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Pignatelli A, Benedusi M, Barbieri M, Pecorelli A, Valacchi G. Tropospheric ozone effect on olfactory perception and olfactory bulb dopaminergic interneuron excitability. Neurotoxicology 2024; 104:36-44. [PMID: 39004287 DOI: 10.1016/j.neuro.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 06/14/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024]
Abstract
Ozone (O3) forms in the Earth's atmosphere, both naturally and by reactions of man-made air pollutants. Deleterious effects of O3 have been found in the respiratory system. Here, we examine whether O3 alters olfactory behavior and cellular properties in the olfactory system. For this purpose, mice were exposed to O3 at a concentration found in highly polluted city air [0.8 ppm], and the behavior elicited by social and non-social odors in habituation/dishabituation tests was assessed. In addition, the electrical responses of dopaminergic olfactory bulb (OB) neurons were also evaluated. O3 differentially compromises olfactory perception to odors: it reduces responses to social and non-social odors in Swiss Webster mice, while this effect was observed in C57BL/6 J mice only for some non-social odors. Additionally, O3 reduced the rate of spontaneous spike firing in periglomerular dopaminergic cells (PG-DA) of the OB. Because this effect could reflect changes in excitability and/or synaptic inputs, the ability of O3 to alter PG-DA spontaneous activity was also tested together with cell membrane resistance, membrane potential, rheobase and chronaxie. Taken together, our data suggest the ability of O3 to affect olfactory perception.
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Affiliation(s)
- Angela Pignatelli
- Dept. of Neuroscience and Rehabilitation, University of Ferrara, Ferrara 44121, Italy.
| | - Mascia Benedusi
- Dept. of Neuroscience and Rehabilitation, University of Ferrara, Ferrara 44121, Italy.
| | - Mario Barbieri
- Dept. of Neuroscience and Rehabilitation, University of Ferrara, Ferrara 44121, Italy.
| | - Alessandra Pecorelli
- Dept. of Environmental and Prevention Sciences, University of Ferrara, Ferrara 44121, Italy.
| | - Giuseppe Valacchi
- Dept. of Environmental and Prevention Sciences, University of Ferrara, Ferrara 44121, Italy; Dept. of Animal Sciences, Plants for Human Health Institute, NC Research Campus, NC State University, Kannapolis, NC 28081, USA; Dept. of Food and Nutrition, Kyung Hee University, Seoul 26723, Republic of Korea.
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Toxicity of environmental ozone exposure on mice olfactory bulbs, using Western blot technique. Toxicol Rep 2020; 7:453-459. [PMID: 32190549 PMCID: PMC7068045 DOI: 10.1016/j.toxrep.2020.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 02/27/2020] [Accepted: 03/01/2020] [Indexed: 11/22/2022] Open
Abstract
Environmental ozone (O3) exposure has adverse effects on different body systems. This experimental work aimed to study the effect(s) of O3 exposure on the olfactory bulbs (OB) of Swiss Webster and C57BL/6J mouse strains, using Western blot technique. Both mice strains were exposed to different O3 doses for different number of exposures and durations. The results indicated that O3 exposure caused a significant increase in the level of the proteins involved in the oxidative stress state such as 4-hydroxynonenal (4HNE) and Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), in addition to the total OB proteins in Swiss Webster mouse strain. However, this effect was not observed in C57BL/6J mouse strain. Furthermore, CYP1A1 was completely absent in the Green fluorescent protein (GFP) C57BL/6J O3 exposed mice. Moreover, O3 exposure caused a significant decrease in the body weight of the tested mice from the two strains.
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Harkema JR, Hotchkiss LA, Vetter NA, Jackson-Humbles DN, Lewandowski RP, Wagner JG. Strain Differences in a Murine Model of Air Pollutant-induced Nonatopic Asthma and Rhinitis. Toxicol Pathol 2016; 45:161-171. [PMID: 28068894 DOI: 10.1177/0192623316674274] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ozone is an irritating gas found in photochemical smog. Epidemiological associations have been made between the onset of asthma and childhood exposures to increasing levels of ambient ozone (i.e., air pollutant-induced nonatopic asthma). Individuals, however, vary in their susceptibility to this outdoor air pollutant, which may be due, in part, to their genetic makeup. The present study was designed to test the hypothesis that there are murine strain-dependent differences in pulmonary and nasal pathologic responses to repeated ozone exposures. C57BL/6NTac and BALB/cNTac mice were exposed to 0 or 0.8 ppm ozone, 4 hr/day, for 9 consecutive weekdays. In both strains of mice, ozone induced eosinophilic inflammation and mucous cell metaplasia in the nasal and pulmonary airways. Lungs of ozone-exposed C57BL/6NTac mice, however, had greater eosinophilic inflammation, mucous cell metaplasia, and expression of genes related to type 2 immunity and airway mucus hypersecretion, as compared to similarly exposed BALB/cNTac mice. Ozone-exposed C57BL/6NTac mice also had greater eosinophilic rhinitis but a similar degree of mucous cell metaplasia in nasal epithelium, as ozone-exposed BALB/cNTac mice. These findings suggest that nonatopic individuals may differ in their inflammatory and epithelial responses to repeated ozone exposures that are due, in part, to genetic factors.
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Affiliation(s)
- Jack R Harkema
- 1 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Lucas A Hotchkiss
- 1 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Nicholas A Vetter
- 1 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Daven N Jackson-Humbles
- 1 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Ryan P Lewandowski
- 1 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA
| | - James G Wagner
- 1 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA
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Soft-X-ray-enhanced electrostatic precipitation for protection against inhalable allergens, ultrafine particles, and microbial infections. Appl Environ Microbiol 2012; 79:1333-41. [PMID: 23263945 DOI: 10.1128/aem.02897-12] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Protection of the human lung from infectious agents, allergens, and ultrafine particles is difficult with current technologies. High-efficiency particulate air (HEPA) filters remove airborne particles of >0.3 μm with 99.97% efficiency, but they are expensive to maintain. Electrostatic precipitation has been used as an inexpensive approach to remove large particles from airflows, but it has a collection efficiency minimum in the submicrometer size range, allowing for a penetration window for some allergens and ultrafine particles. Incorporating soft X-ray irradiation as an in situ component of the electrostatic precipitation process greatly improves capture efficiency of ultrafine particles. Here we demonstrate the removal and inactivation capabilities of soft-X-ray-enhanced electrostatic precipitation technology targeting infectious agents (Bacillus anthracis, Mycobacterium bovis BCG, and poxviruses), allergens, and ultrafine particles. Incorporation of in situ soft X-ray irradiation at low-intensity corona conditions resulted in (i) 2-fold to 9-fold increase in capture efficiency of 200- to 600-nm particles and (ii) a considerable delay in the mean day of death as well as lower overall mortality rates in ectromelia virus (ECTV) cohorts. At the high-intensity corona conditions, nearly complete protection from viral and bacterial respiratory infection was afforded to the murine models for all biological agents tested. When optimized for combined efficient particle removal with limited ozone production, this technology could be incorporated into stand-alone indoor air cleaners or scaled for installation in aircraft cabin, office, and residential heating, ventilating, and air-conditioning (HVAC) systems.
