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ABSTRACT: BACKGROUND: Wholegrain flaxseed (FS), and its lignan component (FLC) consisting mainly of secoisolariciresinol diglucoside (SDG), have potent lung radioprotective properties while not abrogating the efficacy of radiotherapy. However, while the whole grain was recently shown to also have potent mitigating properties in a thoracic radiation pneumonopathy model, the bioactive component in the grain responsible for the mitigation of lung damage was never identified. Lungs may be exposed to radiation therapeutically for thoracic malignancies or incidentally following detonation of a radiological dispersion device. This could potentially lead to pulmonary inflammation, oxidative tissue injury, and fibrosis. This study aimed to evaluate the radiation mitigating effects of FLC in a mouse model of radiation pneumonopathy. METHODS: We evaluated FLC-supplemented diets containing SDG lignan levels comparable to those in 10% and 20% whole grain diets. 10% or 20% FLC diets as compared to an isocaloric control diet (0% FLC) were given to mice (C57/BL6) (n=15-30 mice/group) at 24, 48, or 72-hours after single-dose (13.5 Gy) thoracic x-ray treatment (XRT). Mice were evaluated 4 months post-XRT for blood oxygenation, lung inflammation, fibrosis, cytokine and oxidative damage levels, and survival. RESULTS: FLC significantly mitigated radiation-related animal death. Specifically, mice fed 0% FLC demonstrated 36.7% survival 4 months post-XRT compared to 60--73.3% survival in mice fed 10%-20% FLC initiated 24--72 hours post-XRT. FLC also mitigated radiation-induced lung fibrosis whereby 10% FLC initiated 24-hours post-XRT significantly decreased fibrosis as compared to mice fed control diet while the corresponding TGF-beta1 levels detected immunohistochemically were also decreased. Additionally, 10-20% FLC initiated at any time point post radiation exposure, mitigated radiation-induced lung injury evidenced by decreased bronchoalveolar lavage (BAL) protein and inflammatory cytokine/chemokine release at 16 weeks post-XRT. Importantly, neutrophilic and overall inflammatory cell infiltrate in airways and levels of nitrotyrosine and malondialdehyde (protein and lipid oxidation, respectively) were also mitigated by the lignan diet. CONCLUSIONS: Dietary FLC given early post-XRT mitigated radiation effects by decreasing inflammation, lung injury and eventual fibrosis while improving survival. FLC may be a useful agent, mitigating adverse effects of radiation in individuals exposed to incidental radiation, inhaled radioisotopes or even after the initiation of radiation therapy to treat malignancy.
BMC Cancer 04/2013; 13(1):179. · 3.01 Impact Factor
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ABSTRACT: While dietary wholegrain Flaxseed (FS) has potent anti-inflammatory, anti-fibrotic and antioxidant properties in murine models of acute and chronic lung injury, the main bioactive ingredient that contributes to these protective effects remains unknown. This study evaluated the lignan complex of FS (FLC) enriched in secoisolariciresinol diglucoside with respect to lung radioprotective and tumor radiosensitizing efficacy using a mouse model of thoracic radiation-induced pneumonopathy. C57/Bl6 mice were fed 0% FS, 10% FS, 10% FLC or 20% FLC for 3 weeks, then irradiated with a single fraction (13.5 Gy) of X-ray radiation treatment (XRT). Mouse survival was monitored for 4 months after irradiation and inflammatory lung parameters were evaluated in bronchoalveolar lavage (BAL) fluid. Gene and protein levels of protective antioxidant and phase II enzymes were evaluated in lung tissue using qPCR and protein levels were verified by immunoblotting. Prolonged administration of the FLC diet was well tolerated and was not associated with any toxicity. Importantly, comparable to the whole grain 10% FS diet, irradiated mice fed 10% and 20% FLC diets displayed improved survival. Improved hemodynamic measurements were also recorded in irradiated mice fed 10% FS or 10% FLC diet compared to irradiated 0% FS fed mice. Flaxseed lignan complex diet also attenuated polymorphonuclear infiltration and overall lung inflammation to levels comparable to those in nonirradiated mice. Flaxseed lignan complex, similarly to FS, up-regulated gene expression as well as protein levels of protective antioxidant enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Dietary FLC induced radiosensitizing effects in our murine model of metastatic lung cancer. Importantly, protection of normal tissue does not thwart tumor cell death by radiation treatment. The dietary lignan complex of FS, mainly consisting of the phenolic secoisolariciresinol, is protective against radiation pneumonopathy in vivo while not hindering the tumoricidal effects of radiotherapy.
