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1.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 37(10): 732-736, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31726502

RESUMO

Objective: To observe the changes of extracellular histones and pulmonary microvascular endothelial cells, and study the activating role of extracellular histones to pulmonary microvascular endothelial cells in the pathogenesis of acute respiratory distress syndrome (ARDS) . Methods: The correlation of the severity of acute lung injury with extracellular histones and pulmonary endothelial damage was studied through mice model, and acute lung injury was produced by aspiration of different concentrations of hydrochloric acid (0.01、0.1、0.3 and 0.5 mol/L, 2 ml/kg). Tumor necrosis factor-α (TNF-α), soluble thrombomodulin (sTM) and lung pathological change were measured. The pro-inflammatory role of extracellular histones was tested by injecting calf thymus histones (CTH) or specific anti-H4 antibody through tail vein. The direct activating role of extracellular histones to pulmonary microvascular endothelial cells was studied through pulmonary endothelial model. Results: The extracellular histones in plasma were increased obviously 6h after aspiration of different concentrations of hydrochloric acid in mice. A positive correlation was seen between extracellular histones and concentrations of aspirated hydrochloric acid (r=0.9180, P<0.05). The sTM in plasma also showed a positive correlation with concentrations of aspirated hydrochloric acid (r=0.8701, P<0.05). Merely administering CTH could not only increase TNF-α and sTM in plasma but also cause obvious lung injury, while specific anti-H4 antibody could relieve the inflammation and lung damage caused by CTH. Extracellular histones could directly damage pulmonary endothelial cells to release sTM in pulmonary endothelial model in vitro, while anti-H4 antibody could protect the endothelial cells. Conclusion: Extracellular histones are the key endogenic inflammatory mediators during the pathogenesis of ARDS caused by aspiration of hydrochloric acid, which could promote inflammation by directly activating pulmonary endothelial cells.


Assuntos
Lesão Pulmonar Aguda/patologia , Células Endoteliais/citologia , Histonas/sangue , Síndrome do Desconforto Respiratório do Adulto/patologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Células Endoteliais/patologia , Ácido Clorídrico , Inflamação , Pulmão , Camundongos , Síndrome do Desconforto Respiratório do Adulto/induzido quimicamente , Trombomodulina/sangue , Fator de Necrose Tumoral alfa/sangue
2.
Sheng Li Xue Bao ; 71(5): 689-697, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31646322

RESUMO

The aim of the present study was to investigate the role of ferroptosis in acute lung injury (ALI) mouse model induced by oleic acid (OA). ALI was induced in the mice via the lateral tail vein injection of pure OA. The histopathological score of lung, lung wet-dry weight ratio and the protein content of bronchoalveolar lavage fluid (BALF) were used as the evaluation indexes of ALI. Iron concentration, glutathione (GSH) and malondialdehyde (MDA) contents in the lung tissues were measured using corresponding assay kits. The ultrastructure of pulmonary cells was observed by transmission electron microscope (TEM), and the expression level of prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA was detected by quantitative polymerase chain reaction (q-PCR). Protein expression levels of glutathione peroxidase 4 (GPX4), ferritin and transferrin receptor 1 (TfR1) in lung tissues were determined by Western blot. The results showed that histopathological scores of lung tissues, lung wet-dry weight ratio and protein in BALF in the OA group were higher than those of the control group. In the OA group, the mitochondria of pulmonary cells were shrunken, and the mitochondrial membrane was ruptured. The expression level of PTGS2 mRNA in the OA group was seven folds over that in the control group. Iron overload, GSH depletion and accumulation of MDA were observed in the OA group. Compared with the control group, the protein expression levels of GPX4 and ferritin in lung tissue were down-regulated in the OA group. These results suggest that ferroptosis plays a potential role in the pathogenesis of ALI in our mouse model, which may provide new insights for development of new drugs for ALI.


