone. Results. Ozone (0.8-ppm) caused hyperglycemia and hypothermia beginning 90-min into exposure, with reversal of effects 4-6 hours post-exposure. Glucose monitoring during four daily 4-hour ozone exposures revealed duration of hyperglycemia, adaptation, and diurnal variations. Ozone-induced hyperglycemia was preceded by increased adrenocorticotropic hormone, corticosterone, and epinephrine, but depletion of thyroid-stimulating, prolactin, and luteinizing hormones. Hyperglycemia was inhibited in rats that are adrenalectomized and/or treated with glucocorticoid inhibitor. There was coherence among rats and humans in ozone-induced corticosterone/cortisol increases. Discussion. We demonstrate for the first time the temporality of neuroendocrine-stress-mediated biological sequalae responsible for ozone-induced metabolic dysfunction as exposure occurs. Real-time glucose monitoring with stress hormones assessment may be useful in identifying interactions among pollutants and stress-related illnesses.

Ozone-Induced Dysregulation of Neuroendocrine Axes Requires Adrenal-Derived Stress Hormones

2019 ◽  
Vol 172 (1) ◽  
pp. 38-50 ◽  
Author(s):  
Andres R Henriquez ◽  
John S House ◽  
Samantha J Snow ◽  
Colette N Miller ◽  
Mette C Schladweiler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hedgehog Signaling ◽  
Stress Hormones ◽  
Transcriptional Response ◽  
Global Gene Expression ◽  
Thyroid Stimulating Hormone ◽  
Ozone Exposure ◽  
Short Term ◽  
Sham Surgery ◽  
Wistar Kyoto

Abstract Acute ozone inhalation increases circulating stress hormones through activation of the sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal axes. Rats with adrenalectomy (AD) have attenuated ozone-induced lung responses. We hypothesized that ozone exposure will induce changes in circulating pituitary-derived hormones and global gene expression in the brainstem and hypothalamus, and that AD will ameliorate these effects. Male Wistar-Kyoto rats (13 weeks) that underwent sham surgery (SHAM) or AD were exposed to ozone (0.8 ppm) or filtered-air for 4 h. In SHAM rats, ozone exposure decreased circulating thyroid-stimulating hormone (TSH), prolactin (PRL), and luteinizing hormone (LH). AD prevented reductions in TSH and PRL, but not LH. AD increased adrenocorticotropic hormone approximately 5-fold in both air- and ozone-exposed rats. AD in air-exposed rats resulted in few significant transcriptional differences in the brainstem and hypothalamus (approximately 20 genes per tissue). In contrast, ozone-exposure in SHAM rats resulted in either increases or decreases in expression of hundreds of genes in the brainstem and hypothalamus relative to air-exposed SHAM rats (303 and 568 genes, respectively). Differentially expressed genes from ozone exposure were enriched for pathways involving hedgehog signaling, responses to alpha-interferon, hypoxia, and mTORC1, among others. Gene changes in both brain areas were analogous to those altered by corticosteroids and L-3,4-dihydroxyphenylalanine, suggesting a role for endogenous glucocorticoids and catecholamines. AD completely prevented this ozone-induced transcriptional response. These findings show that short-term ozone inhalation promotes a shift in brainstem and hypothalamic gene expression that is dependent upon the presence of circulating adrenal-derived stress hormones. This is likely to have profound downstream influence on systemic effects of ozone.

scholarly journals Ozone-Induced Vascular Contractility and Pulmonary Injury Are Differentially Impacted by Diets Enriched With Coconut Oil, Fish Oil, and Olive Oil

2018 ◽  
Vol 163 (1) ◽  
pp. 57-69 ◽  
Author(s):  
Samantha J Snow ◽  
Wan-Yun Cheng ◽  
Andres Henriquez ◽  
Myles Hodge ◽  
Virgina Bass ◽  
...  
Keyword(s):  
Fish Oil ◽  
Olive Oil ◽  
Coconut Oil ◽  
Normal Diet ◽  
Ozone Exposure ◽  
Pulmonary Injury ◽  
Vascular Protection ◽  
Altered Expression ◽  
Wistar Kyoto ◽  
Fish Oil Diet

