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1.
Med Sci Monit ; 25: 5690-5699, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31366881

RESUMO

BACKGROUND The aim of the present study was to investigate the protective effects of protease inhibitor MG-132 on sepsis-induced acute lung injury rats. MATERIAL AND METHODS Sprague Dawley rats were employed to induce sepsis by cecal ligation and puncture (CLP) method. Rats were divided into 4 groups: control, sham, model (CLP), and MG-132. Histopathology observation was detected by hematoxylin and eosin staining. The ratio of wet lung to dry lung (W/D) was calculated. In addition, the levels of inflammatory factors in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). Also, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were evaluated. Western blotting was performed to measure the expression of hypoxia-inducible factor-1 alpha (HIF-1alpha). In order to assess the role of HIF-1alpha, YC-1, the inhibitor of HIF-1alpha, was used to treat the rats. The expression of phosphor-mTOR (p-mTOR), p-4EBP1, and p-EIF4E were evaluated by western blotting. RESULTS Obvious pathological injury and increasing ratio of W/D in the model group were observed. Both pathological injury and W/D were improved in the MG-132 group, and the greatest improvement could be seen in the YC-1+MG-132 group. Furthermore, the MDA levels in the MG-132 group was decreased, accompanied by an increase in SOD levels. The level of HIF-1alpha was increased in the model group while a decreased was detected in the MG-132 group. The levels of inflammatory factors were high in the model group, whereas the opposite result was found in the MG-132 group, and the lowest in were in the YC-1+MG-132 group. Furthermore, the expression levels of p-mTOR, p-4EBP1, and p-EIF4E proteins were downregulated in the MG-132 group compared to the model group, and the lowest was in the YC-1+MG-132 group. CONCLUSIONS Our study suggested that MG-132 was able to protect against acute lung injury via inhibition of HIF-1alpha mediated mTOR/4EBP1/EIF4E pathway.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Leupeptinas/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar , China , Fator de Iniciação 4E em Eucariotos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pulmão/patologia , Malondialdeído/metabolismo , Edema Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Superóxido Dismutase/metabolismo , Serina-Treonina Quinases TOR/metabolismo
2.
Life Sci ; 229: 132-138, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31100325

RESUMO

AIMS: HAPE remains the most common lethal high-altitude disease. Although its pathophysiology and other associated causal factors have been partially uncovered along with some potential biomarker proteins, it has not been completely elucidated. A major hindrance to improving the understanding of HAPE pathophysiology and associated molecular events has been the absence of a quick, reliable and definitive animal model of HAPE. This study is aimed at development of a rapid and reliable SD rat model of high altitude pulmonary edema (HAPE) that can be roentgenographically confirmed and be used to study protein markers of HAPE. MAIN METHODS: In this study, we detail the process of rapidly inducing HAPE in male SD rats within 18 h of simulated high-altitude exposure without causing high rates of mortality. Thereafter, we confirmed HAPE using roentgenography. We assessed Sulfotransferase 1A1 (SULT1A1), IL-1 beta, TNF- alpha and IFN-gamma using ELISA. Finally, H&E staining of lung tissues was also performed. KEY FINDINGS: A roentgenographically confirmed HAPE model was demonstrated. SULT 1A1 levels are found to be highest in rats suffering HAPE, as previously confirmed in human patients. Inflammation was also assessed based on levels of inflammatory proteins like IL-1b, TNF-a, and IFN-g in addition to H&E staining of lung tissues. Inflammation and HAPE were observed to be synergistic events and not cause and effect of each other. SIGNIFICANCE: This rat model of HAPE will help researchers and clinicians in evaluating performance of therapies, potential biomarker and also further elucidate underlying molecular processes causing HAPE.


Assuntos
Altitude , Arilsulfotransferase/metabolismo , Biomarcadores/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/diagnóstico , Edema Pulmonar/diagnóstico , Animais , Humanos , Inflamação/diagnóstico por imagem , Inflamação/metabolismo , Masculino , Edema Pulmonar/diagnóstico por imagem , Edema Pulmonar/metabolismo , Radiografia , Ratos , Ratos Sprague-Dawley
3.
J Biochem Mol Toxicol ; 33(7): e22332, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30974023