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microRNAs: implications for air pollution research. Mutat Res 2011; 717:38-45. [PMID: 21515291 DOI: 10.1016/j.mrfmmm.2011.03.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Revised: 03/22/2011] [Accepted: 03/31/2011] [Indexed: 11/20/2022]
Abstract
The purpose of this review is to provide an update of the current understanding on the role of microRNAs in mediating genetic responses to air pollutants and to contemplate on how these responses ultimately control susceptibility to ambient air pollution. Morbidity and mortality attributable to air pollution continues to be a growing public health concern worldwide. Despite several studies on the health effects of ambient air pollution, underlying molecular mechanisms of susceptibility and disease remain elusive. In the last several years, special attention has been given to the role of epigenetics in mediating, not only genetic and physiological responses to certain environmental insults, but also in regulating underlying susceptibility to environmental stressors. Epigenetic mechanisms control the expression of gene products, both basally and as a response to a perturbation, without affecting the sequence of DNA itself. These mechanisms include structural regulation of the chromatin structure, such as DNA methylation and histone modifications, and post-transcriptional gene regulation, such as microRNA mediated repression of gene expression. microRNAs are small noncoding RNAs that have been quickly established as key regulators of gene expression. As such, miRNAs have been found to control several cellular processes including apoptosis, proliferation and differentiation. More recently, research has emerged suggesting that changes in the expression of some miRNAs may be critical for mediating biological, and ultimately physiological, responses to air pollutants. Although the study of microRNAs, and epigenetics as a whole, has come quite far in the field of cancer, the understanding of how these mechanisms regulate gene-environment interactions to environmental exposures in everyday life is unclear. This article does not necessarily reflect the views and policies of the US EPA.
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Bauer AK, Travis EL, Malhotra SS, Rondini EA, Walker C, Cho HY, Trivedi S, Gladwell W, Reddy S, Kleeberger SR. Identification of novel susceptibility genes in ozone-induced inflammation in mice. Eur Respir J 2009; 36:428-37. [PMID: 20032013 DOI: 10.1183/09031936.00145309] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Ozone (O(3)) remains a prevalent air pollutant and public health concern. Inf2 is a significant quantitative trait locus on murine chromosome 17 that contributes to susceptibility to O(3)-induced infiltration of polymorphonuclear leukocytes (PMNs) into the lung, but the mechanisms of susceptibility remain unclear. The study objectives were to confirm and restrict Inf2, and to identify and test novel candidate susceptibility gene(s). Congenic strains of mice that contained overlapping regions of Inf2 and their controls, and mice deficient in either major histocompatibility complex (MHC) class II genes or the Tnf cluster, were exposed to air or O(3). Lung inflammation and gene expression were assessed. Inf2 was restricted from 16.42 Mbp to 0.96 Mbp, and bioinformatic analysis identified MHC class II, the Tnf cluster and other genes in this region that contain potentially informative single nucleotide polymorphisms between the susceptible and resistant mice. Furthermore, O(3)-induced inflammation was significantly reduced in mice deficient in MHC class II genes or the Tnf cluster genes, compared with wild-type controls. Gene expression differences were also observed in MHC class II and Tnf cluster genes. This integrative genetic analysis of Inf2 led to identification of novel O(3) susceptibility genes that may provide important, new therapeutic targets in susceptible individuals.
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Affiliation(s)
- A K Bauer
- Dept of Pathobiology and Diagnostic Investigation Center for Integrative Toxicology B43 Food Safety and Toxicology Bldg, Michigan State University, East Lansing, MI 48824, USA.
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Prows DR, Hafertepen AP, Winterberg AV, Gibbons WJ, Wesselkamper SC, Singer JB, Hill AE, Nadeau JH, Leikauf GD. Reciprocal congenic lines of mice capture the aliq1 effect on acute lung injury survival time. Am J Respir Cell Mol Biol 2007; 38:68-77. [PMID: 17656683 PMCID: PMC2176134 DOI: 10.1165/rcmb.2006-0162oc] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Acute lung injury (ALI) is a devastating condition resulting from diverse causes. Genetic studies of human populations indicate that ALI is a complex disease with substantial phenotypic variance, incomplete penetrance, and gene-environment interactions. To identify genes controlling ALI mortality, we previously investigated mean survival time (MST) differences between sensitive A/J (A) and resistant C57BL/6J (B) mice in ozone using quantitative trait locus (QTL) analysis. MST was significantly linked to QTLs (Aliq1-3) on chromosomes 11, 13, and 17, respectively. Additional QTL analyses of separate and combined backcross and F(2) populations supported linkage to Aliq1 and Aliq2, and established significance for previously suggestive QTLs on chromosomes 7 and 12 (named Aliq5 and Aliq6, respectively). Decreased MSTs of corresponding chromosome substitution strains (CSSs) verified the contribution of most QTL-containing chromosomes to ALI survival. Multilocus models demonstrated that three QTLs could explain the MST difference between progenitor strains, agreeing with calculated estimates for number of genes involved. Based on results of QTL genotype analysis, a double CSS (B.A-6,11) was generated that contained Aliq1 and Aliq4 chromosomes. Surprisingly, MST and pulmonary edema after exposure of B.A-6,11 mice were comparable to B mice, revealing an unpredicted loss of sensitivity compared with separate CSSs. Reciprocal congenic lines for Aliq1 captured the corresponding phenotype in both background strains and further refined the QTL interval. Together, these findings support most of the previously identified QTLs linked to ALI survival and established lines of mice to further resolve Aliq1.