Radiation Research 10/2012; · 2.68 Impact Factor
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ABSTRACT: The aim of this study was to determine the adequacy of archived and fresh fine needle aspiration (FNA) specimens from metastatic head and neck squamous cell carcinoma (SCC) for the molecular detection and genotyping of high-risk (HR) HPV.
Thirty-seven specimens from 26 patients diagnosed by FNA with metastatic SCC were included as retrospective specimens [19 slides stained with Papanicolaou (Pap) and 18 with Diff-Quik® (DQ)]. Twenty fresh FNA specimens from 18 patients were included as prospective specimens. These specimens were analyzed using the standard protocol for ThinPrep® cervical specimens, with a Cervista HR HPV detection kit. The positive specimens were tested for the HPV 16 and 18 genotypes.
Forty-four of 57 specimens (77%) had sufficient cells to yield a valid HPV result. The adequacy rate for Pap-stained slides was 15/19 (79%), for DQ-stained slides it was 13/18 (72%), and for fresh needle aspirates it was 16/20 (80%). HR HPV was detected in 23/44 (52%) specimens. Among the 23 HPV-positive specimens, 19 were genotyped as HPV 16 and 1 as HPV 18.
HR HPV detection and genotyping can be performed on FNA specimens of head and neck SCC prospectively collected in PreservCyt as well as on archival slides with either Pap or DQ stain.
Acta cytologica 01/2012; 56(2):196-8. · 0.49 Impact Factor
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ABSTRACT: Objective: To identify new molecular diagnostic markers for non-small cell lung carcinoma (NSCLC) by analyzing microRNA (miRNA) expression profile differences in samples from NSCLC patients and adults with nonneoplastic diseases. Study Design: miRNA expression was studied in archival formalin-fixed, paraffin-embedded tissues by microarray and confirmed by real-time PCR analysis of NSCLC and normal lung tissues. An algorithm for discriminating normal, squamous cell carcinoma (SQCC), and adenocarcinoma (ADC) tissue was derived from miRNA expression studies and applied towards characterization of poorly differentiated NSCLC samples. Results: Microarray data from a genome-wide scan revealed 34 differentially expressed miRNAs, 5 of which enabled algorithmic discrimination of normal tissue from carcinoma (SQCC or ADC), as well as SQCC from ADC. Expression of miR-21 was significantly increased in both tumor types, whereas levels of miR-451 and miR-486-5p were reduced. SQCC was distinguished from normal tissue and ADC by high-level miR-205 expression and decreased miR-26b. Comparison of miRNA profiles to histological and immunohistochemical findings in 19 poorly differentiated specimens demonstrated the potential clinical utility of miRNA profiling to provide important insights into the classification of SQCC and ADC. Conclusion: This study presents a novel algorithm for specimen classification in cases of poorly differentiated NSCLC.
Acta cytologica 01/2012; 56(6):645-54. · 0.49 Impact Factor
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ABSTRACT: Grading upper tract urothelial carcinomas (UTUC) in cell blocks with small distorted tissue fragments can be challenging; interobserver agreement is poor among pathologists. Mitotic figure (MF) counting along with nuclear features is important in grading these tumors. We evaluated the use of the mitotic-specific marker phosphohistone H3 (PHH3) as an adjunct to hematoxylin and eosin (H&E) stain for grading UTUC in cell blocks.
Formalin-fixed, paraffin-embedded tissues from the cell blocks of 61 UTUC were stained with H&E and PHH3 antibody. The grading of tumors was performed independently by 3 pathologists, on both H&E-stained and PHH3 plus H&E-stained slides. The grading system used was the 1973 WHO 3-point grading system. Gradings were compared by all the pathologists for H&E staining versus PHH3 plus H&E staining with the Stuart-Maxwell test of marginal homogeneity that accounts for the matched data.
The average pairwise agreement by H&E alone was 55%, and 80% by PHH3 plus H&E.