RESUMO

Alpha-naphthylthiourea (ANTU), a rodenticide induces lung toxicity. Chrysin a flavonoid possesses antioxidant, anti-inflammatory, and antihypertensive potential. The aim of this study was to evaluate the efficacy of chrysin against ANTU-induced pulmonary edema (PE) and pulmonary arterial hypertension (PAH) in laboratory rats. Sprague-Dawley rats were used to induce PE (ANTU, 10 mg/kg, ip) and PAH (ANTU, 5 mg/kg, ip, 4 weeks). Animals were treated with chrysin (10, 20, and 40 mg/kg) and various biochemical, molecular, and histological parameters were evaluated. Acute administration of ANTU induces PE revealed by significant (P < 0.05) increase in relative lung weight, pleural effusion volume, lung edema, bronchoalveolar lavage fluid cell counts, total protein, 5-hydroxytryptamine (5-HT), lactate dehydrogenase (LDH), and γ-glutamyl transferase (GGT), whereas pretreatment with chrysin (20 and 40 mg/kg, ip) significantly (P < 0.05) attenuated these ANTU-induced biochemical and histological alterations. Repeated administration of ANTU caused induction of PAH evaluated by significant (P < 0.05) alterations in electrocardiographic, hemodynamic changes, and left ventricular function, whereas chrysin (20 and 40 mg/kg, p.o.) treatment significantly (P < 0.05) attenuated these alterations. ANTU-induced hematological and serum biochemical (aspartate transaminase, alanine transaminase, LDH, and creatinine kinase MB) alterations were significantly (P < 0.05) inhibited by chrysin. It also significantly (P < 0.05) decreased elevated levels of oxido-nitrosative stress in the right ventricle (RV) and lung. Chrysin significantly (P < 0.05) attenuated downregulated endothelial nitric oxide synthase and upregulated vascular endothelial growth factor messenger RNA and protein expressions both in the RV and pulmonary artery. Chrysin inhibited ANTU-induced PE and PAH via modulation of inflammatory responses (5-HT, LDH, and GGT), oxido-nitrosative stress, and VEGF and eNOs levels.


Assuntos
Flavonoides/farmacologia , Hipertensão Pulmonar , Óxido Nítrico Sintase Tipo III/biossíntese , Edema Pulmonar , Tioureia/análogos & derivados , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/prevenção & controle , Pulmão/metabolismo , Pulmão/patologia , Masculino , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Edema Pulmonar/prevenção & controle , Ratos , Ratos Sprague-Dawley , Tioureia/efeitos adversos , Tioureia/farmacologia
4.
Drug Deliv ; 26(1): 147-157, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30822171

RESUMO

Hypoxic pulmonary vasoconstriction (HPV) is a well-characterized vascular response to low oxygen pressures and is involved in life-threatening conditions such as high-altitude pulmonary edema (HAPE) and pulmonary arterial hypertension (PAH). While the efficacy of oral therapies can be affected by drug metabolism, or dose-limiting systemic toxicity, inhaled treatment via pressured metered dose inhalers (pMDI) may be an effective, nontoxic, practical alternative. We hypothesized that a stable water-in-perfluorooctyl bromide (PFOB) emulsion that provides solubility in common pMDI propellants, engineered for intrapulmonary delivery of pulmonary vasodilators, reverses HPV during acute hypoxia (HX). Male Sprague Dawley rats received two 10-min bouts of HX (13% O2) with 20 min of room air and drug application between exposures. Treatment groups: intrapulmonary delivery (PUL) of (1) saline; (2) ambrisentan in saline (0.1 mg/kg); (3) empty emulsion; (4) emulsion encapsulating ambrisentan or sodium nitrite (NaNO2) (0.1 and 0.5 mg/kg each); and intravenous (5) ambrisentan (0.1 mg/kg) or (6) NaNO2 (0.5 mg/kg). Neither PUL of saline or empty emulsion, nor infusions of drugs prevented pulmonary artery pressure (PAP) elevation (32.6 ± 3.2, 31.5 ± 1.2, 29.3 ± 1.8, and 30.2 ± 2.5 mmHg, respectively). In contrast, PUL of aqueous ambrisentan and both drug emulsions reduced PAP by 20-30% during HX, compared to controls. IL6 expression in bronchoalveolar lavage fluid and whole lung 24 h post-PUL did not differ among cohorts. We demonstrate proof-of-concept for delivering pulmonary vasodilators via aerosolized water-in-PFOB emulsion. This concept opens a potentially feasible and effective route of treating pulmonary vascular pathologies via pMDI.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Fluorcarbonetos/administração & dosagem , Hipertensão Pulmonar/tratamento farmacológico , Edema Pulmonar/tratamento farmacológico , Água/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsões/metabolismo , Fluorcarbonetos/metabolismo , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/metabolismo , Masculino , Fenilpropionatos/administração & dosagem , Fenilpropionatos/metabolismo , Circulação Pulmonar/efeitos dos fármacos , Circulação Pulmonar/fisiologia , Edema Pulmonar/diagnóstico por imagem , Edema Pulmonar/metabolismo , Piridazinas/administração & dosagem , Piridazinas/metabolismo , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Água/metabolismo
5.
Life Sci ; 222: 22-28, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30822427