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Affiliation(s)
- Daniel R Prows
- Children's Hospital Medical Center, Division & Program in Human Genetics, 3333 Burnet Ave., MLC 7016, Building R, Room 1464, Cincinnati, OH 45229-3039, USA.
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Bone W, Walden CM, Fritsch M, Voigtmann U, Leifke E, Gottwald U, Boomkamp S, Platt FM, van der Spoel AC. The sensitivity of murine spermiogenesis to miglustat is a quantitative trait: a pharmacogenetic study. Reprod Biol Endocrinol 2007; 5:1. [PMID: 17241468 PMCID: PMC1794412 DOI: 10.1186/1477-7827-5-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2006] [Accepted: 01/22/2007] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND A major event in the post-meiotic development of male germ cells is the formation of the acrosome. This process can be perturbed in C57BL/6 mice by administration of the small molecule miglustat (N-butyldeoxynojirimycin, NB-DNJ). The miglustat-treated mice produce morphologically abnormal spermatozoa that lack acrosomes and are poorly motile. In C57BL/6 mice, miglustat can be used to maintain long-term reversible infertility. In contrast, when miglustat was evaluated in normal men, it did not affect spermatogenesis. To gain more insight into this species difference we have now evaluated the reproductive effects of miglustat in rabbits, in multiple mouse strains and in interstrain hybrid mice. METHODS Male mice of 18 inbred strains were administered miglustat orally or via miniosmotic pumps. Rabbits were given the compound in their food. Fourth-generation interstrain hybrid mice, bred from C57BL/6 and FVB/N mice (which differ in their response to miglustat), also received the drug. Data on fertility (natural mating), sperm motility and morphology, acrosome status, and serum drug levels were collected. RESULTS In rabbits the drug did not induce aberrations of sperm shape or motility, although the serum level of miglustat in rabbits far exceeded the level in C57BL/6 mice (8.4 microM and 0.5 microM, respectively). In some strains of the Swiss and Castle lineages of inbred mice miglustat did not cause infertility, severe morphological sperm aberrations or reduced sperm motility. In these strains miglustat only had milder effects. However, miglustat strongly disturbed acrosome and sperm nucleus development in AKR/J and BALB/c mice and in a number of C57BL/6-related strains. The consequences of drug administration in the interstrain hybrid mice were highly variable. Judging by the number of grossly abnormal spermatozoa, these genetically heterogeneous mice displayed a continuous range of intermediate responses, distinct from either of their parental strains. CONCLUSION The effects of miglustat on spermatogenesis in mice are strain-dependent, while in rabbits the drug is ineffective. Evaluation of interstrain hybrid mice indicated that the sensitivity of spermatogenesis to miglustat is a quantitative trait. These studies pave the way for identifying the genetic factors underlying the strain/species differences in the effect of miglustat.
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MESH Headings
- 1-Deoxynojirimycin/analogs & derivatives
- 1-Deoxynojirimycin/blood
- 1-Deoxynojirimycin/pharmacology
- Acrosome/drug effects
- Animals
- Drug Resistance/genetics
- Enzyme Inhibitors/blood
- Enzyme Inhibitors/pharmacology
- Female
- Infertility, Male/chemically induced
- Male
- Mice
- Mice, Inbred AKR
- Mice, Inbred BALB C
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Mice, Inbred DBA
- Mice, Inbred MRL lpr
- Mice, Inbred NZB
- Pregnancy
- Quantitative Trait, Heritable
- Rabbits
- Sexual Behavior, Animal
- Species Specificity
- Sperm Motility/drug effects
- Spermatogenesis/drug effects
- Spermatogenesis/genetics
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Affiliation(s)
- Wilhelm Bone
- Schering AG, Müllerstr. 178, 13342 Berlin, Germany
| | - Charlotte M Walden
- The Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
- Department of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
| | | | | | | | | | - Stephanie Boomkamp
- The Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
| | - Frances M Platt
- The Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
| | - Aarnoud C van der Spoel
- The Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
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Ku SK, Seong SK, Kim DY, Lee HS, Kim JD, Choi HY, Seo BI, Lee JH. Changes of the intestinal endocrine cells in the C57BL/6 mouse after implantation of murine lung carcinoma (3LL): An immunohistochemical quantitative study. World J Gastroenterol 2005; 11:5460-7. [PMID: 16222737 PMCID: PMC4320354 DOI: 10.3748/wjg.v11.i35.5460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the distributions and frequencies of intestinal endocrine cells in the C57BL/6 mouse with immunohistochemical method using seven types of specific antisera against chromogranin A (CGA), serotonin, somatostatin, glucagons, gastrin, cholecystokinin (CCK)-8 and human pancreatic polypeptide (hPP) after abdominal subcutaneous implantation of murine lung carcinoma (3LL).
METHODS: The experimental animals were divided into two groups, one is non-implanted Sham and the other is 3LL-implanted group. Samples were collected from six regions of intestinal tract at 28th d after implantation of 3LL cells (1×105 cell/mouse).
RESULTS: In this study, five types of immunoreactive (IR) cells were identified except for gastrin and hPP. The regional distributions of the intestinal endocrine cells in the 3LL-implanted group were similar to those of the non-implanted Sham. However, significant decreases of IR cells were detected in 3LL-implanted group compared to those of non-implanted Sham. CGA- and serotonin-IR cells significantly decreased in 3LL-implanted groups compared to that of non-implanted Sham. Somatostatin-IR cells in the jejunum and ileum and CCK-8-IR cells in the jejunum of 3LL-implanted groups significantly decreased compared to that of non-implanted Sham. In addition, glucagon-IR cells were restricted to the ileum and colon of non-implanted Sham.
CONCLUSION: Implantation of tumor cell mass (3LL) induced severe quantifiable changes of intestinal endocrine cell density and the abnormality in density of intestinal endocrine cells may contribute to the development of gastrointestinal symptoms such as anorexia and indigestion, frequently encountered in patients with cancer.