By adding PHH3 immunostain to the H&E, the agreement in grading the carcinomas among the 3 pathologists improved dramatically. PHH3 immunostain may play an important role in grading UTUC in small cell block samples.
Acta cytologica 01/2012; 56(3):285-8. · 0.49 Impact Factor
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ABSTRACT: We have recently discovered that the insulin-like growth factor receptor I (IGF-IR) is up-regulated in human invasive bladder
cancer and promotes migration and invasion of transformed urothelial cells. The proteoglycan decorin, a key component of the
tumor stroma, can positively regulate the IGF-IR system in normal cells. However, there are no available data on the role
of decorin in modulating IGF-IR activity in transformed cells or in tumor models. Here we show that the expression of decorin
inversely correlated with IGF-IR expression in low and high grade bladder cancers (n = 20 each). Decorin bound with high affinity IGF-IR and IGF-I at distinct sites and negatively regulated IGF-IR activity
in urothelial cancer cells. Nanomolar concentrations of decorin promoted down-regulation of IRS-1, one of the critical proteins
of the IGF-IR pathway, and attenuated IGF-I-dependent activation of Akt and MAPK. This led to decorin-evoked inhibition of
migration and invasion upon IGF-I stimulation. Notably, decorin did not cause down-regulation of the IGF-IR in bladder, breast,
and squamous carcinoma cells. This indicates that decorin action on the IGF-IR differs from its known activity on other receptor
tyrosine kinases such as the EGF receptor and Met. Our results provide a novel mechanism for decorin in negatively modulating
both IGF-I and its receptor. Thus, decorin loss may contribute to increased IGF-IR activity in the progression of bladder
cancer and perhaps other forms of cancer where IGF-IR plays a role.
Journal of Biological Chemistry 10/2011; 286(40):34712-34721. · 4.77 Impact Factor
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ABSTRACT: We have recently discovered that the insulin-like growth factor receptor I (IGF-IR) is up-regulated in human invasive bladder cancer and promotes migration and invasion of transformed urothelial cells. The proteoglycan decorin, a key component of the tumor stroma, can positively regulate the IGF-IR system in normal cells. However, there are no available data on the role of decorin in modulating IGF-IR activity in transformed cells or in tumor models. Here we show that the expression of decorin inversely correlated with IGF-IR expression in low and high grade bladder cancers (n = 20 each). Decorin bound with high affinity IGF-IR and IGF-I at distinct sites and negatively regulated IGF-IR activity in urothelial cancer cells. Nanomolar concentrations of decorin promoted down-regulation of IRS-1, one of the critical proteins of the IGF-IR pathway, and attenuated IGF-I-dependent activation of Akt and MAPK. This led to decorin-evoked inhibition of migration and invasion upon IGF-I stimulation. Notably, decorin did not cause down-regulation of the IGF-IR in bladder, breast, and squamous carcinoma cells. This indicates that decorin action on the IGF-IR differs from its known activity on other receptor tyrosine kinases such as the EGF receptor and Met. Our results provide a novel mechanism for decorin in negatively modulating both IGF-I and its receptor. Thus, decorin loss may contribute to increased IGF-IR activity in the progression of bladder cancer and perhaps other forms of cancer where IGF-IR plays a role.
Journal of Biological Chemistry 08/2011; 286(40):34712-21. · 4.77 Impact Factor
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ABSTRACT: Flaxseed (FS) is a dietary supplement known for its antioxidant and anti-inflammatory properties. Radiation exposure of lung tissues occurs either when given therapeutically to treat intrathoracic malignancies or incidentally, such as in the case of exposure from inhaled radioisotopes released after the detonation of a radiological dispersion devise (RDD). Such exposure is associated with pulmonary inflammation, oxidative tissue damage and irreversible lung fibrosis. We previously reported that dietary FS prevents pneumonopathy in a rodent model of thoracic X-ray radiation therapy (XRT). However, flaxseed's therapeutic usefulness in mitigating radiation effects post-exposure has never been evaluated.
We evaluated the effects of a 10%FS or isocaloric control diet given to mice (C57/BL6) in 2 separate experiments (n = 15-25 mice/group) on 0, 2, 4, 6 weeks post a single dose 13.5 Gy thoracic XRT and compared it to an established radiation-protective diet given preventively, starting at 3 weeks prior to XRT. Lungs were evaluated four months post-XRT for blood oxygenation levels, inflammation and fibrosis.