RESUMO

AIMS: Increases in hydrostatic pressure results in endothelial hyperpermeability via eNOS-dependent pathways. Ropivacaine is known to inhibit eNOS activation and to attenuate lung injury. Herein, we sought to determine if ropivacaine regulates pressure-induced lung endothelial hyperpermeability. MAIN METHODS: The effects of ropivacaine on lung permeability were assessed in two models of acute hypertension (AH): the isolated perfused lung preparation where acute increases in left atrial pressure model the hemodynamic changes of severe hypertension, and an animal model of AH induced by norepinephrine. In the IPL model, whole lung filtration coefficient (Kf) was used as the index of lung permeability; pulmonary artery pressure (Ppa), pulmonary capillary pressures (Ppc), and zonal characteristics (ZC) were measured to assess the effects of ropivacaine on hemodynamics and their relationship to Kf2/Kf1. In vivo, ropivacaine effects were investigated on indices of pulmonary edema (changes in PaO2, lung wet-to-dry ratio), changes in plasma volume and nitric oxide (NO) production. KEY FINDINGS: Ropivacaine provided robust protection from pressure-dependent barrier failure; it inhibited pressure-induced increases in Kf without affecting Ppa, Ppc or ZC. In vivo, ropivacaine prevented pressure-induced lung edema and associated hyperpermeability as evidence by maintaining PaO2, lung wet-to-dry ratio and plasma volume in levels similar to sham rats. Ropivacaine inhibited pressure-induced NO production as evidenced by decreased lung nitro-tyrosine content when compared to hypertensive lungs. SIGNIFICANCE: Collectively these data show that ropivacaine inhibits pressure-induced lung endothelial hyperpermeability and suggest that ropivacaine may be a clinically useful agent to prevent endothelial hyperpermeability when pulmonary pressure is acutely increased.


Assuntos
Permeabilidade Capilar/fisiologia , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Hipertensão/metabolismo , Edema Pulmonar/metabolismo , Ropivacaina/uso terapêutico , Doença Aguda , Anestésicos Locais/farmacologia , Anestésicos Locais/uso terapêutico , Animais , Permeabilidade Capilar/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Lesão Pulmonar/fisiopatologia , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Ropivacaina/farmacologia
6.
Life Sci ; 221: 56-64, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30726711

RESUMO

AIMS: The herbicide paraquat causes fatal lung toxicity by induction of xanthine oxidase, production of free radicals and inflammation. Febuxostat, a xanthine oxidase inhibitor and anti-gout has recently shown anti-inflammatory activity. Accordingly, this study was carried out to investigate whether febuxostat may attenuate paraquat-induced lung toxicity and to explore the possible underlying mechanisms. MAIN METHODS: Rats were administered either vehicle, a single dose of paraquat (30 mg/kg, i.p.), febuxostat (15 mg/kg, oral), or both for 14 successive days. Serum LDH and sRAGE were estimated. Lung tissue xanthine oxidase activity, SOD, TAC, MDA, and RAGE, HMGB1 gene expression, PI3K/Akt and ß-catenin protein expression, MMP-9, IL-8, VEGF and COX-2 gene expression were estimated. KEY FINDINGS: Results showed that paraquat induced lung injury characterized by enhanced oxidative stress and inflammation, upregulated RAGE, HMGB1 gene expression, PI3K/Akt and ß-catenin protein expression. Administration of febuxostat inhibited the deleterious effects of paraquat on lung through inhibition of xanthine oxidase activity and related oxidative stress, downregulation of RAGE/PI3K/Akt pathway, and suppression of ß-catenin protein expression and its downstream inflammatory mediators. SIGNIFICANCE: The present study showed that febuxostat may abrogate paraquat-induced lung toxicity and demonstrated a novel mechanism for its ameliorative effects.


Assuntos
Febuxostat/metabolismo , Febuxostat/farmacologia , Edema Pulmonar/tratamento farmacológico , Animais , Inflamação/metabolismo , Pulmão , Lesão Pulmonar/induzido quimicamente , Masculino , Estresse Oxidativo , Paraquat/farmacologia , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Edema Pulmonar/metabolismo , Ratos , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/efeitos dos fármacos , Xantina Oxidase , beta Catenina/efeitos dos fármacos
7.
Clin Sci (Lond) ; 133(2): 321-334, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30622219

RESUMO

Acute respiratory distress syndrome (ARDS) in a deadly disease that can be brought on by endotoxins such as lipopolysaccharide (LPS). ARDS is characterized by vascular permeability, a severe inflammatory response, lung leukocyte infiltration, and resultant lung edema. Polymerase δ-interacting protein 2 (Poldip2) is a novel regulator of blood-brain barrier permeability; however, its role in regulating lung permeability and vascular inflammation is unknown. Here, the role of Poldip2 in regulating vascular permeability and inflammation in a mouse model of ARDS was assessed. Heterozygous deletion of Poldip2 was found to reduce LPS-induced mortality within 20 h, lung inflammatory signaling, and leukocyte infiltration. Moreover, reduced Poldip2-suppressed LP-induced vascular cell adhesion molecule (VCAM)-1 induction, leukocyte recruitment, and mitochondrial reactive oxygen species (ROS) production in vitro These data indicate that Poldip2 is an important regulator of the debilitating consequences of ARDS, potentially through the regulation of mitochondrial ROS-induced inflammatory signaling. Consequently, inhibition of Poldip2 may be a viable option for therapeutic discovery moving forward.