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Affiliation(s)
- Sae-Kwang Ku
- Pharmacology and Toxicology Laboratory, Central Research Laboratories, Dong-Wha Pharmaceutical Industrial Co, Ltd, Anyang 430-017, Republic of Korea
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Ku SK, Lee HS, Byun JS, Seo BI, Lee JH. Changes of the gastric endocrine cells in the C57BL/6 mouse after implantation of murine lung carcinoma: An immunohistochemical quantitative study. World J Gastroenterol 2005; 11:1317-23. [PMID: 15761969 PMCID: PMC4250678 DOI: 10.3748/wjg.v11.i9.1317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: The regional distributions and relative frequencies of some gastric endocrine cells of C57BL/6 mice were studied by immunohistochemical method using seven types of specific antisera against chromogranin A (CGA), serotonin, somatostatin, gastrin, cholecystokinin (CCK)-8, glucagon and human pancreatic polypeptide (HPP) after subcutaneous implantation of murine lung carcinoma (3LL) cells.
METHODS: The experimental animals were divided into two groups, one is non-implanted sham and the other is 3LL-implanted group. Samples were collected from the two regions of stomach (fundus and pylorus) at 28 d after implantation of 3LL cells (1×105 cell/mouse).
RESULTS: In this study, all the seven types of immunoreactive (IR) cells were identified except for HPP. Most of these IR cells in the gastric portion were generally spherical or spindle in shape (open-type cell) while cells showing round in shape (closed-type cell) were found occasionally. The regional distributions of gastric endocrine cells in the 3LL-implanted group were similar to those of non-implanted sham. However, significant decreases of some types of IR cells were detected in 3LL-implanted group compared to those of non-implanted sham. In addition, the IR cells showing degranulation were numerously detected in 3LL-implanted group. CGA-, serotonin- and somatostatin-IR cells in the fundus and pylorus regions, and gastrin-IR cells in the pylorus regions of 3LL-implanted groups significantly decreased compared to those of non-implanted sham. However, no changes on frequencies of CCK-8- and glucagon-IR cells were demonstrated between 3LL-implanted and non-implanted groups.
CONCLUSION: Endocrine cells are the anatomical units responsible for the production of gut hormones, and the change in their density would reflect a change in the capacity of producing these hormones. Implantation of tumor cell mass (3LL) induced severe quantitative changes of gastric endocrine cell density, and the abnormality in density of gastric endocrine cells may contribute to the development of gastrointestinal symptoms such as anorexia and indigestion, frequently encountered in patients with cancer.
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Affiliation(s)
- Sae-Kwang Ku
- Pharmacology and Toxicology Laboratory, Central Research Laboratories, Dong-Wha Pharmaceutical Industrial Co. Ltd, Anyang 430-017, Republic of Korea
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Bauer AK, Malkinson AM, Kleeberger SR. Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities. Am J Physiol Lung Cell Mol Physiol 2004; 287:L685-703. [PMID: 15355860 DOI: 10.1152/ajplung.00223.2003] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Chronic inflammation predisposes toward many types of cancer. Chronic bronchitis and asthma, for example, heighten the risk of lung cancer. Exactly which inflammatory mediators (e.g., oxidant species and growth factors) and lung wound repair processes (e.g., proangiogenic factors) enhance pulmonary neoplastic development is not clear. One approach to uncover the most relevant biochemical and physiological pathways is to identify genes underlying susceptibilities to inflammation and to cancer development at the same anatomic site. Mice develop lung adenocarcinomas similar in histology, molecular characteristics, and histogenesis to this most common human lung cancer subtype. Over two dozen loci, called Pas or pulmonary adenoma susceptibility, Par or pulmonary adenoma resistance, and Sluc or susceptibility to lung cancer genes, regulate differential lung tumor susceptibility among inbred mouse strains as assigned by QTL (quantitative trait locus) mapping. Chromosomal sites that determine responsiveness to proinflammatory pneumotoxicants such as ozone (O3), particulates, and hyperoxia have also been mapped in mice. For example, susceptibility QTLs have been identified on chromosomes 17 and 11 for O3-induced inflammation (Inf1, Inf2), O3-induced acute lung injury (Aliq3, Aliq1), and sulfate-associated particulates. Sites within the human and mouse genomes for asthma and COPD phenotypes have also been delineated. It is of great interest that several susceptibility loci for mouse lung neoplasia also contain susceptibility genes for toxicant-induced lung injury and inflammation and are homologous to several human asthma loci. These QTLs are described herein, candidate genes are suggested within these sites, and experimental evidence that inflammation enhances lung tumor development is provided.
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Affiliation(s)
- Alison K Bauer
- Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
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Brochmann EJ, Duarte ME, Zaidi HA, Murray SS. Effects of dietary restriction on total body, femoral, and vertebral bone in SENCAR, C57BL/6, and DBA/2 mice. Metabolism 2003; 52:1265-73. [PMID: 14564677 DOI: 10.1016/s0026-0495(03)00194-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Dietary restriction (DR) increases the life span and retards aging, in part, by limiting free radical generation and oxidative damage. DR also reduces body mass, a major determinant of bone mass across the life span. We tested the hypothesis that DR has its most beneficial effects on bone in mouse strains with high free radical generation (sensitive to carcinogenesis [SENCAR] > C57 > DBA) versus the hypothesis that bone mass at weight-bearing sites is determined by body mass in DR and ad libitum (AL)-fed mice. Male mice of each strain were killed at 10 weeks of age (t(0)) or randomized to an AL-fed or 30% DR feeding regimen for 6 months. Food consumption by AL-fed mice was measured daily, and DR mice received 70% of the amount of food consumed by their respective AL-fed mice the previous day. Body fat (%) and bone mineral density (BMD) and content (BMC) were determined by PIXImus densitometry. There were strain-dependent effects on body mass, crown-to-rump length, percent body fat, and total body, femoral, and vertebral BMD and BMC under all conditions. SENCAR mice were heavier, longer, had larger bones, and generally exhibited higher total body, femoral, and vertebral BMC and BMD than C57 and DBA mice. DR had beneficial effects on BMD and BMC in the vertebrae of the SENCAR mouse model of high free radical generation and in the obese, diabetes-prone C57 mouse model of high end-stage protein glycation. DR DBA and SENCAR mice had lower femoral BMDs and BMCs than their respective AL-fed controls. Regression analysis confirmed linear relationships between total and lean body mass and total body and femoral BMDs and BMCs, suggesting that physiologic adaptation to a lower body mass accounts for the lower femoral bone mineral values observed in DR versus AL-fed mice. Thus, both hypotheses are, at least, partially valid. DR is beneficial in the trabeculae-rich vertebrae of animal models of high oxidant stress, and total/lean body mass determines BMD and BMC in the weight-bearing femur in DR and AL-fed mice.