Irradiated mice fed a 0%FS diet had a 4-month survival rate of 40% as compared to 70-88% survival in irradiated FS-fed mouse groups. Additionally, all irradiated FS-fed mice had decreased fibrosis compared to those fed 0%FS. Lung OH-Proline content ranged from 96.5 ± 7.1 to 110.2 ± 7.7 μg/ml (Mean ± SEM) in all irradiated FS-fed mouse groups, as compared to 138 ± 10.8 μg/ml for mice on 0%FS. Concomitantly, bronchoalveolar lavage (BAL) protein and weight loss associated with radiation cachexia was significantly decreased in all FS-fed groups. Inflammatory cell influx to lungs also decreased significantly except when FS diet was delayed by 4 and 6 weeks post XRT. All FS-fed mice (irradiated or not), maintained a higher blood oxygenation level as compared to mice on 0%FS. Similarly, multiplex cytokine analysis in the BAL fluid revealed a significant decrease of specific inflammatory cytokines in FS-fed mice.
Dietary FS given post-XRT mitigates radiation effects by decreasing pulmonary fibrosis, inflammation, cytokine secretion and lung damage while enhancing mouse survival. Dietary supplementation of FS may be a useful adjuvant treatment mitigating adverse effects of radiation in individuals exposed to inhaled radioisotopes or incidental radiation.
BMC Cancer 06/2011; 11:269. · 3.01 Impact Factor
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James C Lee,
Paul A Kinniry,
Evguenia Arguiri,
Matthew Serota,
Stathis Kanterakis,
Shampa Chatterjee, Charalambos C Solomides,
Prashanthi Javvadi,
Constantinos Koumenis,
Keith A Cengel,
Melpo Christofidou-Solomidou
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ABSTRACT: The effectiveness of lung radiotherapy is limited by radiation tolerance of normal tissues and by the intrinsic radiosensitivity of lung cancer cells. The chemopreventive agent curcumin has known antioxidant and tumor cell radiosensitizing properties. Its usefulness in preventing radiation-induced pneumonopathy has not been tested previously. We evaluated dietary curcumin in radiation-induced pneumonopathy and lung tumor regression in a murine model. Mice were given 1% or 5% (w/w) dietary curcumin or control diet prior to irradiation and for the duration of the experiment. Lungs were evaluated at 3 weeks after irradiation for acute lung injury and inflammation by evaluating bronchoalveolar lavage (BAL) fluid content for proteins, neutrophils and at 4 months for pulmonary fibrosis. In a separate series of experiments, an orthotopic model of lung cancer using intravenously injected Lewis lung carcinoma (LLC) cells was used to exclude possible tumor radioprotection by dietary curcumin. In vitro, curcumin boosted antioxidant defenses by increasing heme oxygenase 1 (HO-1) levels in primary lung endothelial and fibroblast cells and blocked radiation-induced generation of reactive oxygen species (ROS). Dietary curcumin significantly increased HO-1 in lungs as early as after 1 week of feeding, coinciding with a steady-state level of curcumin in plasma. Although both 1% and 5% w/w dietary curcumin exerted physiological changes in lung tissues by significantly decreasing LPS-induced TNF-alpha production in lungs, only 5% dietary curcumin significantly improved survival of mice after irradiation and decreased radiation-induced lung fibrosis. Importantly, dietary curcumin did not protect LLC pulmonary metastases from radiation killing. Thus dietary curcumin ameliorates radiation-induced pulmonary fibrosis and increases mouse survival while not impairing tumor cell killing by radiation.
Radiation Research 05/2010; 173(5):590-601. · 2.68 Impact Factor
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ABSTRACT: Poorly reversible airflow obstruction is a hallmark feature of chronic obstructive pulmonary disease (COPD). However, some COPD patients demonstrate significant bronchodilator reversibility (BDR). The pathologic features associated with the presence or absence of this phenomenon are not known.