Assuntos
Permeabilidade Capilar , Células Endoteliais/metabolismo , Pulmão/irrigação sanguínea , Proteínas Mitocondriais/deficiência , Proteínas Nucleares/deficiência , Edema Pulmonar/prevenção & controle , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Vasculite/prevenção & controle , Animais , Adesão Celular , Técnicas de Cocultura , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Edema Pulmonar/genética , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Síndrome do Desconforto Respiratório do Adulto/genética , Síndrome do Desconforto Respiratório do Adulto/patologia , Transdução de Sinais , Células THP-1 , Molécula 1 de Adesão de Célula Vascular/metabolismo , Vasculite/genética , Vasculite/metabolismo , Vasculite/patologia
8.
FASEB J ; 33(2): 2599-2609, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30281335

RESUMO

Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., Renné, T., Vieira, M. L., Müller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.


Assuntos
Permeabilidade da Membrana Celular , Endotélio Vascular/fisiologia , Inflamação/patologia , Sistema Calicreína-Cinina/fisiologia , Neutrófilos/metabolismo , Edema Pulmonar/patologia , Animais , Bradicinina/metabolismo , Endotélio Vascular/citologia , Fator XII/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Cininogênio de Alto Peso Molecular/metabolismo , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Edema Pulmonar/etiologia , Edema Pulmonar/metabolismo
9.
Drug Des Devel Ther ; 13: 71-77, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30587929

RESUMO

Background: The aim of this study was to investigate the bioactive constituents of Qingwen Baidu Decoction (QBD) in a rat model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Our previous studies showed that ethyl gallate (EG) and pentagalloylglucose (PGG) were the active components of QBD for the treatment of ALI. Materials and methods: We isolated two compounds and identified the structures of them by nuclear magnetic resonance and mass spectrometer. Lung injury was induced by intratracheal instillation with LPS (5 mg/kg). Rats were randomly divided into six groups: Control group; LPS group; 5 mL/kg DEX + LPS group; 6.6 g/kg QBD extract + LPS group; 17.16 mg/kg PGG + LPS group; 7.26 mg/kg EG + LPS group. The effects of compounds on LPS-induced the number of total cells, neutrophils influx, protein leakage, W/D weight ratio and pulmonary histological changes were examined. Results: The results demonstrated that pretreatment with EG and PGG could notably inhibit lung edema and attenuate the pulmonary histological changes (P<0.05). The pretreatment also decreased the number of total cells and polymorphonuclear leukocytes in bronchoalveolar lavage fluid (BALF) (P<0.05). Conclusion: Ethyl gallate and pentagalloylglucose of QBD played a protective role in preventing LPS-induced ALI. The results supported further study of EG and PGG as potential candidates for preventing ALI.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Ácido Gálico/análogos & derivados , Taninos Hidrolisáveis/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Ácido Gálico/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Edema Pulmonar/prevenção & controle , Ratos Sprague-Dawley
10.
Life Sci ; 218: 38-46, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30571954

RESUMO

AIMS: In the present study, we aimed to evaluate the role of aspirin-triggered resolvin D1 (AT-RvD1) in paraquat (PQ)-induced acute lung injury (ALI) in mice. MAIN METHODS: We used C57BL/6J mice as experimental subjects to establish mouse models of ALI via intraperitoneal (IP) injection of PQ (28 mg/kg). The mice were then administered AT-RvD1 (10 or 100 ng) via the tail vein 2 h after exposure to PQ and were sacrificed at 72 h post exposure to harvest bronchoalveolar lavage fluid (BALF), blood and lung tissue samples. The samples were used to evaluate the histopathological changes, inflammation reaction and oxidative stress in the lung tissues. KEY FINDINGS: Compared with those of the PQ group, the administration of AT-RvD1 significantly (1) alleviated the histopathological changes in the lung tissues; (2) reduced the lung W/D weight ratio and the total protein content in the BALF; (3) activated nuclear factor erythroid-2 related factor 2 (Nrf2) and up-regulated the expression of its downstream genes (NADPH: quinone oxidoreductase-1, NQO1 and heme oxygenase-1, HO-1); (4) reduced the malondialdehyde(MDA) level in the lung tissues; (5) reduced the total cell, neutrophil, and macrophage counts in the BALF; (6) reduced the myeloperoxidase (MPO) activity in the lung tissues; (7) reduced the percent of Ly-6G+ CD41+ cells in the peripheral blood; (8) inhibited the activation of nuclear factor-κB (NF-κB) and the expression of P-selectin; and (9) reduced interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) levels in the BALF. SIGNIFICANCE: Administration of AT-RvD1 can effectively inhibit PQ-induced oxidative stress injury, inflammatory responses, and pulmonary edema, thereby alleviating PQ-induced ALI.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Aspirina/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/prevenção & controle , Paraquat/toxicidade , Edema Pulmonar/prevenção & controle , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Citocinas/metabolismo , Herbicidas/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo
11.
Toxicol Lett ; 302: 60-74, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30447258