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Affiliation(s)
- Elsa J Brochmann
- Geriatric Research Education and Clinical Center, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA 91343, USA
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Prows DR, McDowell SA, Aronow BJ, Leikauf GD. Genetic susceptibility to nickel-induced acute lung injury. CHEMOSPHERE 2003; 51:1139-1148. [PMID: 12718980 DOI: 10.1016/s0045-6535(02)00710-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Human exposure to insoluble and soluble nickel compounds is extensive. Besides wide usage in many industries, nickel compounds are contained in cigarette smoke and, in low levels, in ambient particulate matter. Soluble nickel particulate, especially nickel sulfate (NiSO(4)), has been associated with acute lung injury. To begin identifying genes controlling susceptibility to NiSO(4), mean survival times (MSTs) of eight inbred mouse strains were determined after aerosol exposure. Whereas A/J (A) mice were sensitive, C57BL/6J (B6) mice survived nearly twice as long (resistant). Their offspring were similarly resistant, demonstrating heritability as a dominant trait. Quantitative trait locus (QTL) analysis of backcross mice generated from these strains identified a region on chromosome 6 significantly linked to survival time. Regions on chromosomes 1 and 12 were suggestive of linkage and regions on chromosomes 8, 9, and 16 contributed to the response. Haplotype analysis demonstrated that QTLs on chromosomes 6, 9, 12, and 16 could explain the MST difference between the parental strains. To complement QTL analysis results, cDNA microarray analysis was assessed following NiSO(4) exposure of A and B6 mice. Significant expression changes were identified in one or both strains for >100 known genes. Closer evaluation of these changes revealed a temporal pattern of increased cell proliferation, extracellular matrix repair, hypoxia, and oxidative stress, followed by diminished surfactant proteins. Certain expressed sequence tags clustered with known genes, suggesting possible co-regulation and novel roles in pulmonary injury. Together, results from QTL and microarray analyses of nickel-induced acute lung injury survival allowed us to generate a short list of candidate genes.
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Affiliation(s)
- Daniel R Prows
- Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, USA.
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Ku SK, Lee HS, Lee JH. An immunohistochemical study of the gastrointestinal endocrine cells in the C57BL/6 mice. Anat Histol Embryol 2003; 32:21-8. [PMID: 12733269 DOI: 10.1046/j.1439-0264.2003.00433.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The regional distributions and relative frequencies of some gastrointestinal endocrine cells in the eight portions (fundus, pylorus, duodenum, jejunum, ileum, cecum, colon and rectum) of the gastrointestinal tract of C57BL/6 mouse was studied with immunohistochemical method using seven types of specific anti-sera against chromogranin A (CGA), serotonin, somatostatin, human pancreatic polypeptide (HPP), glucagon, gastrin and cholecystokinin (CCK)-8. In this study, all these seven types of immunoreactive (IR) cells were identified. Most of these IR cells in the intestinal portion were generally spherical or spindle in shape (open-type cell) while cells showing round in shape (closed-type cell) were found in the intestinal gland and stomach regions occasionally. Their relative frequencies were varied according to each portion of gastrointestinal tract. CGA-IR cells were demonstrated throughout the whole gastrointestinal tract and they showed most predominant in the pylorus and duodenum. Serotonin-IR cells were detected throughout whole gastrointestinal tract and they showed highest frequency in the stomach and colon. Somatostatin-IR cells were demonstrated throughout whole gastrointestinal tract except for large intestine and showed highest frequency in the fundus. HPP-IR cells were found in the fundus with rare frequency. Peculiarly, glucagon-IR cells were restricted to the fundus, ileum and colon with a few frequencies. Gastrin-IR cells were restricted to the pylorus with numerous frequency and CCK-8-IR cells were observed in the pylorus, duodenum and jejunum with numerous and/or a few frequencies, respectively. In conclusion, some peculiar distributional patterns of gastrointestinal endocrine cells were found in C57BL/6 mouse.
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Affiliation(s)
- S K Ku
- Pharmacology and Toxicology Laboratory, Central Research Laboratories, Dong-Wha Pharmaceutical Industrial Co., Ltd, Anyang 430-017, Republic of Korea
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Cho HY, Zhang LY, Kleeberger SR. Ozone-induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor-alpha receptors. Am J Physiol Lung Cell Mol Physiol 2001; 280:L537-46. [PMID: 11159038 DOI: 10.1152/ajplung.2001.280.3.l537] [Citation(s) in RCA: 119] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
This study was designed to investigate the mechanisms through which tumor necrosis factor (Tnf) modulates ozone (O(3))-induced pulmonary injury in susceptible C57BL/6J (B6) mice. B6 [wild-type (wt)] mice and B6 mice with targeted disruption (knockout) of the genes for the p55 TNF receptor [TNFR1(-/-)], the p75 TNF receptor [TNFR2(-/-)], or both receptors [TNFR1/TNFR2(-/-)] were exposed to 0.3 parts/million O(3) for 48 h (subacute), and lung responses were determined by bronchoalveolar lavage. All TNFR(-/-) mice had significantly less O(3)-induced inflammation and epithelial damage but not lung hyperpermeability than wt mice. Compared with air-exposed control mice, O(3) elicited upregulation of lung TNFR1 and TNFR2 mRNAs in wt mice and downregulated TNFR1 and TNFR2 mRNAs in TNFR2(-/-) and TNFR1(-/-) mice, respectively. Airway hyperreactivity induced by acute O(3) exposure (2 parts/million for 3 h) was diminished in knockout mice compared with that in wt mice, although lung inflammation and permeability remained elevated. Results suggested a critical role for TNFR signaling in subacute O(3)-induced pulmonary epithelial injury and inflammation and in acute O(3)-induced airway hyperreactivity.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/physiology
- Bronchial Hyperreactivity/chemically induced
- Bronchial Hyperreactivity/pathology