We analyzed 67 patients with advanced upper lobe predominant emphysema who underwent lung volume reduction surgery and divided them into 2 groups: the reversible group [BD(+)] had a >12% and >200 mL increase in FEV(1) or FVC with bronchodilator; the irreversible group [BD(-)] had a <or=12% and <or=20 mL increase in FEV(1) and FVC. We measured the epithelial height (EH) and areas of epithelium (EA), subepithelium (SEA), smooth muscle (SMWA), and total wall (TWA) of the small airways (<2 mm in internal diameter) in the resected specimens, and adjusted these measurements for basement membrane area (BMA) or perimeter (BMP).
Despite similar baseline characteristics, the BD(+) group had a smaller EH (0.036 mm vs. 0.042 mm, p = 0.005) and EH/BMP (0.012 vs. 0.014, p = 0.007), and a greater SMWA/BMA (0.491 vs. 0.430, p = 0.034) compared to the BD(-) group. In addition, EA trended to be smaller in the BD(+) group when compared to the BD(-) group (0.160 mm(2) vs. 0.184 mm(2), p = 0.06). In a subset of patients with consistent patterns of BDR on serial testing, the BD(+) group had greater SMWA/BMA (0.518 vs. 0.433, p = 0.049) and TWA/BMA (1.405 vs. 1.266, p = 0.036) compared to the BD(-) group.
Small airway smooth muscle mass may play a role in determining BDR in severe emphysema.
COPD Journal of Chronic Obstructive Pulmonary Disease 04/2010; 7(2):93-101. · 1.79 Impact Factor
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Michele M Hickey,
Theresa Richardson,
Tao Wang,
Matias Mosqueira,
Evguenia Arguiri,
Hongwei Yu,
Qian-Chun Yu, Charalambos C Solomides,
Edward E Morrisey,
Tejvir S Khurana,
Melpo Christofidou-Solomidou,
M Celeste Simon
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ABSTRACT: Mutation of the von Hippel-Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (VhlR/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating VhlR/R mice as a model for Chuvash disease. Lungs from VhlR/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2alpha activity was increased in lungs from VhlR/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the VhlR/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in VhlR/R lungs, suggesting a selective role for HIF-2alpha in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2alpha and suggest potential treatments for Chuvash patients.
The Journal of clinical investigation 02/2010; 120(3):827-39. · 15.39 Impact Factor
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Radiographics 01/2010; 30(1):295-9. · 2.85 Impact Factor
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Vladimir V Shuvaev,
Melpo Christofidou-Solomidou,
Faiz Bhora,
Karine Laude,
Hua Cai,
Sergei Dikalov,
Evguenia Arguiri, Charalambos C Solomides,
Steven M Albelda,
David G Harrison,
Vladimir R Muzykantov
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ABSTRACT: Oxidative stress underlies diverse vascular diseases, but its management remains elusive, in part because of our inability to selectively detoxify reactive oxygen species (ROS) in pathological sites and our limited understanding which species need to be eliminated. The antioxidant enzymes (AOEs) superoxide dismutase (SOD) and catalase (which decompose and H(2)O(2), respectively), conjugated with an antibody to platelet-endothelial cell adhesion molecule-1 (PECAM-1), bind to endothelial cells and alleviate oxidative stress in cell culture models. Here, we studied the effects of these antioxidant conjugates in mouse models of vascular oxidative stress. Anti-PECAM/catalase and anti-PECAM/SOD conjugates, in contrast to control IgG/AOE conjugates, accumulated in the lungs and vascularized organs after intravenous injection in wild-type, but not PECAM KO mice. Anti-PECAM/catalase, but not anti-PECAM/SOD, protected mice from lung injury induced by H(2)O(2) produced by glucose oxidase deposited in the pulmonary vasculature. Anti-PECAM/catalase also reduced alveolar edema and attenuated decline in arterial oxygen in mice that underwent unilateral lung ischemia/reperfusion, whereas anti-PECAM/SOD was not effective, implying the key role of H(2)O(2) in tissue damage in this pathology. In contrast, anti-PECAM/SOD, but not anti-PECAM/catalase prevented oxidation of tetrahydrobiopterin and normalized vasoreactivity in the vessels of mice rendered hypertensive by pretreatment with angiotensin-II. This outcome agrees with reports implicating superoxide and peroxynitrite in altered endothelium-dependent vasodilatation in hypertension. Therefore, the use of endothelial cell-targeted antioxidants identifies the key specific species of ROS involved in various forms of vascular disease and holds promise for the mechanistically tailored treatment of these pathologies.