RESUMO

BACKGROUND: Fine ambient particle matter (PM2.5) induces inflammatory lung injury; however, whether intratracheal administration of PM2.5 increases pulmonary polymorphonuclear leukocyte (PMN) infiltration, the mechanism of infiltration, and if these cells exacerbate PM2.5-induced lung injury are unknown. METHODS: Using 32,704 subjects, the association between blood PMNs and ambient PM2.5 levels on the previous day was retrospectively analyzed. Neutropenia was achieved by injecting mice with PMN-specific antibodies. Inhibition of PMN infiltration was achieved by pretreating PMNs with soluble vascular cell adhesion molecule-1 (sVCAM-1). The effects of PMNs on PM2.5-induced lung injury and endothelial dysfunction were observed. RESULT: Short-term PM2.5 (> 75 µg/m3 air) exposure increased the PMN/white blood cell ratio and the PMN count in human peripheral blood observed during routine examination. A significant number of PM2.5-treated PMNs was able to bind sVCAM-1. In mice, intratracheally-instilled PM2.5 deposited in the alveolar space and endothelial cells, which caused significant lung edema, morphological disorder, increased permeability of the endothelial-alveolar epithelial barrier, and PMN infiltration with increased VCAM-1 expression. Depletion of circulatory PMNs inhibited these adverse effects. Replenishment of untreated PMNs, but not those pretreated with soluble VCAM-1, restored lung injury. In vitro, PM2.5 increased VCAM-1 expression and endothelial and epithelial monolayer permeability, and promoted PMN adhesion to, chemotaxis toward, and migration across these monolayers. PMNs, but not those pretreated with soluble VCAM-1, exacerbated these effects. CONCLUSION: VCAM-1-mediated PMN infiltration was essential for a detrimental cycle of PM2.5-induced inflammation and lung injury. Results suggest that drugs that inhibit PMN function might prevent acute deterioration of chronic pulmonary and cardiovascular diseases triggered by PM2.5.


Assuntos
Lesão Pulmonar/induzido quimicamente , Pulmão/metabolismo , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Material Particulado , Edema Pulmonar/induzido quimicamente , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Permeabilidade Capilar , Adesão Celular , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neutropenia/imunologia , Neutropenia/metabolismo , Neutropenia/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Tamanho da Partícula , Edema Pulmonar/imunologia , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Estudos Retrospectivos , Molécula 1 de Adesão de Célula Vascular/imunologia , Adulto Jovem
12.
Biomed Res Int ; 2018: 4608150, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30515398

RESUMO

High-mountain sickness is characterized by brain and pulmonary edema and cognitive deficits. The definition can be fulfilled by a rat model of high-altitude exposure (HAE) used in the present study. This study aimed to investigate the protective effect of hyperbaric oxygen therapy (HBO2T) and to determine the underlying mechanisms. Rats were subjected to an HAE (9.7% O2 at 0.47 absolute atmosphere of 6,000 m for 3 days). Immediately after termination of HAE, rats were treated with HBO2T (100% O2 at 2.0 absolute atmosphere for 1 hour per day for 5 consecutive days) or non-HBO2T (21% O2 at 1.0 absolute atmosphere for 1 hour per day for 5 consecutive days). As compared to non-HAE+non-HBO2T controls, the HAE+non-HBO2T rats exhibited brain edema and resulted in cognitive deficits, reduced food and water consumption, body weight loss, increased cerebral inflammation and oxidative stress, and pulmonary edema. HBO2T increased expression of both hippocampus and lung heat shock protein (HSP-70) and also reversed the HAE-induced brain and pulmonary edema, cognitive deficits, reduced food and water consumption, body weight loss, and brain inflammation and oxidative stress. Decreasing the overexpression of HSP-70 in both hippocampus and lung tissues with HSP-70 antibodies significantly attenuated the beneficial effects exerted by HBO2T in HAE rats. Our data provide in vivo evidence that HBO2T works on a remodeling of brain/lung to exert a protective effect against simulated high-mountain sickness via enhancing HSP-70 expression in HAE rats.


Assuntos
Doença da Altitude/terapia , Disfunção Cognitiva/terapia , Proteínas de Choque Térmico HSP70/genética , Oxigenação Hiperbárica , Edema Pulmonar/terapia , Altitude , Doença da Altitude/genética , Doença da Altitude/metabolismo , Animais , Anticorpos/administração & dosagem , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Encefalite/metabolismo , Encefalite/fisiopatologia , Encefalite/terapia , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/uso terapêutico , Edema Pulmonar/genética , Edema Pulmonar/metabolismo , Edema Pulmonar/fisiopatologia , Ratos
13.
Can J Physiol Pharmacol ; 96(12): 1261-1267, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30326195

RESUMO

Acute lung injury (ALI) is the leading cause of mortality in the intensive care unit. Currently, there is no effective pharmacological treatment for ALI. In our previous study, we reported that Lg25 and Lg26, two indole-2-carboxamide derivatives, inhibited the lipopolysaccharide (LPS)-induced inflammatory cytokines in vitro and attenuated LPS-induced sepsis in vivo. In the present study, we confirmed data from previous studies that LPS significantly induced pulmonary edema and pathological changes in lung tissue, increased protein concentration and number of inflammatory cells in bronchoalveolar lavage fluids (BALF), and increased inflammatory cytokine TNF-α expression in serum and BALF, pro-inflammatory genes expression, and macrophages infiltration in lung tissue. However, pretreatment with Lg25 and Lg26 significantly attenuated the LPS-induced changes in mice. Taken together, these data indicate that the newly discovered indole-2-carboxamide derivatives could be particularly useful in the treatment of inflammatory diseases such as ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Amidas/farmacologia , Indóis/farmacologia , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/metabolismo
14.
Biosci Rep ; 38(6)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30355657