Assuntos
Lesão Pulmonar Aguda/patologia , Apoptose , Ácido Oleico , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/química , Ciclo-Oxigenase 2/metabolismo , Ferritinas/metabolismo , Glutationa/análise , Glutationa Peroxidase/metabolismo , Ferro/análise , Sobrecarga de Ferro/fisiopatologia , Pulmão/citologia , Pulmão/patologia , Malondialdeído/análise , Camundongos , Microscopia Eletrônica de Transmissão , Membranas Mitocondriais/ultraestrutura
3.
Life Sci ; 238: 116962, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628913

RESUMO

AIMS: Electroacupuncture (EAc) has a pulmonary protective effect during cardiopulmonary bypass (CPB), but its molecular mechanisms including inflammasome activation signaling pathways remains unclear. MATERIALS AND METHODS: Male Sprague Dawley rats were divided into control, CPB + EAc and CPB groups. Lung injury model was developed by CPB treatment and EAc (2/100 Hz) was carried out before CPB in the CPB + EAc group. Lung tissues were collected at two time points (0.5 h; 2 h) to determine cytokines release by ELISA kits, and protein expressions by Western blot. Serum collected at two time points (0.5 h; 2 h) from CPB and CPB + EAc treated groups were used in NR8383 cells to confirm the effect of EAc. KEY FINDINGS: CPB significantly increased the inflammatory mediators, histological damage and expression of inflammasome related protein and apoptosis, when compared with control group. The level of tumor necrosis factor-α(TNF-α), interleukin (IL)-18 and IL-1ß in the CPB + EAc treated group was significantly decreased along with histological changes compared to CPB. Moreover, EAc inhibited the activation of Nod like receptor protein-3 (NLRP3) inflammasome complex, caspase-8 and activated NF-E2-related factor 2 (p-Nrf2). In addition, serum from the CPB + EAc group prevented CPB induced activation of inflammasome and related mediators, reducing ROS generation and apoptosis in NR8383 macrophages. SIGNIFICANCE: These findings indicate that EAc had a critical anti-apoptotic role by suppression of ROS/Nrf2/NLRP3 inflammasome pathway. EAc might be a possible therapeutic treatment for CPB-induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Apoptose , Ponte Cardiopulmonar/efeitos adversos , Eletroacupuntura/métodos , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Inflamassomos , Masculino , Ratos , Ratos Sprague-Dawley
4.
Nat Commun ; 10(1): 4241, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534124

RESUMO

Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8+T cells with anti-CD8ß antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8+T cells into PbA-infected TCRß-/- mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8+T cells in an IFNγ-dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8+T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.


Assuntos
Lesão Pulmonar Aguda/patologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Interferon gama/imunologia , Malária/imunologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/parasitologia , Animais , Modelos Animais de Doenças , Células Endoteliais/imunologia , Feminino , Pulmão/parasitologia , Pulmão/patologia , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium berghei/imunologia , Edema Pulmonar/parasitologia , Edema Pulmonar/patologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/parasitologia
5.
Gene ; 721: 144095, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31476403