Journal of Pharmacology and Experimental Therapeutics 09/2009; 331(2):404-11. · 3.83 Impact Factor
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ABSTRACT: Mucous metaplasia is an important determinant of small airway obstruction in COPD. Its relationship to small airway inflammation is poorly defined. We analyzed 4 to 6 small airways in 19 COPD patients, GOLD stages 0-4, from lobectomy or lung volume reduction surgery tissue samples. To identify intracellular mucin, periodic acid fluorescent Schiff's (PAFS) stained slides were imaged by fluorescence microscopy. PAFS+ staining area, basement membrane length (L(BM)), epithelial height and area were measured. Mucin was expressed as a percentage of epithelial area. Mucin volume density (MVD) was calculated as PAFS+ area divided by the product of L(BM) and 4/pi. Airways were Giemsa stained for eosinophils and immunostained with antibodies against CD3, CD4, CD8, CD68, and neutrophil elastase (NE), and the number of positively stained cells/mm(2) was quantified in the airway wall. Mucin percent correlated with CD3(+) cell density (r = 0.553, P < 0.0001), and MVD correlated with CD3(+) (r = 0.570, P < 0.0001) and CD8(+) cell density (r = 0.279, P = 0.016). There were weak negative correlations between mucin percent as well as MVD and CD68(+) cell density (r = -0.270, P = 0.02 and r = -0.245, P = 0.036). There was no relationship between epithelial mucin content and CD4(+), NE(+), or eosinophil cell density. CD3(+) and CD8(+) lymphocytic inflammation is related to small airway mucous metaplasia in COPD and may play a causative role in its development.
COPD Journal of Chronic Obstructive Pulmonary Disease 12/2008; 5(6):329-38. · 1.79 Impact Factor
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ABSTRACT: Dietary flaxseed (FS) is a nutritional whole grain with high contents of omega-3 fatty acids and lignans with anti-inflammatory and antioxidant properties. We evaluated FS in a murine model of pulmonary ischemia-reperfusion injury (IRI) by dietary supplementation of 0% (control) or 10% (treatment) FS before IRI. Mice fed 0% FS undergoing IRI had a significant decrease in arterial oxygenation (Pa(O(2))) and a significant increase in bronchoalveolar lavage (BAL) protein compared with sham-operated mice. However, mice fed 10% FS undergoing IRI had a significant improvement in both Pa(O(2)) and BAL protein compared with mice fed 0% FS undergoing IRI. In addition, oxidative lung damage was decreased in 10% FS-supplemented mice undergoing IRI, as assessed by malondialdehyde levels. Immunohistochemical staining of lungs for iPF(2alpha)-III F(2) isoprostane, a measure of lipid oxidation, was diminished. FS-supplemented mice had less reactive oxygen species (ROS) release from the vascular endothelium in lungs in an ex vivo model of IRI, and alveolar macrophages isolated from FS-fed mice had significantly reduced ROS generation in response to oxidative burst. Pulmonary microvascular endothelial cells produced less ROS in a flow cessation model of ischemia when preincubated with purified FS lignan metabolites. Pharmacological inhibition of heme oxygenase-1 (HO-1) resulted in only a partial reduction of FS protection in the same model. We conclude that dietary FS is protective against IRI in an experimental murine model and that FS affects ROS generation and ROS detoxification via pathways not limited to upregulation of antioxidant enzymes such as HO-1.
AJP Lung Cellular and Molecular Physiology 03/2008; 294(2):L255-65. · 3.66 Impact Factor
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Mitchell Machtay,
Arnaud Scherpereel,
José Santiago,
James Lee,
Jim McDonough,
Paul Kinniry,
Evguenia Arguiri,
Vladimir V Shuvaev,
Jing Sun,
Keith Cengel, Charalambos C Solomides,
Melpo Christofidou-Solomidou
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ABSTRACT: Since oxidative injury is implicated in radiation-induced tissue damage to the lung, we studied systemically administered polyethylene glycol (PEGylated) antioxidant enzymes (AOEs) as pulmonary radioprotectors in mice.
C57/bl6 Mice received 13.5 Gy single-dose irradiation to the thorax. One cohort also received 100 microg of a 1:1 mixture of PEG-AOEs {PEG-catalase and PEG-superoxide dismutase (SOD)} intravenously, pre-irradiation and subgroups were evaluated at variable time-points for inflammation and fibrosis. Potential for AOE tumor protection was studied by thoracic irradiation of mice with Lewis lung carcinoma.