RESUMO

Aims: Acute increases in left ventricular end diastolic pressure (LVEDP) can induce pulmonary edema (PE). The mechanism(s) for this rapid onset edema may involve more than just increased fluid filtration. Lung endothelial cell permeability is regulated by pressure-dependent activation of nitric oxide synthase (NOS). Herein, we demonstrate that pressure-dependent NOS activation contributes to vascular failure and PE in a model of acute heart failure (AHF) caused by hypertension.Methods and results: Male Sprague-Dawley rats were anesthetized and mechanically ventilated. Acute hypertension was induced by norepinephrine (NE) infusion and resulted in an increase in LVEDP and pulmonary artery pressure (Ppa) that were associated with a rapid fall in PaO2, and increases in lung wet/dry ratio and injury scores. Heart failure (HF) lungs showed increased nitrotyrosine content and ROS levels. L-NAME pretreatment mitigated the development of PE and reduced lung ROS concentrations to sham levels. Apocynin (Apo) pretreatment inhibited PE. Addition of tetrahydrobiopterin (BH4) to AHF rats lung lysates and pretreatment of AHF rats with folic acid (FA) prevented ROS production indicating endothelial NOS (eNOS) uncoupling.Conclusion: Pressure-dependent NOS activation leads to acute endothelial hyperpermeability and rapid PE by an increase in NO and ROS in a model of AHF. Acute increases in pulmonary vascular pressure, without NOS activation, was insufficient to cause significant PE. These results suggest a clinically relevant role of endothelial mechanotransduction in the pathogenesis of AHF and further highlights the concept of active barrier failure in AHF. Therapies targetting the prevention or reversal of endothelial hyperpermeability may be a novel therapeutic strategy in AHF.


Assuntos
Insuficiência Cardíaca/enzimologia , Hipertensão Pulmonar/enzimologia , Mecanotransdução Celular , Óxido Nítrico Sintase/genética , Edema Pulmonar/enzimologia , Animais , Biopterina/administração & dosagem , Biopterina/análogos & derivados , Pressão Sanguínea/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Ácido Fólico/administração & dosagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Norepinefrina/efeitos adversos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Tirosina/administração & dosagem , Tirosina/análogos & derivados
15.
Cell Tissue Res ; 374(1): 137-148, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29869715

RESUMO

The triggering receptor expressed by myeloid cells-1 (TREM-1) plays an important role in infectious and autoimmune diseases but how it contributes to ventilation-induced lung injury (VILI) and inflammation is unclear. Here, we examine the possibility that TREM-1 activates signaling dependent on Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and nuclear factor (NF)-κB, which leads in turn to VILI. In a mouse model of VILI, which we validated based on lung edema and histopathology as well as cytokine levels, we examine mRNA and protein levels of TREM-1, TLR4, MyD88, NF-κB and its inhibitory protein I-κB in animals subjected to ventilation at normal or high tidal volume. The extent of lung edema, injury and inflammation were higher in the high tidal volume animals, as were the expression levels of all proteins examined. Treatment with TREM-1 agonist aggravated these effects, whereas treatment with TREM-1 antagonist attenuated them. Our results suggest that aggravation of VILI by TREM-1 in mice may be associated with TLR4-MyD88-NF-κB-dependent signaling.


Assuntos
Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Pneumonia/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Pneumonia/etiologia , Pneumonia/patologia , Edema Pulmonar/etiologia , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Respiração Artificial/efeitos adversos , Transdução de Sinais , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia
16.
Biochem Biophys Res Commun ; 503(1): 94-101, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-29852175

RESUMO

Paraquat (PQ) is one of the most extensively used herbicides, possessing high toxicity for humans and animals. The lung is the main target organ by the poisoning of PQ resulting in acute lung injury. Nonetheless, molecular mechanisms underlying PQ-induced lung injury remain unclear. Here, we ask if angiopoietin-like protein 2 (Angptl2), a pro-inflammatory protein, contributes to inflammation that accelerates acute lung injury. The results indicated that abundant Angptl2 expression was observed in lung tissues of PQ-treated mice. Histological analysis revealed that PQ-induced histological changes were alleviated by Angptl2 knockout (Angptl2-/-). Angptl2-/- in PQ-treated mice attenuated acute lung injury progression by reducing the number of total cells, total leukocytes, neutrophils and macrophages in bronchoalveolar lavage fluid (BALF) and reducing inflammatory response through the inactivation of nuclear factor kappa B (NF-κB) pathway. Angptl2-/- reduced oxidative stress in PQ-treated mice, as evidenced by the enhanced superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) levels in serum or lung tissue samples, which was accompanied with increased expressions of nuclear respiratory factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1). PQ-induced fibrosis was also improved in Angptl2-/- mice by decreasing pulmonary transforming growth factor (TGF)-ß1 expressions. In vitro, we found that Angptl2 knockdown-suppressed inflammation, oxidative stress and fibrosis was restored by increasing NF-κB activation in PQ-incubated A549 cells; however, the results above were significantly reversed by inactivating NF-κB using its inhibitor, Bay 11-7085 or LY2409881. Therefore, Angptl2 could provide therapeutic effects on PQ-induced acute lung injury through inhibiting inflammation, oxidative stress and fibrosis by regulating NF-κB pathway.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Proteínas Semelhantes a Angiopoietina/deficiência , NF-kappa B/metabolismo , Edema Pulmonar/prevenção & controle , Células A549 , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Proteínas Semelhantes a Angiopoietina/genética , Proteínas Semelhantes a Angiopoietina/metabolismo , Animais , Técnicas de Silenciamento de Genes , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle , Transdução de Sinais
17.
Inhal Toxicol ; 30(4-5): 178-186, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29947284