RESUMO

Penehyclidine hydrochloride (PHC) is a novel anticholinergic drug applied broadly in surgeries as a preanesthetic medication. A substantial amount of research indicates that PHC has lung defensive properties. Considering that endoplasmic reticulum (ER) stress exerts a crucial function in cell apoptosis associated with the lipopolysaccharides (LPS)-induced acute lung injury (ALI) model, we aimed to determine whether regulation of ER stress in the LPS-induced ALI model was associated with the lung defensive role of PHC. Adult male SD rats were administered LPS (5 mg/kg, intratracheally) followed by PHC (1.0 mg/kg, intravenously) for 24 h. The NR8383 alveolar macrophages were randomly separated into Sham, LPS (100 ng/mL), and PHC (1, 2.5, or 5 µg/mL) + LPS groups. PHC (1, 2.5, or 5 µg/mL) + LPS groups were treated with PHC alone for 1 h after LPS exposure. Posttreatment with PHC relieved LPS-induced pulmonary impairment and blocked LPS-mediated lung apoptosis, indicated by the downregulation of the lung apoptotic indicators malondialdehyde and superoxide dismutase in serum at 24 h after LPS-induced ALI. PHC (1-5 µg/mL) did not influence the activity of cultivated NR8383 alveolar macrophages in vitro. However, postconditioning with PHC dosage-dependently reduced LPS-mediated cell apoptosis. Additionally, many studies have indicated that PHC administration inhibits ER stress and initiates hairy and enhancer of split 1 (Hes1)/(Notch1) signaling by decreasing phosphorylated α subunit of eukaryotic initiation factor 2α (p-eIF2α)/eukaryotic translation initiation factor 2α (eIF2α) and Phospho-protein kinase R-like ER kinase (p-PERK)/ protein kinase R-like ER kinase (PERK) proportions; inhibiting C/EBP-homologous protein (CHOP), activating transcription factor 4 (ATF4), caspase-3, and Bcl2-associated x (Bax) activity; and enhancing notch1 intracellular domain (NICD), Notch1, B-cell lymphoma-2 (Bcl-2), and Hes1 activity in vivo and in vitro. In addition, the defensive functions of PHC on LPS-activated NR8383 alveolar macrophages were abrogated through the Notch1 pathway antagonist [(3,5-difluorophenacetyl)-1-alanyl] -phenylglycine-butyl ester (DAPT). In conclusion, PHC alleviates LPS-induced ALI by ameliorating ER stress-mediated apoptosis and promoting Hes1/Notch1 signaling in vivo and in vitro.


Assuntos
Lesão Pulmonar Aguda , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hialuronan Sintases/metabolismo , Lipopolissacarídeos/toxicidade , Quinuclidinas/farmacologia , Receptor Notch1/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
6.
In Vivo ; 33(5): 1477-1484, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471395

RESUMO

BACKGROUND/AIM: Leukocyte activation is thought to be a major step in sepsis-induced pulmonary edema. We attempted to confirm whether pulmonary edema can be reproduced under intravital microscopy in a model of transfusion-related acute lung injury (TRALI) using MHC class I-specific antibody. MATERIALS AND METHODS: The surface pulmonary microcirculation was observed using an epi-fluorescence microscope through a thoracic window in 50 male mice. Monoclonal MHC class I-specific antibody (Ab) was administered to the animals, while the control group received saline. The leukocytes and macro-molecular leakage in the pulmonary circulation were analyzed. RESULTS: Leukocytes accumulated in the capillaries (52.5±12.7 leukocytes per designated area in Ab group vs. 20.8±3.1 in control). The air-containing alveolus area significantly shrank from 2,224.9±934.9 µm2 to 509.7±380.8 µm2 in the Ab group. CONCLUSION: Pulmonary edema develops rapidly following leukocyte accumulation in the lung. We confirmed that leukocyte accumulation without an underlining condition is sufficient to induce pulmonary edema.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antígenos H-2/imunologia , Edema Pulmonar/etiologia , Edema Pulmonar/patologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Biomarcadores , Biópsia , Contagem de Células Sanguíneas , Gasometria , Modelos Animais de Doenças , Injeções Intravenosas , Masculino , Camundongos , Imagem Óptica , Edema Pulmonar/diagnóstico por imagem
7.
Acta Cir Bras ; 34(6): e201900609, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31433000