At 48 h post-irradiation, control irradiated mice had marked elevations of tissue p21, Bax and TGF-beta1 in lungs, not seen in irradiated, PEG-AOE-treated mice. TUNEL staining of lung sections was performed at just one time-point (24 h post-irradiation) and revealed a decrease in apoptotic cells with AOE treatment. At four months post-irradiation, these mice had significantly increased pulmonary fibrosis as measured by hydroxyproline content. Mice treated with PEG-AOE prior to irradiation had 4-month hydroxyproline levels that were similar to that of unirradiated controls (p = 0.28). This corresponded to less pulmonary fibrosis as visualized histologically when compared with mice irradiated without AOEs. PEG-AOEs did not prevent post-irradiation pulmonary inflammation or lung cancer response to irradiation.
A mixture of PEG-SOD and PEG-CAT successfully diminished radiation pulmonary fibrosis in mice. There was also a corresponding effect on several early biomarkers of lung injury and decreased apoptosis. There were no significant effects on acute pneumonitis or tumor protection.
Radiotherapy and Oncology 12/2006; 81(2):196-205. · 5.58 Impact Factor
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ABSTRACT: The objective of this study was to quantitatively assess changes in cell adhesion molecule (CAM) expression on the pulmonary endothelial surface during hyperoxia and to assess the functional significance of those changes on cellular trafficking and development of oxygen-induced lung injury. Mice were placed in >95% O(2) for 0-72 h, and pulmonary injury and neutrophil (PMN) sequestration were assessed. Specific pulmonary CAM expression was quantified with a dual-radiolabeled MAb technique. To test the role of CAMs in PMN trafficking during hyperoxia, blocking MAbs to murine P-selectin, ICAM-1, or platelet-endothelial cell adhesion molecule-1 (PECAM-1) were injected in wild-type mice. Mice genetically deficient in these CAMs and PMN-depleted mice were also evaluated. PMN sequestration occurred within 8 h of hyperoxia, although alveolar emigration occurred later (between 48 and 72 h), coincident with rapid escalation of the lung injury. Hyperoxia significantly increased pulmonary uptake of radiolabeled antibodies to P-selectin, ICAM-1, and PECAM-1, reflecting an increase in their level on pulmonary endothelium and possibly sequestered blood cells. Although both anti-PECAM-1 and anti-ICAM-1 antibodies suppressed PMN alveolar influx in wild-type mice, only mice genetically deficient in PECAM-1 showed PMN influx suppression. Neither CAM blockade, nor genetic deficiency, nor PMN depletion attenuated lung injury. We conclude that early pulmonary PMN retention during hyperoxia is not temporally associated with an increase in endothelial CAMs; however, subsequent PMN emigration into the alveolar space may be supported by PECAM-1 and ICAM-1. Blocking PMN recruitment did not prevent lung injury, supporting dissociation between PMN infiltration and lung injury during hyperoxia in mice.
AJP Lung Cellular and Molecular Physiology 12/2006; 291(5):L1050-8. · 3.66 Impact Factor
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ABSTRACT: KL(4)-surfactant contains the novel KL(4) peptide, sinapultide, which mimics properties of the hydrophobic pulmonary surfactant protein SP-B, in a phospholipid formulation and may be lung protective in experimental acute respiratory distress syndrome/acute lung injury. Our objective was to determine the protective role of airway delivery of KL(4)-surfactant in murine models of hyperoxic and lipopolysaccharide (LPS)-induced lung injury and further explore the mechanisms of protection. For the hyperoxic injury model, mice exposed to 80% O(2) for 6 days received an intranasal bolus of vehicle, beractant, or KL(4)-surfactant on days 3, 4, 5, and 6 of the exposure, and lungs were evaluated on day 7. Mice in the LPS-induced lung injury model received an intratracheal bolus of LPS followed by an intranasal bolus of KL(4)-surfactant or control at 1, 3, and 19 hr post-LPS challenge, and lungs were evaluated after 24 hr. To explore the mechanisms of protection, in vitro assays were performed with human and murine endothelial cell monolayers, and polymorphonuclear leukocyte (PMN) transmigration in the presence or absence of KL(4)-surfactant or lipid controls was evaluated. Based on morphology, histopathology, white blood cell count, percentage of PMNs, and protein concentration in bronchoalveolar lavage fluid, our data showed KL(4)-surfactant, unlike vehicle or beractant, blocked neutrophil influx into alveoli and suppressed lung injury. Furthermore, in vitro assays showed KL(4)-surfactant decreased neutrophil transmigration at the endothelial cell level. KL(4)-surfactant decreased inflammation and lung permeability compared with controls in both mouse models of lung injury. Evidence suggests the anti-inflammatory mechanism of the KL(4)-peptide is through inhibition of PMN transmigration through the endothelium.