- Lung/pathology
- Male
- Mice
- Mice, Inbred Strains
- Mice, Knockout/genetics
- Ozone
- Pneumonia/chemically induced
- Pneumonia/pathology
- RNA, Messenger/metabolism
- Receptors, Tumor Necrosis Factor/genetics
- Receptors, Tumor Necrosis Factor/physiology
- Receptors, Tumor Necrosis Factor, Type I
- Receptors, Tumor Necrosis Factor, Type II
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Affiliation(s)
- H Y Cho
- Department of Environmental Health Sciences, The Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA
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Wesselkamper SC, Prows DR, Biswas P, Willeke K, Bingham E, Leikauf GD. Genetic susceptibility to irritant-induced acute lung injury in mice. Am J Physiol Lung Cell Mol Physiol 2000; 279:L575-82. [PMID: 10956633 DOI: 10.1152/ajplung.2000.279.3.l575] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Recent studies suggest that genetic variability can influence irritant-induced lung injury and inflammation. To begin identifying genes controlling susceptibility to inhaled irritants, seven inbred mouse strains were continuously exposed to nickel sulfate (NiSO(4)), polytetrafluoroethylene, or ozone (O(3)), and survival time was recorded. The A/J (A) mouse strain was sensitive, the C3H/He (C3) strain was intermediate, and the C57BL/6 (B6) strain was resistant to NiSO(4)-induced acute lung injury. The B6AF(1) offspring were also resistant. The strain sensitivity pattern for NiSO(4) exposure was similar to that of polytetrafluoroethylene or ozone (O(3)). Pulmonary pathology was comparable for A and B6 mice. In the A strain, 15 microg/m(3) of NiSO(4) produced 20% mortality. The strain sensitivity patterns for lavage fluid proteins (B6 > C3 > A) and neutrophils (A >/= B6 > C3) differed from those for acute lung injury. This phenotype discordance suggests that these traits are not causally linked (i.e., controlled by independent arrays of genes). As in acute lung injury, B6C3F(1) offspring exhibited phenotypes (lavage fluid proteins and neutrophils) resembling those of the resistant parental strain. Agreement of acute lung injury strain sensitivity patterns among irritants suggested a common mechanism, possibly oxidative stress, and offspring resistance suggested that sensitivity is inherited as a recessive trait.
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Affiliation(s)
- S C Wesselkamper
- Departments of Environmental Health, Molecular and Cellular Physiology, Medicine, and Civil and Environmental Engineering, University of Cincinnati, Cincinnati, Ohio 45267, USA
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Prows DR, Daly MJ, Shertzer HG, Leikauf GD. Ozone-induced acute lung injury: genetic analysis of F(2) mice generated from A/J and C57BL/6J strains. THE AMERICAN JOURNAL OF PHYSIOLOGY 1999; 277:L372-80. [PMID: 10444532 DOI: 10.1152/ajplung.1999.277.2.l372] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Acute lung injury (or acute respiratory distress syndrome) is a devastating and often lethal condition. This complex disease (trait) may be associated with numerous candidate genes. To discern the major gene(s) controlling mortality from acute lung injury, two inbred mouse strains displaying contrasting survival times to 10 parts/million ozone were identified. A/J (A) mice were sensitive [6.6 +/- 1 (SE) h] and C57BL/6J (B) were resistant (20.6 +/- 1 h). The designation for these phenotypes was 13 h, a point that clearly separated their survival time distributions. Our prior segregation studies suggested that survival time to ozone-induced acute lung injury was a quantitative trait, and genetic analysis identified three linked loci [acute lung injury-1, -2, and -3 (Ali1-3, respectively)]. In this report, acute lung injury in A or B mice was characterized histologically and by measuring lung wet-to-dry weight ratios at death. Ozone produced comparable effects in both strains. To further delineate genetic loci associated with reduced survival, a genomewide scan was performed with F(2) mice generated from the A and B strains. The results strengthen and extend our initial findings and firmly establish that Ali1 on mouse chromosome 11 has significant linkage to this phenotype. Ali3 was suggestive of linkage, supporting previous recombinant inbred analysis, whereas Ali2 showed no linkage. Together, our findings support the fact that several genes, including Ali1 and Ali3, control susceptibility to death after acute lung injury. Identification of these loci should allow a more focused effort to determine the key events leading to mortality after oxidant-induced acute lung injury.
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Affiliation(s)
- D R Prows
- Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio 45267-0056, USA.
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Mango GW, Johnston CJ, Reynolds SD, Finkelstein JN, Plopper CG, Stripp BR. Clara cell secretory protein deficiency increases oxidant stress response in conducting airways. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 275:L348-56. [PMID: 9700096 DOI: 10.1152/ajplung.1998.275.2.l348] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Little is known about the molecular basis for differential pulmonary oxidant sensitivity observed between genetically disparate members of the same species. We have generated mice that are deficient in Clara cell secretory protein (CCSP -/-) and that exhibit an oxidant-sensitive phenotype. We characterized the kinetics and distribution of altered stress-response [interleukin-6 (IL-6) and metallothionein (MT)] and epithelial cell-specific [cytochrome P-450 2F2 (CYP2F2)] gene expression to further understand the cellular and molecular basis for altered oxidant sensitivity in 129 strain CCSP -/- mice. Increases in IL-6 and MT mRNA abundance were detected by 2 h of exposure to 1 part/million ozone and preceded reductions in Clara cell CYP2F2 mRNA expression. Despite being qualitatively similar, increases in IL-6 and MT mRNA expression were enhanced in CCSP -/- mice with respect to coexposed 129 strain wild-type mice. Increased MT mRNA expression, indicative of the stress response, localized to the airway epithelium, surrounding mesenchyme, and endothelium of blood vessels. These results demonstrate a protective role for Clara cells and their secretions and indicate potential genetic mechanisms that may influence susceptibility to oxidant stress.