RESUMO

PURPOSE: The research is intended for clarification of the efficacy as well as the underlying mechanism of GSK-3ß inhibitors on the advancement of acute lung injuries in acute necrotizing pancreatitis (ANP) in rats. METHODS: Seventy-two rats were randomly divided into 6 groups: (1)ANP-vehicle; (2)ANP-TDZD-8;(3)ANP-SB216763;(4)Sham-vehicle;(5)Sham-TDZD-8;(6)Sham-SB216763; Blood biochemical test, histopathological examination and immunohistochemical analysis of rats pancreas and lung tissues were performed. The protein expression of GSK-3ß, phospho-GSK-3ß (Ser9), iNOS, ICAM-1, TNF-α, and IL-10 were detected in lung tissues by Western-blot. RESULTS: The outcomes revealed that the intervention of GSK-3ß inhibitors alleviated the pathological damage of pancreas and lung (P<0.01), reduced serum amylase, lipase, hydrothorax and lung Wet-to-Dry Ratio, attenuated serum concentrations of IL-1ß and IL-6 (P<0.01), inhibited the activation of NF-κB, and abated expression of iNOS, ICAM-1 and TNF-α protein, but up-regulated IL-10 expression in lung of ANP rats (P<0.01). The inflammatory response and various indicators in ANP-TDZD-8 groups were lower than those in ANP-SB216763 groups. CONCLUSIONS: Inhibition of GSK-3ß weakens acute lung injury related to ANP via the inhibitory function of NF-κB signaling pathway. Different kinds of GSK-3ß inhibitors have different effects to ANP acute lung injury.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Pancreatite Necrosante Aguda/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Masculino , NF-kappa B/metabolismo , Pancreatite Necrosante Aguda/patologia , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Mol Sci ; 20(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31373289

RESUMO

The pathogenic mechanisms of acute lung injury due to direct and indirect pulmonary insults are incompletely understood. Using an unbiased, discovery and quantitative proteomic approach, we examined bronchoalveolar lavage fluid (BALF) proteome following lipopolysaccharide (LPS)-induced direct and indirect lung injury in mice. A total of 1017 proteins were both identified and quantitated in BALF from control, intratracheal (I.T., direct) and intraperitoneal (I.P., indirect) LPS-treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS; however, the magnitude of activation was much greater in the I.T. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation, and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. but suppressed by I.P. LPS. Cxcl15 (also known as lungkine) was also up-regulated by I.T. but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities, as well as significant differences in BALF protein expression profiles between LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury resulted in suppression of select components of lung innate immunity.


Assuntos
Lesão Pulmonar Aguda/patologia , Líquido da Lavagem Broncoalveolar/química , Lipopolissacarídeos/efeitos adversos , Pulmão/patologia , Proteoma/análise , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Quimiocinas CXC/biossíntese , Escherichia coli/patogenicidade , Perfilação da Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo
9.
Respir Res ; 20(1): 155, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311539

