RESUMO
Background: There is need to understand biological markers and mechanisms in Gulf War illness (GWI). Goal: To examine whether and how eicosanoids - prostaglandins and leukotrienes - are altered in veterans with GWI. Methods: Seventy participants including 37 GWI and 33 healthy controls, shared exposure information, and had plasma eicosanoids assessed - prostaglandin F2 alpha (pgf2α), prostaglandin D2 (pgd2), leukotriene B4 (lb4) among others. Values were compared for GWI versus controls. Eicosanoid intercorrelations were compared in cases vs. controls. For the most significantly altered eicosanoid in GWI, exposure and symptom relations were assessed. Results: Prostaglandins and leukotrienes were depressed in GWI, strongest for pgf2α, then lb4. Eicosanoid intercorrelations differed in GWI vs. controls. Fuel-solvent, pesticide, radioactive chemicals and metal exposures related negatively to pgf2α; as, in GWI, did chemical attack and vaccines. Multivariate predictors included fuels-solvents and radioactive chemicals (negative); tetanus vaccine and herbicides (positive). Fuels-solvents and radioactive chemicals predicted lower pgf2α in cases, controls, and all participants controlled for case status. Lower pgf2α related to GWI "Kansas criteria" domains of pain, respiratory, and (borderline significantly) skin symptoms. Conclusion: Multiple eicosanoids are depressed in GWI, particularly pgf2α and lb4. Prior fuel-solvent exposures, radioactive chemicals, and (in GWI cases) vaccines were linked to lower pgf2α.
Assuntos
Leucotrienos/sangue , Síndrome do Golfo Pérsico/sangue , Prostaglandinas/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Dinoprosta/sangue , Feminino , Guerra do Golfo , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome do Golfo Pérsico/etiologia , Saúde dos VeteranosRESUMO
We employed our inhalation methodology to examine whether biomarkers of inflammation and oxidative stress would be produced in mice following inhalation of aerosols containing carbonaceous particles or the vapor of pesticides prevalent during the first Gulf War. Exposure to two putative Gulf War Illness toxins, fine airborne particles and the pesticide malathion, increased biomarkers of inflammation and oxidative stress in Friend virus B (FVB) female mice. Mice inhaling particles 24 h before had increased lung lavage and plasma Leukotriene B4 (LTB4) (a biomarker of inflammation) and PGF2α (a biomarker of oxidative stress) levels, lung lavage protein and lung lavage lactic dehydrogenase (LDH) levels. These changes were a function of particle density and exposure time. Compared to particle inhalation, mice inhaling malathion 24 h before had small increase in plasma LTB4 and PGF2α levels but no increase in lung lavage LTB4, lung lavage protein, lung lavage LDH, and lung lavage alveolar macrophage (AM) levels compared to unexposed control mice. AM from particle-exposed mice contained phagocytosed particles, while AM from malathion-exposed mice showed no abnormalities. Our results indicate that inhaling particles or malathion can alter inflammatory and oxidative biomarkers in mice and raise the possibility that these toxins may have altered inflammation and oxidative stress biomarkers in Gulf War-exposed individuals.
Assuntos
Aerossóis/toxicidade , Malation/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Administração por Inalação , Aerossóis/administração & dosagem , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar , Dinoprosta/análise , Dinoprosta/metabolismo , Exposição Ambiental/efeitos adversos , Feminino , Guerra do Golfo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Leucotrieno B4/análise , Leucotrieno B4/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Malation/administração & dosagem , Camundongos , Camundongos Endogâmicos , Tamanho da PartículaRESUMO
BACKGROUND: Glutamine (GLN) attenuates acute lung injury (ALI) but its effect on alveolar macrophages is unknown. We hypothesized that GLN pretreatment would induce the anti-inflammatory CD163/heme oxygenase (HO)-1/p38-MAPK dephosphorylation pathway in alveolar macrophages and reduce ALI in rats insufflated with interleukin-1 (IL-1) and lipopolysaccharide (LPS). METHODS: Male Sprague-Dawley rats were randomized to the following groups: GLN-IL-1/LPS-, GLN+IL-1/LPS-, GLN-IL-1/LPS+, and GLN+IL-1/LPS+. GLN pretreatment was given via gavage (1 g/kg L-alanyl-L-glutamine) daily for 2 days. ALI was subsequently induced by insufflating 50 ng IL-1 followed by 5mg/kg E.coli LPS. After 24h, bronchoalveolar lavage (BAL) protein, lactate dehydrogenase (LDH) and neutrophil concentrations were analyzed. BAL alveolar macrophage CD163+ expression, HO-1 and p38-MAPK concentrations were measured, as well as alveolar macrophage tumor necrosis factor (TNF)-α and interleukin (IL)-10 concentrations. Histology and immunofluorescence studies were also performed. RESULTS: Following IL-1/LPS insufflation, GLN pretreated rats had significantly decreased BAL protein and LDH concentrations, but not BAL neutrophil counts, compared to non-GLN pretreated rats. The number of alveolar macrophages and the number of CD163+ macrophages were significantly increased in GLN pretreated IL-1/LPS-insufflated rats compared to non-GLN pretreated, IL-1/LPS-insufflated rats. GLN pretreatment before IL-1/LPS also significantly increased HO-1 concentrations and dephosphorylated p38-MAPK levels but not cytokine levels in alveolar macrophages. Immunofluorescence localized CD163 and HO-1 in alveolar macrophages. CONCLUSION: Short-term GLN pretreatment activates the anti-inflammatory CD163/HO-1/p38-MAPK dephosphorylation pathway of alveolar macrophages and decreases capillary damage but not neutrophil recruitment in IL-1/LPS-insufflated rats.
Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Capilares/patologia , Glutamina/farmacologia , Heme Oxigenase-1/metabolismo , Interleucina-1/administração & dosagem , Lipopolissacarídeos/administração & dosagem , Macrófagos Alveolares/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Receptores de Superfície Celular/metabolismo , Lesão Pulmonar Aguda/prevenção & controle , Animais , Líquido da Lavagem Broncoalveolar , Glutamina/administração & dosagem , Macrófagos Alveolares/enzimologia , Macrófagos Alveolares/metabolismo , Fosforilação , Ratos , Ratos Sprague-DawleyRESUMO
Early detection and prevention is an important goal in acute respiratory distress syndrome research. We determined the concentration of the anti-inflammatory 15-deoxy-Δ(12,14)-prostaglandin-J2 (15d-PGJ2) and other components of the cyclopentenone prostaglandin cascade in relation to lung inflammation in cytokine (IL-1/LPS)-insufflated rats. We found that 15d-PGJ2 levels increase in the bronchoalveolar lavage (BAL) fluid of rats insufflated with cytokines 2 h before. BAL 15d-PGJ2 increases preceded neutrophil recruitment, lung injury, and oxidative stress in the lungs of cytokine-insufflated rats. 15d-PGJ2 was localized in alveolar macrophages that decreased following cytokine insufflation. 15d-PGJ2 may constitute an early biomarker of lung inflammation and may reflect an endogenous attempt to regulate ongoing inflammation in macrophages and elsewhere after cytokine insufflation.
Assuntos
Líquido da Lavagem Broncoalveolar/citologia , Macrófagos Alveolares/metabolismo , Infiltração de Neutrófilos/imunologia , Prostaglandina D2/análogos & derivados , Síndrome do Desconforto Respiratório/metabolismo , Animais , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/química , Contagem de Células , Citocinas/administração & dosagem , Inflamação , Insuflação , L-Lactato Desidrogenase/metabolismo , Lipopolissacarídeos , Pulmão/citologia , Pulmão/imunologia , Estresse Oxidativo , Prostaglandina D2/metabolismo , Ratos , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório/diagnósticoRESUMO
OBJECTIVE: The Acute Respiratory Distress Syndrome (ARDS), the most severe form of Acute Lung Injury (ALI), is a highly-fatal, diffuse non-cardiogenic edematous lung disorder. The pathogenesis of ARDS is unknown but lung inflammation and lung oxidative stress are likely contributing factors. Since no specific pharmacologic intervention exists for ARDS, our objective was to determine the effect of treatment with ergothioneine-a safe agent with multiple anti-inflammatory and antioxidant properties on the development of lung injury and inflammation in rats insufflated with cytokines found in lung lavages of ARDS patients. METHOD: Sprague-Dawley rats (3-10/group) were given 15 mg/kg or 150 mg/kg l-ergothioneine intravenously 1h before or 18 h after cytokine (IL-1 and IFNγ) insufflation. Lung injury (lavage LDH levels) and lung inflammation (lavage neutrophil numbers) were measured 24h after cytokine insufflation. RESULTS: Ergothioneine pre- and post-treatment generally decreased lung injury and lung inflammation in cytokine insufflated rats. CONCLUSION: Ergothioneine should be considered for additional testing as a potential therapy for treating and preventing ARDS.