Abstract Fish, olive, and coconut oil dietary supplementation have several cardioprotective benefits, but it is not established if they protect against air pollution-induced adverse effects. We hypothesized that these dietary supplements would attenuate ozone-induced systemic and pulmonary effects. Male Wistar Kyoto rats were fed either a normal diet, or a diet supplemented with fish, olive, or coconut oil for 8 weeks. Animals were then exposed to air or ozone (0.8 ppm), 4 h/day for 2 days. Ozone exposure increased phenylephrine-induced aortic vasocontraction, which was completely abolished in rats fed the fish oil diet. Despite this cardioprotective effect, the fish oil diet increased baseline levels of bronchoalveolar lavage fluid (BALF) markers of lung injury and inflammation. Ozone-induced pulmonary injury/inflammation were comparable in rats on normal, coconut oil, and olive oil diets with altered expression of markers in animals fed the fish oil diet. Fish oil, regardless of exposure, led to enlarged, foamy macrophages in the BALF that coincided with decreased pulmonary mRNA expression of cholesterol transporters, cholesterol receptors, and nuclear receptors. Serum microRNA profile was assessed and demonstrated marked depletion of a variety of microRNAs in animals fed the fish oil diet, several of which were of splenic origin. No ozone-specific changes were noted. Collectively, these data indicate that although fish oil offered vascular protection from ozone exposure, it increased pulmonary injury/inflammation and impaired lipid transport mechanisms resulting in foamy macrophage accumulation, demonstrating the need to be cognizant of potential off-target pulmonary effects that might offset the overall benefit of this vasoprotective supplement.

Neutral Sugar Accumulation in Lung Lavage Fluid Following Ozone Exposure

1991 ◽  
Vol 7 (5-6) ◽  
pp. 465-471 ◽  
Author(s):  
Ziro Nambu ◽  
Isamu Ichikawa ◽  
Eiji Yokoyama
Keyword(s):  
Lavage Fluid ◽  
Lung Lavage ◽  
Ozone Exposure ◽  
Sugar Accumulation ◽  
Neutral Sugar

Adenosine induces histamine release from human bronchoalveolar lavage mast cells

1999 ◽  
Vol 96 (4) ◽  
pp. 349-355 ◽  
Author(s):  
P. FORSYTHE ◽  
L. P. A. MCGARVEY ◽  
L. G. HEANEY ◽  
J. MACMAHON ◽  
M. ENNIS
Keyword(s):  
Mast Cells ◽  
Bronchoalveolar Lavage ◽  
Histamine Release ◽  
Adenosine Receptor ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Maximal Response ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
Endogenous Adenosine

Previous studies have shown that in vitroadenosine enhances histamine release from activated human lung mast cells obtained by enzymic dispersion of lung parenchyma. However, adenosine alone has no effect on histamine release from these cells. Given the evidence for direct activation of mast cells after endobronchial challenge with adenosine and previous studies indicating that mast cells obtained at bronchoalveolar lavage are a better model for asthma studies than those obtained by enzymic dispersion of lung tissue, the histamine-releasing effect of adenosine was examined on lavage mast cells. Bronchoalveolar lavage fluid was obtained from patients attending hospital for routine bronchoscopy (n = 54). Lavage cells were challenged with adenosine or adenosine receptor agonists (20 min, 37 °C) and histamine release determined using an automated fluorometric assay. Endogenous adenosine levels were also measured in lavage fluid (n = 9) via an HPLC method. Adenosine alone caused histamine release from lavage mast cells in 37 of 54 patients with a maximal histamine release of 20.56±2.52% (range 5.2–61%). The adenosine receptor agonists (R)-N6-(2-phenylisopropyl)adenosine, 5'-N-ethylcarboxamidoadenosine and CGS21680 also induced histamine release from lavage mast cells. Preincubation of lavage mast cells with the adenosine receptor antagonist xanthine amine congener caused significant inhibition of the response to adenosine (P = 0.007). There was an inverse correlation between endogenous adenosine levels in the lavage fluid and the maximal response to in vitro adenosine challenge of the lavage cells. The findings of the present study indicate a means by which adenosine challenge of the airways can induce bronchoconstriction and support a role for adenosine in the pathophysiology of asthma. The results also suggest that cells obtained from bronchoalveolar lavage fluid may provide the ideal model for the testing of novel, adenosine receptor, targeted therapies for asthma.

Sensitivity of lungs of aging Fischer 344 rats to ozone: assessment by bronchoalveolar lavage

1996 ◽  
Vol 271 (4) ◽  
pp. L555-L565 ◽  
Author(s):  
R. Vincent ◽  
D. Vu ◽  
G. Hatch ◽  
R. Poon ◽  
K. Dreher ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Biological Effects ◽  
Age Groups ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Ozone Exposure ◽  
Fischer 344 Rats ◽  
Adult Rats ◽  
Fischer 344 ◽  
Old Rats

Biological effects indicators in bronchoalveolar lavage fluid were studied in Fischer 344 rats of different ages after exposure to 0.4-0.8 ppm ozone for periods of 2-6 h on a single day or on 4 consecutive days. The magnitude of alveolar protein transudation induced by ozone was not different between age groups, but the interindividual variability of protein changes was higher in senescent (24-mo-old) rats. By comparison to juvenile (2-mo-old) and adult (9-mo-old) rats, senescent animals had higher increases of interleukin-6 (up to 10-fold higher) and N-acetyl-beta-D-glucosaminidase (NAGA; 2-fold higher) in lung lavage after ozone. Ascorbic acid was lower in lungs of senescent rats (one-half of juvenile values), and acute ozone exposure brought a further decrease in lung ascorbate. Whereas alveolar protein transudation was attenuated after ozone exposure on 4 days, persistent elevation of NAGA in senescent rats suggested only partial adaptation. Injection of endotoxin did not modify the patterns of effects. Incorporation of 18O-ozone into macrophages and surfactant was not different between age groups, indicating that the magnified biological responses in senescent rats were not dominated by differences in internal dose of ozone. The results indicate that senescent rats respond differently than juvenile and adult rats to lung injury.