RESUMO

BACKGROUND: Conflicting data have reported beneficial effects of crystalloids, hyper-oncotic albumin (20%ALB), and iso-oncotic albumin (5%ALB) in critically ill patients. Although hyper-oncotic albumin may minimize lung injury, recent studies have shown that human albumin may lead to kidney damage proportional to albumin concentration. In this context, we compared the effects of Ringer's lactate (RL), 20%ALB, and 5%ALB, all titrated according to similar hemodynamic goals, on pulmonary function, lung and kidney histology, and molecular biology in experimental acute lung injury (ALI). METHODS: Male Wistar rats received Escherichia coli lipopolysaccharide intratracheally (n = 24) to induce ALI. After 24 h, animals were anesthetized and randomly assigned to receive RL, 20%ALB, or 5%ALB (n = 6/group) to maintain hemodynamic stability (distensibility index of inferior vena cava < 25%, mean arterial pressure > 65 mmHg). Rats were then mechanically ventilated for 6 h. Six animals, which received neither ventilation nor fluids (NV), were used for molecular biology analyses. RESULTS: The total fluid volume infused was higher in RL compared to 5%ALB and 20%ALB (median [interquartile range], 10.8[8.2-33.2] vs. 4.8[3.6-7.7] and 4.3[3.9-6.6] mL, respectively; p = 0.02 and p = 0.003). B-line counts on lung ultrasound (p < 0.0001 and p = 0.0002) and serum lactate levels (p = 0.01 and p = 0.01) were higher in RL than 5%ALB and 20%ALB. Diffuse alveolar damage score was lower in 5%ALB (10.5[8.5-12]) and 20%ALB (10.5[8.5-14]) than RL (16.5[12.5-20.5]) (p < 0.05 and p = 0.03, respectively), while acute kidney injury score was lower in 5%ALB (9.5[6.5-10]) than 20%ALB (18[15-28.5], p = 0.0006) and RL (16 [15-19], p = 0.04). In lung tissue, mRNA expression of interleukin (IL)-6 was higher in RL (59.1[10.4-129.3]) than in 5%ALB (27.0[7.8-49.7], p = 0.04) or 20%ALB (3.7[7.8-49.7], p = 0.03), and IL-6 protein levels were higher in RL than 5%ALB and 20%ALB (p = 0.026 and p = 0.021, respectively). In kidney tissue, mRNA expression and protein levels of kidney injury molecule (KIM)-1 were lower in 5%ALB than RL and 20%ALB, while nephronectin expression increased (p = 0.01 and p = 0.01), respectively. CONCLUSIONS: In a rat model of ALI, both iso-oncotic and hyper-oncotic albumin solutions were associated with less lung injury compared to Ringer's lactate. However, hyper-oncotic albumin resulted in greater kidney damage than iso-oncotic albumin. This experimental study is a step towards future clinical designs.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Albuminas/toxicidade , Soluções Cristaloides/toxicidade , Animais , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar
10.
Mol Med Rep ; 20(2): 2021-2029, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257497

RESUMO

Long­noncoding RNAs (lncRNAs) are crucial for the pathophysiology of acute lung injury (ALI). Metastasis­associated lung adenocarcinoma transcript 1 (MALAT1) suppresses inflammatory responses via microRNA (miR)­146a in lipopolysaccharide (LPS)­induced ALI. However, the molecular mechanisms underlying the MALAT1­mediated regulation of cell proliferation and apoptosis in LPS­induced ALI remain unclear. In the present study, it was found that LPS treatment upregulated MALAT1 expression and suppressed the proliferation of A549 cells. MALAT1 knockdown significantly promoted the proliferation and G1/S phase transition and inhibited apoptosis in LPS­treated A549 cells. In addition, miR­17­5p was a direct target of MALAT1. miR­17­5p expression was downregulated and FOXA1 expression was upregulated in LPS­treated A549 cells. Further, MALAT1 knockdown promoted miR­17­5p expression and inhibited FOXA1 expression, whereas the combined suppression of MALAT1 and miR­17­5p induced FOXA1 expression. Moreover, miR­17­5p knockdown reversed the effects of MALAT1 suppression on LPS­induced A549 cell proliferation. These results indicated that MALAT1 serves as a competing endogenous lncRNA that, by sequestering miR­17­5p, stimulates FOXA1 expression and mediates LPS­induced A549 cell injury. In conclusion, the present study demonstrated that MALAT1 knockdown alleviates LPS­induced A549 cell injury by targeting the miR­17­5p/FOXA1 axis.


Assuntos
Lesão Pulmonar Aguda/genética , Adenocarcinoma de Pulmão/genética , Fator 3-alfa Nuclear de Hepatócito/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Células A549 , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Adenocarcinoma de Pulmão/patologia , Apoptose/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Lipopolissacarídeos/toxicidade , Transdução de Sinais/genética
11.
J Surg Res ; 243: 316-324, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31255931