Assuntos
Antioxidantes/farmacologia , Citocinas/administração & dosagem , Ergotioneína/farmacologia , Pneumonia/tratamento farmacológico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Citocinas/metabolismo , Ergotioneína/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório/fisiopatologiaRESUMO
Laudable supportive advances have been made to improve the care of patients with the Acute Respiratory Distress Syndrome (ARDS) but no pharmacologic interventions are known to reduce the high mortality of this disorder once it is established. This commentary discusses some of the challenges that arise in preventing ARDS in at-risk individuals and the likely dependence of this approach on biomarker panels that can be done in real time.
Assuntos
Síndrome do Desconforto Respiratório/prevenção & controle , Biomarcadores , Humanos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/mortalidade , Estados Unidos/epidemiologiaRESUMO
The protective effects of pharmacological inhibitors of xanthine oxidoreductase (XOR) have implicated XOR in many inflammatory diseases. Nonetheless, the role played by XOR during inflammation is poorly understood. We previously observed that inhibition of XOR within the inflammatory mononuclear phagocytes (MNP) prevented neutrophil recruitment during adoptive transfer demonstrating the role of XOR in MNP-mediated neutrophil recruitment. To further explore the role of XOR in the inflammatory state of MNP, we studied MNP isolated from inflammatory lungs combined with analyses of MNP cell lines. We demonstrated that XOR activity was increased in inflammatory MNP following insufflation of Th-1 cytokines in vivo and that activity was specifically increased by MNP differentiation. Inhibition of XOR reduced levels of CINC-1 secreted by MNP. Expression of peroxisome proliferator-activated receptor γ (PPARγ) in purified rat lung MNP and MNP cell lines reflected both the presence of PPARγ isoforms and PPARγ SUMOylation, and XOR inhibitors increased levels of SUMO-PPARγ in MNP cell lines. Both ectopic overexpression of XOR cDNA and uric acid supplementation reduced SUMO-PPARγ in MNP cells. Levels of the M2 markers CD36, CD206, and arginase-1 were modulated by uric acid and oxonic acid, whereas siRNA to SUMO-1 or PIAS-1 also reduced arginase-1 in RAW264.7 cells. We also observed that HIF-1α was increased by XOR inhibitors in inflammatory MNP and in MNP cell lines. These data demonstrate that XOR promotes the inflammatory state of MNP through effects on chemokine expression, PPARγ SUMOylation, and HIF-1α and suggest that strategies for inhibiting XOR may be valuable in modulating lung inflammatory disorders.
Assuntos
Quimiocinas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , PPAR gama/metabolismo , Fagócitos/imunologia , Pneumonia/imunologia , Xantina Desidrogenase/imunologia , Animais , Diferenciação Celular/imunologia , Quimiocina CXCL1/metabolismo , Ativação Enzimática/imunologia , Células HL-60 , Humanos , Masculino , Neutrófilos/imunologia , Fagócitos/citologia , Fagócitos/enzimologia , Pneumonia/metabolismo , Ratos , Ratos Sprague-Dawley , Sumoilação/imunologia , Células Th1/citologia , Células Th1/enzimologia , Células Th1/imunologia , Células U937 , Ácido Úrico/metabolismo , Xantina Desidrogenase/antagonistas & inibidores , Xantina Desidrogenase/metabolismoRESUMO
The negative impacts on human health that accompany inhalation of atmospheric particles are documented in numerous epidemiologic studies, but the effect of specific chemical properties of the particles is generally unknown. We developed and employed technology for generating inhalable aerosols of carbonaceous air pollution particles that have specific physical and chemical properties. We find that inhaling particles with greater unpaired electron spin (free radical) densities stimulates greater lung inflammatory and oxidative stress responses. Cultured alveolar macrophages take up more particles of greater free radical content, develop mitochondrial abnormalities, and release more leukotriene B(4) (LTB(4)) than alveolar macrophages exposed to lesser free-radical-containing particles in vitro. Mice exposed to high free radical particles in vivo also develop mitochondrial abnormalities in alveolar macrophages and increased oxidative stress, which is reflected by increases in lung nitrotyrosine staining and lung lavage nitrogen oxide levels compared with those of lesser free radical density. These results provide insight for the unexplained geographic differences and have implications for fossil fuel combustion conditions and the impact of fine particles on health and disease.