Ozone induces clear cellular and molecular responses in the mouse lung independently of the transcription-coupled repair status

2007 ◽  
Vol 102 (3) ◽  
pp. 1185-1192 ◽  
Author(s):  
Ingeborg M. Kooter ◽  
Jeroen L. A. Pennings ◽  
Paul H. B. Fokkens ◽  
Daan L. A. C. Leseman ◽  
A. John F. Boere ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Ozone Exposure ◽  
Factor Α ◽  
Necrosis Factor ◽  
Transcription Coupled Repair

The oxidant ozone is a well-known air pollutant, inhalation of which is associated with respiratory tract inflammation and functional alterations of the lung. It is well established as an inducer of intracellular oxidative stress. We investigated whether Cockayne syndrome B, transcription-coupled, repair-deficient mice ( Csb−/−), known to be sensitive to oxidative stressors, respond differently to ozone than repair-proficient controls ( Csb+/−). Mice were exposed to 0.8 parts/million ozone for 8 h, and we examined a wide range of biological parameters in the lung at the gene expression, protein, and cellular level 4 h after the ozone exposure. Relevant biological responses to ozone for both repair-deficient Csb−/− and repair-proficient Csb+/− mice, as determined by biochemical analysis of bronchoalveolar lavage fluid (e.g., increases of polymorphonuclear neutrophils, alkaline phosphatase, macrophage-inflammatory protein-2, and tumor necrosis factor-α), pathological examinations, and gene expression (upregulation of oxidative-stress-related genes) analyses were observed. The bronchoalveolar lavage fluid showed significantly more tumor necrosis factor-α in repair-deficient Csb−/− mice than in repair-proficient Csb+/− mice after ozone exposure. In addition, a clear trend was observed toward fewer differentially expressed genes with a lower fold ratio in repair-deficient Csb−/− mice than in repair-proficient Csb+/− mice. However, repair-deficient Csb−/− mice do not respond significantly more sensitively to ozone compared with repair-proficient Csb+/− mice at the level of gene expression. We conclude that, under the conditions employed here, although small differences at the transcriptional level exist between repair-proficient Csb+/− mice and transcription-coupled repair defective Csb−/− mice, these do not have a significant effect on the ozone-induced lung injury.

Ozone exposure decreases the effect of a deep inhalation on forced expiratory flow in normal subjects

2004 ◽  
Vol 96 (5) ◽  
pp. 1651-1657 ◽  
Author(s):  
S. K. Kjærgaard ◽  
O. F. Pedersen ◽  
M. R. Miller ◽  
T. R. Rasmussen ◽  
J. C. Hansen ◽  
...  
Keyword(s):  
Fish Oil ◽  
Normal Subjects ◽  
Lavage Fluid ◽  
Forced Expiratory Volume ◽  
Ozone Exposure ◽  
Double Blind ◽  
Forced Expiratory Flow ◽  
Clean Air ◽  
Nasal Lavage Fluid ◽  
Expiratory Flow

Sixteen healthy nonsmoking subjects (7 women), 21-49 yr old, were exposed in a climate chamber to either clean air or 300 parts/billion ozone on 4 days for 5 h each day. Before each exposure, the subjects had been pretreated with either oxidants (fish oil) or antioxidants (multivitamins). The study design was double-blind crossover with randomized allocation to the exposure regime. Full and partial flow-volume curves were recorded in the morning and before and during a histamine provocation at the end of the day. Nasal cavity volume and inflammatory markers in nasal lavage fluid were also measured. Compared with air, ozone exposure decreased peak expiratory flow, forced expiratory volume in 1 s, and forced vital capacity (FVC), with no significant effect from the pretreatment regimens. Ozone decreased the ratio of maximal to partial flow at 40% FVC by 0.08 ± 0.03 (mean ± SE, analysis of variance: P = 0.018) and at 30% FVC by 0.10 ± 0.05 ( P = 0.070). Ozone exposure did not significantly increase bronchial responsiveness, but, after treatment with fish oil, partial flows decreased more than after vitamins during the histamine test, without changing the maximal-to-partial flow ratio. The decreased effect of a deep inhalation after ozone exposure can be explained by changes in airway hysteresis relative to parenchymal hysteresis, due either to ozone-induced airway inflammation or to less deep inspiration after ozone, not significantly influenced by multivitamins or fish oil.

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