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Affiliation(s)
- G W Mango
- Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642, USA
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Prows DR, Shertzer HG, Daly MJ, Sidman CL, Leikauf GD. Genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice. Nat Genet 1997; 17:471-4. [PMID: 9398853 DOI: 10.1038/ng1297-471] [Citation(s) in RCA: 96] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Epidemiological studies have found air pollution to be associated with excessive mortality, particularly death from respiratory and cardiovascular causes. Interpretation of these findings is controversial, however, because toxicological mechanisms controlling mortality are uncertain. Susceptibility to many air pollutants entails an oxidative stress response. Accordingly, the best-characterized oxidant air pollutant is ozone, which causes direct oxidative damage of lung biomolecules. An underlying characteristic derived from clinical and epidemiological studies of healthy and asthmatic individuals of all ages is marked variability in the respiratory effects of ozone. This susceptibility difference among humans suggests that genetic determinants may control predisposition to the harmful effects of ozone. Mice also vary considerably in their response to ozone. Moreover, ozone-induced differences in strain responses indicate that susceptibility in mice can be genetically determined. Therefore, we used inbred mice to investigate the genetic determinants of acute lung injury. Recombinant inbred (RI) strains derived from A/J (A) mice (sensitive) and C57BL/6J (B) mice (resistant) showed a continuous phenotypic pattern, suggesting a multigenic trait. Quantitative trait locus and RI analyses suggested three major loci linked to ozone susceptibility. Differences in phenotype ratios among the reciprocal back-crosses were consistent with parental imprinting. These findings implicate various genetic and epigenetic factors in individual susceptibility to air pollution.
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Affiliation(s)
- D R Prows
- Department of Environmental Health, University of Cincinnati, Ohio 45267-0056, USA
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Abstract
Because of the impact that oxidizing air pollutants such as ozone (O3) may have on public health, identification of factors that influence susceptibility to exposure remains a critical issue. The role of genetic background as a susceptibility factor is becoming increasingly clear. In this paper, evidence is reviewed which suggests that susceptibility to O3 is a heritable trait in humans. Experimental studies are also described that characterize the mode of inheritance of O3-induced lung injury in inbred strains of mice. It is suggested that future investigations should strive to identify phenotypic markers of susceptibility as a means to identify individuals who are genetically at risk for the development of oxidant-induced lung injury.
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Affiliation(s)
- S R Kleeberger
- Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
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Gilmour MI, Park P, Selgrade MK. Ozone-enhanced pulmonary infection with Streptococcus zooepidemicus in mice. The role of alveolar macrophage function and capsular virulence factors. THE AMERICAN REVIEW OF RESPIRATORY DISEASE 1993; 147:753-60. [PMID: 8442612 DOI: 10.1164/ajrccm/147.3.753] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Ozone exposure has been shown to increase the susceptibility of mice to pulmonary bacterial infection. We report here the differences in susceptibility of two strains of mice (C3H/HeJ and C57Bl/6) to pulmonary challenge with Streptococcus zooepidemicus, and demonstrate an association between O3 exposure, reduced alveolar macrophage (AM) function, and increased mortality to infection. After a 3-h exposure to air or to 0.4 or 0.8 ppm O3, mice received an infection of bacteria by aerosol. Subsequent mortality observed over a 20-day period for any given exposure concentration was greater in the C3H/HeJ mice than in the C57Bl/6 mice. Phagocytosis assays identified the AM from O3-exposed lungs as having an impaired ability to engulf the bacteria. Baseline phagocytic activity in C3H/HeJ mice was lower than that in C57Bl/6 mice. Microbiologic assessment of the lungs at various times after infection revealed that the streptococci proliferated rapidly in the lungs of O3-exposed mice, grew more quickly upon isolation, and displayed a mucoid colony appearance indicative of increased encapsulation. In vitro assays confirmed that the encapsulated isolates prevented binding of the bacteria to AM, and reinfection of nonexposed mice with the encapsulated isolate resulted in increased mortality compared with infection with similar numbers of the original unencapsulated bacteria. We have demonstrated that O3 inhalation impairs AM activity in the lung. The streptococci are then able to proliferate and more fully express virulence factors, in particular, the antiphagocytic capsule, which prohibits the ingestion of bacteria by pulmonary phagocytes and leads to increased severity of infection.
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Affiliation(s)
- M I Gilmour
- Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill
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Sagai M, Arakawa K, Ichinose T, Shimojo N. Biochemical effects on combined gases of nitrogen dioxide and ozone. I. Species differences of lipid peroxides and phospholipids in lungs. Toxicology 1987; 46:251-65. [PMID: 3672534 DOI: 10.1016/0300-483x(87)90207-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
In the present study, changes of lipid peroxides, phospholipids and antioxidant levels in lungs of 4 animal species exposed to the combined gases of NO2 and O3 were compared. Male mice, hamsters, rats and guinea pigs were used. Lipid peroxides were increased significantly in the lungs of mice and guinea pigs exposed to the combined gases, but not in hamsters and rats. Changes of alpha-tocopherol (VE) contents were slight. On the other hand, non-protein sulfhydryl (NPSH) contents were increased strikingly, especially in hamsters, but were not increased in guinea pigs. Phosphatidylcholine (PC) contents were increased and phosphatidylethanolamine (PE) contents were decreased by the exposure to the combined gases, with the order guinea pig greater than mouse greater than rat. In hamsters no changes were seen. The changes of fatty acid composition in guinea pigs and mice were marked, the increases of palmitate and palmitolate and the decreases of polyunsaturated fatty acid were especially characteristic. These changes in phospholipid class and fatty acid composition may be a "a kind of adaptation phenomenon" to avoid further lipid peroxidation. On the other hand, the changes in hamsters and rats were small. The results show the existence of species differences in lipid peroxide formation by exposure to the combined gases of NO2 and O3. They were found to be related to the contents of antioxidants and the compositions of phospholipids and their fatty acids.
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Affiliation(s)
- M Sagai
- Division of Basic Medical Sciences, National Institute for Environmental Studies, Ibaraki, Japan
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Hatch GE, Slade R, Stead AG, Graham JA. Species comparison of acute inhalation toxicity of ozone and phosgene. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH 1986; 19:43-53. [PMID: 3746940 DOI: 10.1080/15287398609530905] [Citation(s) in RCA: 68] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
A comparison of the concentration-response effects of inhaled ozone (O3) and phosgene (COCl2) in different species of laboratory animals was made in order to better understand the influence of the choice of species in inhalation toxicity studies. The effect of 4-h exposures to ozone at concentrations of 0.2, 0.5, 1.0, and 2.0 ppm, and to COCl2 and 0.1, 0.2, 0.5, and 1.0 ppm was determined in rabbits, guinea pigs, rats, hamsters, and mice. Lavage fluid protein (LFP) accumulation 18-20 h after exposure was used as the indicator of O3- and COCl2-induced pulmonary edema. All species had similar basal levels of LFP (250-350 mg/ml) when a volume of saline that approximated the total lung capacity was used to lavage the collapsed lungs. Ozone effects were most marked in guinea pigs, which showed significant effects at 0.2 ppm and above. Mice, hamsters, and rats showed effects at 1.0 ppm O3 and above, while rabbits responded only at 2.0 ppm O3. Phosgene similarly affected mice, hamsters, and rats at 0.2 ppm and above, while guinea pigs and rabbits were affected at 0.5 ppm and above. Percent recovery of lavage fluid varied significantly between species, guinea pigs having lower recovery than other species with both gases. Lavage fluid recovery was lower following exposure to higher levels of O3 but not COCl2. Results of this study indicate that significant species differences are seen in the response to low levels of O3 and COCl2. These differences do not appear to be related in a simple manner to body weight.