Assuntos
Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Material Particulado/toxicidade , Fuligem/toxicidade , Aerossóis , Animais , Líquido da Lavagem Broncoalveolar , Células Cultivadas , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Radicais Livres/análise , Radicais Livres/metabolismo , Exposição por Inalação , Leucotrieno B4/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Óxido Nítrico/metabolismo , Estresse Oxidativo , Material Particulado/administração & dosagem , Material Particulado/química , Fuligem/administração & dosagem , Fuligem/química , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMO
Hyperpolarized (hp) (83)Kr (spin I=9/2) is a promising gas-phase contrast agent that displays sensitivity to the surface chemistry, surface-to-volume ratio, and surface temperature of the surrounding environment. This proof-of-principle study demonstrates the feasibility of ex vivo hp (83)Kr magnetic resonance imaging (MRI) of lungs using natural abundance krypton gas (11.5% (83)Kr) and excised, but otherwise intact, rat lungs located within a custom designed ventilation chamber. Experiments comparing the (83)Kr MR signal intensity from lungs to that arising from a balloon with no internal structure inflated to the same volume with krypton gas mixture suggest that most of the observed signal originated from the alveoli and not merely the conducting airways. The (83)Kr longitudinal relaxation times in the rat lungs ranged from 0.7 to 3.7s but were reproducible for a given lung. Although the source of these variations was not explored in this work, hp (83)Kr T(1) differences may ultimately lead to a novel form of MRI contrast in lungs. The currently obtained 1200-fold signal enhancement for hp (83)Kr at 9.4T field strength is found to be 180 times below the theoretical upper limit.
Assuntos
Meios de Contraste/farmacocinética , Aumento da Imagem/métodos , Radioisótopos de Criptônio/farmacocinética , Pulmão/anatomia & histologia , Pulmão/metabolismo , Imageamento por Ressonância Magnética/métodos , Administração por Inalação , Animais , Radioisótopos de Criptônio/administração & dosagem , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Ferritin regulates iron levels and, for unknown reasons, serum ferritin concentrations are increased in patients at risk for and with acute lung injury (ALI) and multiple organ failure. Uncomplexed iron could exacerbate the toxicity of the increased oxidative stress that occurs in patients with ALI and multiple organ failure and thereby contribute to disease. In the present investigation, the authors found that serum and lung lavage ferritin concentrations increased in hemorrhaged rats that develop ALI as manifested by increased lung inflammation (increased lung lavage leukocyte counts and lung myeloperoxidase activities) and increased lung leak (increased lung lavage protein concentrations). Treatment with mepacrine, a phospholipase A2 inhibitor, attenuated the increases in serum and lung lavage ferritin concentrations, lung inflammation, and lung leak that occur in rats subjected to hemorrhage. The findings show that serum and lung ferritin levels increase and may play a role in the development of acute lung injury caused by hemorrhage.
Assuntos
Inibidores Enzimáticos/farmacologia , Ferritinas/sangue , Hemorragia/tratamento farmacológico , Quinacrina/farmacologia , Síndrome do Desconforto Respiratório/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Hemorragia/sangue , Hemorragia/imunologia , Leucócitos/imunologia , Masculino , Oxidantes/sangue , Pneumonia/sangue , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Ratos , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/imunologiaRESUMO
Acute lung injury (ALI) is characterized by increased alveolar cytokines, inflammatory cell infiltration, oxidative stress, and alveolar cell apoptosis. Previous work suggested that xanthine oxidoreductase (XOR) may contribute to oxidative stress in ALI as a product of the vascular endothelial cell. We present evidence that cytokine induced lung inflammation and injury involves activation of XOR in the newly recruited mononuclear phagocytes (MNP). We found that XOR was increased predominantly in the MNP that increase rapidly in the lungs of rats that develop ALI following intratracheal cytokine insufflation. XOR was recovered from the MNP largely converted to its oxygen radical generating, reversible O-form, and alveolar MNP exhibited increased oxidative stress as evidenced by increased nitrotyrosine staining. Cytokine insufflation also increased alveolar cell apoptosis. A functional role for XOR in cytokine-induced inflammation was demonstrated when feeding rats two different XOR inhibitors, tungsten and allopurinol, decreased MNP XOR induction, nitrotyrosine staining, inflammatory cell infiltration, and alveolar cell apoptosis. Transfer of control or allopurinol treated MNP into rat lungs confirmed a specific role for MNP XOR in promoting lung inflammation. These data indicate that XOR can contribute to lung inflammation by its expression and conversion in a highly mobile inflammatory cell population.