Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation.
ABSTRACT Surfactant protein-D (Sftpd) is a pulmonary collectin important in down regulating macrophage inflammatory responses. In these studies we analyzed the effects of chronic macrophage inflammation due to loss of Sftpd on the persistence of ozone-induced injury, macrophage activation, and altered functioning in the lung. Wild type (Sftpd+/+) and Sftpd-/- mice (8 wk) were exposed to air or ozone (0.8 ppm, 3 h). Bronchoalveolar lavage fluid (BAL) and tissue were collected 72 h later. In Sftpd-/- mice, but not Sftpd+/+ mice, increased BAL protein and nitrogen oxides were observed following ozone inhalation indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL and in histologic sections from Sftpd-/- mice. These cells were enlarged and foamy suggesting that they are activated. This is supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd+/+ and Sftpd-/- mice, inhalation of ozone was associated with functional alterations in the lung. Whereas this was limited to central airway mechanics in Sftpd+/+ mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd-/- mice. Most notable changes were in resistance and elastance spectra and baseline lung functioning, in lung responsiveness to changes in positive end-expiratory pressure. These data demonstrate that loss of Sftpd is associated with prolonged lung injury, oxidative stress and macrophage accumulation and activation in response to ozone, and more extensive functional changes consistent with the loss of parenchymal integrity.
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ABSTRACT: Reactive nitrogen species (RNS) generated after exposure to radiation have been implicated in lung injury. Surfactant protein D (SP-D) is a pulmonary collectin that suppresses inducible nitric oxide synthase (iNOS) mediated RNS production. Herein, we analyzed the role of iNOS and SP-D in radiation-induced lung injury. Exposure of wild type (WT) mice to gamma radiation (8 Gy) caused acute lung injury and inflammation, as measured by increases in bronchoalveolar lavage (BAL) protein and cell content at 24 h. Radiation also caused alterations in SP-D structure at 24 h and 4 wk post exposure. These responses were blunted in iNOS(-/-) mice. Conversely, loss of iNOS had no effect on radiation-induced expression of phospho-H2A.X or tumor necrosis factor (TNF)-α. Additionally, at 24 h post radiation, cyclooxygenase expression and BAL lipocalin-2 levels were increased in iNOS(-/-) mice, and heme oxygenase (HO)-1(+) and Ym1(+) macrophages were evident. Loss of SP-D resulted in increased numbers of enlarged HO-1(+) macrophages in the lung following radiation, along with upregulation of TNF-α, CCL2 and CXCL2, while expression of phospho-H2A.X was diminished. To determine if RNS play a role in the altered sensitivity of SP-D(-/-) mice to radiation, iNOS(-/-)/SP-D(-/-) mice were used. Radiation-induced injury, oxidative stress and tissue repair were generally similar in iNOS(-/-)/SP-D(-/-) and SP-D(-/-) mice. In contrast, TNF-α, CCL2 and CXCL2 expression was attenuated. These data indicate that although iNOS is involved in radiation-induced injury and altered SP-D structure, in the absence of SP-D, it functions to promote proinflammatory signaling. Thus, multiple inflammatory pathways contribute to the pathogenic response to radiation. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: email@example.com.Toxicological Sciences 12/2014; DOI:10.1093/toxsci/kfu255 · 4.48 Impact Factor
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ABSTRACT: Background and objectiveAlthough surfactant protein-D (SP-D) has been suggested as a biomarker for chronic obstructive pulmonary disease (COPD), the relationship between genetic variants of SP-D and disease outcome of COPD remains unknown. We hypothesized that genetic polymorphisms of SP-D are associated with COPD-related phenotypes and disease prognosis.MethodsA hospital-based, case-controlled study was conducted prospectively. Six single nucleotide polymorphisms of the SFTPD gene were determined for genetic association analysis. Inflammatory cytokines and SP-D serum level were quantified. Frequency of exacerbation and change of lung function were assessed. All-cause 3-year mortality was registered.ResultsWe studied 320 smokers (192 with COPD and 128 at-risk for COPD) who were prospectively monitored for at least 3 years. The serum levels of SP-D in COPD patients were significantly associated with the degree of airflow obstruction and frequency of exacerbation. Haplotype association analysis revealed that haplotype G-G-C-C-A was associated with lower risk of COPD (P = 0.03) in our study population. COPD patients with haplotype G-G-C-C-A had lower serum SP-D levels (P < 0.001), higher rates of positive response to bronchodilator treatment (P = 0.01), more improvement of forced expiratory volume in 1 s in yearly follow-up (P = 0.03) and better 3-year survival rate than COPD patients with non G-G-C-C-A haplotype (P = 0.03).Conclusions Genetic haplotype of SP-D may serve as a valuable prognostic indicator in Chinese patients with COPD.Respirology 12/2014; DOI:10.1111/resp.12427 · 3.50 Impact Factor
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ABSTRACT: INTRODUCTION. Oxidative stress increases brain lipid peroxidation, memory and motor deficits and progressive neurodegeneration. Tibolone, a treatment for menopausal symptoms, decreases lipid peroxidation levels and improves memory and learning. AIM. To study the effect of chronic administration of tibolone on lipid peroxidation, memory and motor deficits in ozone induced oxidative stress. MATERIALS AND METHODS. 100 male Wistar adult rats were randomly divided into 10 experimental groups: control (C) was exposed to an airstream for 60 days; C + tibolone, airstream exposure plus 1 mg/kg of tibolone for 60 days; groups 3-6 were exposed to ozone for 7, 15, 30, and 60 days, and groups 7-10 received 1 mg/kg of tibolone treatment by oral gavage for 7, 15, 30 and 60 days and were then exposed to ozone. We determined the effect of tibolone on memory and motor activity. Hippocampus was processed to determine the content of 4-hydroxynonenal and nitrotyrosine by Western blot. Four animals were perfused and processed for analysis of neuronal death. RESULTS. In the hippocampus, administration of 1 mg/kg of tibolone for 30 days prevented increased levels of lipid peroxidation and protein oxidation, whereas after 60 days prevented neuronal death in the CA3 region caused by exposure to ozone. Therefore, tibolone prevents cognitive deficits in short- and long-term memory on the passive avoidance task and prevents a decrease in exploratory behavior and an increase in freezing behavior. CONCLUSION. Our results indicate a possible neuroprotective role of tibolone as a useful treatment to prevent oxidative stress neurodegeneration.Revista de neurologia 05/2014; 58(10):441-449. · 0.93 Impact Factor