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Abstract
Rats were initially exposed to 2 ppm ozone for 3 hr in order to induce ozone tolerance. The time course of the content of nonprotein SH as well as the activities of glutathione peroxidase, glutathione reductase, and glucose 6-phosphate dehydrogenase (so-called antioxidant system) in lungs of the animals was compared to the development of tolerance in the animals to a challenge exposure of 5.6 ppm ozone for 3 hr. An enhancement of a part of the antioxidant system was detected on the second day and thereafter following the initial exposure, but the clear and complete tolerance to ozone was demonstrated 1 day before the enhancement of the antioxidant system. Alternatively, the induction of tolerance to ozone was found to be experimentally suppressed by actinomycin D or colchicine, but the levels of the antioxidant system in animals thus treated were not significantly different from the matched controls, or only partly enhanced. These events suggest that the tolerance to ozone is not related to an enhancement of the antioxidant system.
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Ichinose T, Suzuki AK, Tsubone H, Sagai M. Biochemical studies on strain differences of mice in the susceptibility to nitrogen dioxide. Life Sci 1982; 31:1963-72. [PMID: 7176805 DOI: 10.1016/0024-3205(82)90035-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Strain differences of mice in their susceptibility to nitrogen dioxide (NO2) were examined by measuring the activities of antioxidative protective enzymes, and the amounts of antioxidants and lipid peroxides in lungs. Four strains of mice: ICR, BALB/c, ddy and C57BL/6 were used in this study and their LC50 values after exposure to NO2 for 16 hr were: 38, 49, 51 and 64 ppm, respectively (1). Genetic strain differences were observed in the enzyme activities, the antioxidant contents and lipid peroxide contents among these four different strains. The activities of glutathione peroxidase (GPX), glutathione S-transferase, and superoxide dismutase (SOD), and the contents of non-protein sulfhydryls (NPSH), alpha-tocopherol (alpha-Toc) and total lipids in lungs of the four strains were related to their LC50, while TBA reactants in lungs of the four strains were inversely related to their LC50. After exposure to 20 ppm NO2 for 16 hr, the activities of the protective enzymes and the contents of NPSH decreased, while the level of alpha-Toc increased markedly. The activities of GPX, 6-phosphogluconate dehydrogenase, SOD and disulfide reductase, and the contents of NPSH, alpha-Toc and total lipids were also related to their LC50. On the other hand, TBA reactants increased higher than those of the control groups and were inversely related to their LC50. These results suggest that the protective enzymes and the antioxidants are important factors at defence mechanism in lungs to NO2 and that the intensity of the protective systems in pigmented strains is generally greater than that in albino strains.
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Stupfel M, Pesce VH, Perrot A. Phenotypic differences in survival to an experimental acute carbon monoxide intoxication. ENVIRONMENTAL RESEARCH 1980; 21:207-216. [PMID: 7389700 DOI: 10.1016/0013-9351(80)90023-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
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Richkind KE, Hacker AD. Responses of natural wildlife populations to air pollution. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH 1980; 6:1-10. [PMID: 7381962 DOI: 10.1080/15287398009529826] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Deer mice (Peromyscus californicus) trapped in areas of Los Angeles with high ambient air pollution are significantly more resistant to ozone (6.6 ppm for 12 h) than are mice trapped from areas with low ambient pollution (56 versus 0% survival, respectively). Laboratory-born progeny of these mice show similar response patterns, indicating a genetic basis to this resistance. Young mice (less than 1 yr of age) are more sensitive than older mice (15 versus 44% survival, respectively). Sensitivity is also affected by degree of inbreeding; progeny of full-sib crosses are more sensitive than randomly bred deer mice. The data suggest that deer mice are more resistant to ozone toxicity than are commercially bred laboratory mice and rats.
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Miller FJ, Illing JW, Gardner DE. Effect of urban ozone levels on laboratory-induced respiratory infections. Toxicol Lett 1978. [DOI: 10.1016/0378-4274(78)90091-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Abstract
The toxicity of ozone is solely due to its action as an oxidant. It is an extremely reactive gas which rapidly forms intermediate oxidizing derivatives after inhalation. High concentrations cause death from pulmonary oedema. Both pulmonary and extrapulmonary toxicity have been observed at lower concentrations of ozone, including those currently present in urban air. Pulmonary cellular and subcellular membranes appear to be particularly susceptible. A primary mechanism of this effect is the oxidative decomposition of polyunsaturated fatty acids, which has been demonstrated in rodent lungs after inhalation of ozone. Supporting evidence includes the potentiation of ozone toxicity by vitamin E deficiency and an increased use of this antioxidant vitamin during repetitive exposure to ozone. Other membrane effects include oxidation of thiol groups and, perhaps, of tryptophan. Microsomal alterations include a loss of lung cytochrome P450 which may also be related to lipid peroxidation. Extrapulmonary toxicity is not directly due to ozone but may represent in effect due to lipid peroxide decomposition products, particularly malonaldehyde. This three-carbon dialdehyde has been shown to alter cell membrane fluidity and to have mutagenic properties; the latter perhaps due to cross-linkage of DNA to histone.
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Goldstein BD, Hamburger SJ, Falk GW, Amoruso MA. Effect of ozone and nitrogen dioxide on the agglutination of rat alveolar macrophages by concanavalin A. Life Sci 1977; 21:1637-44. [PMID: 600016 DOI: 10.1016/0024-3205(77)90242-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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