RESUMO

Apelin has cardiopulmonary protective properties that promote vasodilation and maintenance of the endothelial barrier. While reductions in apelin have been identified as a contributor to various lung diseases, including pulmonary edema, its role in the effect of air pollutants has not been examined. Thus, in the current study, we sought to investigate if apelin is a downstream target of inhaled ozone and if such change in expression is related to altered DNA methylation in the lung. Male, Long-Evans rats were exposed to filtered air or 1.0 ppm ozone for 4 h. Ventilation changes were assessed using whole-body plethysmography immediately following exposure, and markers of pulmonary edema and inflammation were assessed in the bronchoaveolar lavage (BAL) fluid. The enzymatic regulators of DNA methylation were measured in the lung, along with methylation and hydroxymethylation of the apelin promoter. Data showed that ozone exposure was associated with increased enhanced pause and protein leakage in the BAL fluid. Ozone exposure reduced DNA cytosine-5-methyltransferase (DNMT) activity and Dnmt3a/b gene expression. Exposure-induced upregulation of proliferating cell nuclear antigen, indicative of DNA damage, repair, and maintenance methylation. Increased methylation and reduced hydroxymethylation were measured on the apelin promoter. These epigenetic modifications accompanied ozone-induced reduction of apelin expression and development of pulmonary edema. In conclusion, epigenetic regulation, specifically increased methylation of the apelin promoter downstream of DNA damage, may lead to reductions in protective signaling of the apelinergic system, contributing to the pulmonary edema observed following the exposure to oxidant air pollution.


Assuntos
Apelina/genética , Dano ao DNA , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Exposição por Inalação , Pulmão/efeitos dos fármacos , Ozônio/toxicidade , Edema Pulmonar/induzido quimicamente , Animais , Apelina/metabolismo , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Regiões Promotoras Genéticas , Edema Pulmonar/genética , Edema Pulmonar/metabolismo , Edema Pulmonar/fisiopatologia , Ventilação Pulmonar/efeitos dos fármacos , Ratos Long-Evans
18.
Am J Physiol Lung Cell Mol Physiol ; 315(2): L301-L312, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29745255

RESUMO

Ischemia-reperfusion (I/R) injury (IRI), which involves inflammation, vascular permeability, and edema, remains a major challenge after lung transplantation. Pannexin-1 (Panx1) channels modulate cellular ATP release during inflammation. This study tests the hypothesis that endothelial Panx1 is a key mediator of vascular inflammation and edema after I/R and that IRI can be blocked by Panx1 antagonism. A murine hilar ligation model of IRI was used whereby left lungs underwent 1 h of ischemia and 2 h of reperfusion. Treatment of wild-type mice with Panx1 inhibitors (carbenoxolone or probenecid) significantly attenuated I/R-induced pulmonary dysfunction, edema, cytokine production, and neutrophil infiltration versus vehicle-treated mice. In addition, VE-Cad-CreERT2+/Panx1fl/fl mice (tamoxifen-inducible deletion of Panx1 in vascular endothelium) treated with tamoxifen were significantly protected from IRI (reduced dysfunction, endothelial permeability, edema, proinflammatory cytokines, and neutrophil infiltration) versus vehicle-treated mice. Furthermore, extracellular ATP levels in bronchoalveolar lavage fluid is Panx1-mediated after I/R as it was markedly attenuated by Panx1 antagonism in wild-type mice and by endothelial-specific Panx1 deficiency. Panx1 gene expression in lungs after I/R was also significantly elevated compared with sham. In vitro experiments demonstrated that TNF-α and/or hypoxia-reoxygenation induced ATP release from lung microvascular endothelial cells, which was attenuated by Panx1 inhibitors. This study is the first, to our knowledge, to demonstrate that endothelial Panx1 plays a key role in mediating vascular permeability, inflammation, edema, leukocyte infiltration, and lung dysfunction after I/R. Pharmacological antagonism of Panx1 activity may be a novel therapeutic strategy to prevent IRI and primary graft dysfunction after lung transplantation.


