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1.
Toxicol Sci ; 170(2): 489-498, 2019 08 01.
Article in English | MEDLINE | ID: mdl-31020321

ABSTRACT

Inhalation of environmental toxicants such as cigarette smoke, metal or wood dust, silica, or asbestos is associated with increased risk for idiopathic pulmonary fibrosis (IPF). IPF involves progressive scarring of lung tissue, which interferes with normal respiration and is ultimately fatal; however, the complex cellular mechanisms of IPF pathogenesis remain unclear. Fibroblast apoptosis is essential in normal wound healing but is dysregulated in IPF. Recent studies suggest that Toll-like receptor 4 (TLR4) is key in the onset of IPF. Here, radiation-induced PF was used as a model for IPF because it very closely mimics the progressive and intractable nature of IPF. Female C57BL/6J (C57) and C57BL/6J TLR4-/- mice were exposed to a single dose of 13 Gy whole-thorax ionizing radiation. Although both strains showed similar levels of immediate radiation-induced damage, C57 mice exhibited more extensive fibrosis at 22-week postirradiation (PI) than TLR4-/- mice. Isolated C57 primary 1° MLFs showed decreased apoptosis susceptibility as early as 8-week postirradiation, a phenotype that persisted for the remainder of the radiation response. TLR4-/- 1° mouse lung fibroblasts did not exhibit significant apoptosis resistance at any point. Systemic release of high mobility group box 1, a TLR4 agonist, during the pneumonitis phase of the radiation response may act through TLR4 to contribute to fibroblast apoptosis resistance and thus interfere with wound resolution. These findings demonstrate that apoptosis resistance occurs earlier in pulmonary fibrosis pathogenesis than previously assumed, and that TLR4 signaling is a key mediator in this process.


Subject(s)
Apoptosis , Cicatrix/etiology , Fibroblasts/pathology , Idiopathic Pulmonary Fibrosis/etiology , Toll-Like Receptor 4/physiology , Animals , Cells, Cultured , Female , HMGB1 Protein/physiology , Idiopathic Pulmonary Fibrosis/pathology , Mice , Mice, Inbred C57BL , Radiation Injuries/etiology
2.
Radiat Res ; 179(6): 617-29, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23621375

ABSTRACT

Viral infections have been associated with exacerbation of disease in human cases of idiopathic pulmonary fibrosis. Since pulmonary fibrosis is a common outcome after irradiation to the lung, we hypothesized that viral infection after radiation exposure would exacerbate radiation-induced lung injury. Epithelial injury, a frequent outcome after infection, has been hypothesized to contribute to the pathogenesis of pulmonary fibrosis and bronchiolar epithelial Clara cells participate in epithelial repair. Therefore, it was further hypothesized that altered responses after irradiation involve the bronchiolar epithelial Clara cells. C57BL/6J or CCSP(-/-) mice were irradiated with 0 (sham), 5, 10 or 15 Gy to the whole thorax. At ten weeks post-irradiation, animals were mock infected or infected with influenza A virus and body weight and survival were monitored. Pulmonary function was assessed by whole-body plethysmography. The Clara cell markers, CCSP and Cyp2f2, were measured in the lung by qRT-PCR, and protein expression was visualized in the lung by immunofluorescence. Following pulmonary function tests, mice were sacrificed and tissues were collected for pathological analysis. In 15 Gy irradiated animals infected with influenza A virus, accelerated respiratory rates, reduced pulmonary function, and exacerbated lung pathology occurred earlier post-irradiation than previously observed after irradiation alone, suggesting infection accelerates the development of radiation injury. After irradiation alone, CCSP and Cyp2f2 mRNA levels were reduced, correlating with reductions in the number of Clara cells lining the airways. When combined with infection, these markers further declined and an apparent delay in recovery of mRNA expression was observed, suggesting that radiation injury leads to a chronic reduction in the number of Clara cells that may potentiate the epithelial injury observed after influenza A virus infection. This novel finding may have considerable therapeutic implications with respect to both thoracic tumor patients and recipients of bone marrow transplants.