RESUMO

BACKGROUND: 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine (LYRM03) has been shown to be beneficial in a rat model of acute lung injury (ALI). Nonetheless, the pharmacologic action of LYRM03 interference has not been demonstrated to occur through oxidative stress and apoptosis in a rat lipopolysaccharide (LPS)-induced ALI model, and the potential pathogenic mechanism needs to be clarified. Our research intended to explore the mechanism of action using an in vivo rat LPS-induced ALI model and highlight the associated pathogenesis. METHODS: Sprague-Dawley rats were randomly assigned to the following five groups: Sham; LPS (5 mg/kg); LPS + LYRM03 (5 mg/kg); LPS + LYRM03 (10 mg/kg); and LPS + LYRM03 (20 mg/kg). Pulmonary injury indicators were documented at 24 h after LPS-induced ALI. Morphologic alterations, such as the extent of the injury, were determined using hematoxylin-eosin staining. Furthermore, expression levels of oxidative stress indicators (malondialdehyde, superoxide dismutase, and glutathione peroxidase) and inflammatory molecules (tumor necrosis factor-α, interleukin-8, and interleukin-6) in circulation were observed. The production of apoptosis-associated proteins (poly ADP-ribose polymerase, c-caspase 3, B-cell lymphoma-2, and Bcl2 associated X), inflammatory mediators (high mobility group box-1, toll-like receptor 4, nuclear factor-kappa B p65, and myeloid differentiation primary response 88), and inhibitor of kappa B-α were determined through Western blotting. Real-time polymerase chain reaction was applied to assess the messenger RNA expression of the inflammatory mediators. RESULTS: The LPS-treated group exhibited a remarkable increase in the extent of the pulmonary injury, oxidative stress indicator secretion, inflammatory molecule release, and inflammatory mediator production and an increase in the inhibitor of kappa B-α levels relative to the Sham group. The LYRM03 (5 and 10 mg/kg)-treated groups exhibited a remarkable decrease relative to the LPS group. In addition, treatment with LYRM03 (20 mg/kg) powerfully limited the extent of the injury and demonstrated anti-inflammatory actions. CONCLUSIONS: The results of this investigation indicated that treatment with LYRM03 plays a role in lung defense by inhibiting the NF-κB/MyD88/TLR4 pathway.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Oligopeptídeos/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Lipopolissacarídeos , Pulmão/enzimologia , Pulmão/patologia , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Oligopeptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo
12.
Int Immunopharmacol ; 73: 568-574, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203114

RESUMO

PIM kinase is involved in the cellular processes of growth, differentiation and apoptosis. However, the role of PIM1 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains largely unknown. A trend of PIM1 in the lung tissue of LPS-induced ALI at different time points was detected. Histology, wet/dry (W/D) ratio, inflammatory cells in the bronchoalveolar lavage fluid (BALF) and survival rate analyses were performed when mice received the PIM1 inhibitor SMI-4a intratracheally 3 h before LPS administration. Cytokine production in vivo and in vitro was measured after SMI-4a pretreatment. NF-κB subunit p65 expression in nuclei and phosphorylation at Ser276 in lung tissues or cells were detected by Western blot analysis. The results showed that PIM1 mRNA and protein were upregulated in the lung tissue of LPS-induced ALI. The PIM1 inhibitor SMI-4a markedly improved the survival rate after lethal LPS administration, reduced the severity of lung edema, attenuated the histologic injuries of the lung tissue and reduced the counts of infiltrated inflammatory cells in the BALF. The PIM1 inhibitor SMI-4a suppressed the production of cytokines in LPS-treated RAW264.7 cell supernatants and BALF. Furthermore, LPS administration upregulated the levels of nuclear p65 and phosphorylated p65 (p-p65) at Ser276, whereas pretreatment with the PIM1 inhibitor SMI-4a reduced p65 upregulation in the nucleus and p-p65 at Ser276. Taken together, these data indicate that the PIM1 inhibitor SMI-4a may serve as a promising therapeutic strategy for LPS-induced ALI by suppressing macrophage production of cytokines via a reduction of p65 activities.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Compostos de Benzilideno/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Tiazolidinedionas/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Compostos de Benzilideno/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Tiazolidinedionas/farmacologia , Fator de Transcrição RelA/imunologia
13.
Int J Mol Med ; 44(2): 617-629, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173158