Pediatric Pulmonology 11/2006; 41(10):916-28. · 2.53 Impact Factor
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ABSTRACT: Flaxseed (FS) is a nutritional supplement with high concentrations of (n-3) fatty acids and lignans that have anti-inflammatory and antioxidant properties. The use of FS in the prevention or treatment of acute lung disease is unknown. In this study, we evaluated diets with high FS content in experimental murine models of acute lung injury and inflammation. The kinetics of lignan accumulation in blood, following 10% FS supplementation, was determined using liquid chromatography tandem mass spectrometry. Mice were fed isocaloric control and 10% FS-supplemented diets for at least 3 wk and challenged by hyperoxia (80% oxygen), intratracheal instillation of lipopolysaccharide, or acid aspiration. Bronchoalveolar lavage was evaluated for white blood cells, neutrophils, and proteins after a 24 h postintratracheal challenge of hydrochloric acid or lipopolysaccharide, or after 6 d of hyperoxia. Lung lipid peroxidation was assessed by tissue malondialdehyde concentrations. The plasma concentrations of the FS lignans, enterodiol and enterolactone, were stable after mice had eaten the diets for 2 wk. Following hyperoxia and acid aspiration, bronchoalveolar lavage neutrophils decreased in FS-supplemented mice (P = 0.012 and P = 0.027, respectively), whereas overall alveolar white blood cell influx tended to be lower (P = 0.11). In contrast, neither lung injury nor inflammation was ameliorated by FS following lipopolysaccharide instillation. Lung malondialdehyde levels were lower in hyperoxic mice than in unchallenged mice (P = 0.0001), and decreased with FS treatment following acid aspiration (P = 0.011). Dietary FS decreased lung inflammation and lipid peroxidation, suggesting a protective role against pro-oxidant-induced tissue damage in vivo.
Journal of Nutrition 07/2006; 136(6):1545-51. · 3.92 Impact Factor
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ABSTRACT: We examined small airway morphometry from resected lung specimens in 25 patients with severe emphysema undergoing lung volume reduction surgery (LVRS) and correlated their pathologic findings to changes in FEV(1) 6 months after LVRS. Patients were classified into two groups: responders had a more than 12% and a more than 200-ml change in FEV(1) at 6 months, and nonresponders had 12% or less and/or 200 ml or less change in FEV(1). Epithelial height (EH) and perimeters and areas of peribronchial smooth muscle, epithelium, and subepithelial space were measured quantitatively. The degrees of interstitial fibrosis, vascular sclerosis, goblet cell hyperplasia, squamous metaplasia, chronic inflammation, peribronchial fibrosis, and bullous disease were assessed semiquantitatively. Despite similar baseline characteristics, nonresponders had a greater EH (0.045 vs. 0.035 mm, p = 0.025), greater EH adjusted for basement membrane perimeter (0.040 vs. 0.011, p = 0.016), greater epithelial area adjusted for basement membrane area (0.561 vs. 0.499, p = 0.040), and less bullous disease (1.7 vs. 2.6, p = 0.011) compared with responders. We found a linear relationship between percentage change in FEV(1) and bullous disease and inverse relationships between percentage change in FEV(1) and interstitial fibrosis, goblet cell hyperplasia, peribronchial fibrosis, and vascular sclerosis. We conclude that small airway morphometry and lung histopathology in patients with severe emphysema have an important influence on changes in FEV(1) 6 months after LVRS.
American Journal of Respiratory and Critical Care Medicine 02/2005; 171(1):40-7. · 11.08 Impact Factor