Subject(s)
Influenza A virus/physiology , Lung Injury/pathology , Lung Injury/virology , Lung/virology , Radiation Injuries, Experimental/pathology , Radiation Injuries, Experimental/virology , Uteroglobin/metabolism , Animals , Female , Gene Expression Regulation/radiation effects , Lung/metabolism , Lung/pathology , Lung/radiation effects , Lung Injury/genetics , Lung Injury/metabolism , Mice , Mice, Inbred C57BL , Radiation Dosage , Radiation Injuries, Experimental/genetics , Radiation Injuries, Experimental/metabolism , Uteroglobin/genetics
3.
Int J Radiat Oncol Biol Phys ; 86(1): 128-35, 2013 May 01.
Article in English | MEDLINE | ID: mdl-23195776

ABSTRACT

PURPOSE: To address whether irradiation-induced changes in the lung environment alter responses to a viral challenge delivered late after exposure but before the appearance of late lung radiation injury. METHODS AND MATERIALS: C57BL/6J mice received either lung alone or combined lung and whole-body irradiation (0-15 Gy). At 10 weeks after irradiation, animals were infected with 120 HAU influenza virus strain A/HKx31. Innate and adaptive immune cell recruitment was determined using flow cytometry. Cytokine and chemokine production and protein leakage into the lung after infection were assessed. RESULTS: Prior irradiation led to a dose-dependent failure to regain body weight after infection and exacerbated mortality, but it did not affect virus-specific immune responses or virus clearance. Surviving irradiated animals displayed a persistent increase in total protein in bronchoalveolar lavage fluid and edema. CONCLUSIONS: Lung irradiation increased susceptibility to death after infection with influenza virus and impaired the ability to complete recovery. This altered response does not seem to be due to a radiation effect on the immune response, but it may possibly be an effect on epithelial repair.


Subject(s)
Influenza A virus , Lung/radiation effects , Orthomyxoviridae Infections/mortality , Adaptive Immunity/immunology , Animals , Bronchoalveolar Lavage Fluid/chemistry , Chemokines/immunology , Cytokines/immunology , Disease Models, Animal , Dose-Response Relationship, Radiation , Female , Hematopoietic Stem Cells/radiation effects , Immunity, Innate/immunology , Immunoglobulin G/analysis , Immunoglobulin G/immunology , Influenza A virus/immunology , Lung/immunology , Lung/virology , Mice , Mice, Inbred C57BL , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , Proteins/analysis , Weight Loss , Whole-Body Irradiation/adverse effects
4.
Am J Physiol Lung Cell Mol Physiol ; 286(1): L30-6, 2004 Jan.
Article in English | MEDLINE | ID: mdl-12909591

ABSTRACT

The alveolar macrophage is an important source of interleukin (IL)-8 during pulmonary injury. The IL-8 gene promoter sequence contains nuclear factor (NF)-kappa B, NF-IL6, and activator protein (AP)-1 binding sequences. These sites may have differing regulatory roles in hyperoxia-exposed macrophages than in those stimulated by bacterial lipopolysaccharide (LPS). U-937 and THP-1 macrophage-like cells were exposed to air-5% CO2 or 95% O2-5% CO2, with or without 1.0 microg/ml of LPS, and transfected with an IL-8 promoter-reporter containing NF-kappa B, NF-IL6, or AP-1 mutations. Hyperoxia and LPS caused additive increases in IL-8 production by U-937 cells, whereas THP-1 cells responded only to LPS. An NF-kappa B mutation ablated baseline and O2- and LPS-stimulated reporter activity in both cell lines, whereas NF-IL6 mutations had little effect. An AP-1 mutation had an intermediate effect. LPS, but not hyperoxia, stimulated nuclear translocation of NF-kappa B in both cell lines. Pharmacological blockade of NF-kappa B nuclear translocation ablated LPS-, but not hyperoxia-, stimulated IL-8 production. Although an intact promoter NF-kappa B site is crucial to macrophage IL-8 production, only LPS-stimulated production appears to require additional nuclear translocation of NF-kappa B.


Subject(s)
Hyperoxia/physiopathology , Interleukin-8/genetics , Lipopolysaccharides/pharmacology , Macrophages/physiology , NF-kappa B/metabolism , Oxygen/pharmacology , CCAAT-Enhancer-Binding Protein-beta/metabolism , Cell Nucleus/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Interleukin-8/metabolism , Macrophages/drug effects , Oxidative Stress/physiology , Promoter Regions, Genetic , RNA, Messenger/analysis , Transcription Factor AP-1/metabolism , U937 Cells
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