Assuntos
Conexinas/metabolismo , Células Endoteliais/metabolismo , Pulmão/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Edema Pulmonar/metabolismo , Traumatismo por Reperfusão/metabolismo , Vasculite/metabolismo , Animais , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/genética , Carbenoxolona/farmacologia , Conexinas/genética , Modelos Animais de Doenças , Células Endoteliais/patologia , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Probenecid/farmacologia , Edema Pulmonar/dietoterapia , Edema Pulmonar/genética , Edema Pulmonar/patologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Vasculite/tratamento farmacológico , Vasculite/genética , Vasculite/patologia
19.
Am J Physiol Lung Cell Mol Physiol ; 315(3): L432-L442, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29722565

RESUMO

Because of the expansion of aging and smoking populations, chronic obstructive pulmonary disease (COPD) is predicted to be the third leading cause of death worldwide in 2030. Therefore, it is pertinent to develop effective therapy to improve management for COPD. Cigarette smoke-mediated protease-antiprotease imbalance is a major pathogenic mechanism for COPD and results in massive pulmonary infiltration of neutrophils and macrophages, releasing excessive neutrophil elastase (NE) and matrix metalloproteinases (MMPs). Our previous studies indicated that placenta growth factor (PGF) and PGF-triggered downstream signaling molecules mediate NE-induced lung epithelial cell apoptosis, which is a major pathogenic mechanism for pulmonary emphysema. However, the relationship between MMP-directed COPD and PGF remains elusive. We hypothesize that MMPs may upregulate PGF expression and be involved in MMP-mediated pathogenesis of COPD. In this study, we demonstrate that only MMP-12 can increase the expression of PGF by increasing early-growth response protein 1 (Egr-1) level through the activation of protease-activated receptor 1 (PAR-1). The PGF-mediated downstream signaling molecules drive caspase-3 and caspase-9-dependent apoptosis in bronchial epithelial cells. Both the upregulation of PGF by MMP-12 and PGF downstream signaling molecules with pulmonary apoptosis and emphysema were also demonstrated in animals. Given these findings, we suggest that both human COPD-associated elastases, NE, and MMP-12, upregulate PGF expression and promote the progression of emphysema and COPD.


Assuntos
Metaloproteinase 12 da Matriz/metabolismo , Fator de Crescimento Placentário/biossíntese , Doença Pulmonar Obstrutiva Crônica/metabolismo , Edema Pulmonar/metabolismo , Receptor PAR-1/metabolismo , Regulação para Cima , Animais , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Humanos , Metaloproteinase 12 da Matriz/genética , Camundongos , Camundongos Knockout , Fator de Crescimento Placentário/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Edema Pulmonar/genética , Edema Pulmonar/patologia , Receptor PAR-1/genética , Transdução de Sinais/genética
20.
Korean J Intern Med ; 33(6): 1137-1142, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29843494

RESUMO

BACKGROUND/AIMS: This study tested the hypothesis that prolonged low-dose cyclophosphamide (CTX) treatment after pulse therapy attenuate paraquat (PQ)-induced lung injury in rats. METHODS: PQ (25 mg/kg) was administered intraperitoneally to induce PQ-intoxicated rat model. The rats were randomly divided into four groups: control group (1 mL/day saline solution for 14 days), PQ group (1 mL/day saline solution for 14 days after PQ exposure), pulse group (15 mg/kg/day CTX in 1 mL of saline solution for 2 days and subsequent 1 mL/day saline solution for 12 days), and prolonged low-dose group (15 mg/kg/day CTX in 1 mL of saline solution for 2 days and subsequent 1.5 mg/kg/day CTX in 1 mL of saline solution for 12 days). A 14-day follow-up was conducted to determine the survival rat, and lung hydroxyproline (HYP), wet-to-dry weight ratios (W/Dc) and histopathological changes were evaluated. RESULTS: Results showed similar survival rate (55% vs. 50%, p > 0.05) between prolonged low-dose and pulse groups. Lung W/Dc (4.94 ± 0.38 vs. 5.47 ± 0.28, p < 0.01), HYP (3.34 ± 0.29 µg/mg vs. 3.65 ± 0.19 µg/mg, p < 0.001), and fibrosis score (2.69 ± 0.84 vs. 3.13 ± 0.63, p < 0.05) were lower in prolonged low-dose group than those in the pulse group. CONCLUSION: These findings suggested prolonged low-dose CTX treatment after pulse therapy could attenuate PQ-induced lung injury in rats.


Assuntos
Ciclofosfamida/administração & dosagem , Imunossupressores/administração & dosagem , Pulmão/efeitos dos fármacos , Paraquat , Edema Pulmonar/prevenção & controle , Fibrose Pulmonar/prevenção & controle , Animais , Biomarcadores/metabolismo , Citoproteção , Modelos Animais de Doenças , Esquema de Medicação , Hidroxiprolina/metabolismo , Injeções Intraperitoneais , Pulmão/metabolismo , Pulmão/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Pulsoterapia , Ratos Wistar , Fatores de Tempo
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