RESUMO

Classical dendritic cells (cDCs) are involved in the pathogenesis of inflammatory lung diseases; however, their contributions in acute respiratory distress syndrome (ARDS), which is pathophysiologically inflammatory, remain unknown. The present study aimed to explore the regulatory effects of pulmonary cDCs on acute lung inflammation and injury in lipopolysaccharide (LPS)­induced ARDS. Fms­like tyrosine kinase 3­ligand (FLT3L) and lestaurtinib, a specific activator and an inhibitor of FLT3 signaling respectively, were used separately for the pretreatment of C57BL/6 mice for 5 consecutive days. ARDS was induced by intratracheal injection of LPS, and mice were sacrificed 6 and 24 h later. Flow cytometry was used to measure the aggregation and maturation of pulmonary cDCs. The ratio of lung wet weight to body weight (LWW/BW) and histopathological analyses were assessed to evaluate lung edema and lung injury. Tumor necrosis factor­α and interleukin (IL)­6 levels were measured by ELISA to evaluate acute lung inflammation. The levels of interferon­Î³, IL­1ß, IL­4 and IL­10, and the expression of the transcription factors T­box­expressed­in­T­cells (T­bet) and GATA binding protein 3, were quantified by ELISA, RT­qPCR and western blotting to evaluate the balance of the Th1/Th2 response. Myeloperoxidase (MPO) activity was measured to evaluate neutrophil infiltration. The results demonstrated that the aggregation and maturation of pulmonary cDCs reached a peak at 6 h after LPS challenge, followed by a significant decrease at 24 h. FLT3L pretreatment further stimulated the aggregation and maturation of pulmonary cDCs, resulting in elevated lung MPO activity and increased T­bet expression, which in turn led to aggravated LWW/BW, acute lung inflammation and injury. However, lestaurtinib pretreatment inhibited the aggregation and maturation of pulmonary cDCs, decreased lung MPO activity and T­bet expression, and eventually improved LWW/BW, acute lung inflammation and injury. The present results suggested that pulmonary cDCs regulated acute lung inflammation and injury in LPS­induced ARDS through the modulation of neutrophil infiltration and balance of the Th1/Th2 response.


Assuntos
Lesão Pulmonar Aguda/imunologia , Células Dendríticas/imunologia , Pneumonia/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Células Dendríticas/patologia , Modelos Animais de Doenças , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/patologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Tirosina Quinase 3 Semelhante a fms/imunologia
14.
Mol Med Rep ; 20(1): 455-462, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180535

RESUMO

Acute lung injury (ALI) is a major cause of morbidity and mortality globally, and is characterized by widespread inflammation in the lungs. Increased production of reactive oxygen species is hypothesized to be associated with ALI. Matrine and lycopene are active products present in traditional Chinese medicine. Matrine is an effective inhibitor of inflammation, whereas lycopene decreases lipid peroxidation. Therefore, it was hypothesized that combinatorial treatment with matrine and lycopene may provide synergistic protection against ALI. In the present study, mice were treated with dexamethasone (DEX; 5 mg/kg), matrine (25 mg/kg), lycopene (100 mg/kg), and matrine (25 mg/kg) + lycopene (100 mg/kg) for 7 days prior to injury induction using lipopolysaccharide (LPS; 5 mg/kg) for 6 h. Lung tissues were collected following the sacrifice of the mice and hematoxylin and eosin staining was used for histological analysis. Malondialdehyde (MDA), glutathione (GSH) and myeloperoxidas (MPO) levels were examined by respective kits. The expressions of interleukin­6 (IL­6) and tumor necrosis factor­α (TNF­α) were evaluated by ELISA. The expressions of IκBα and NF­κB p65 were examined by reverse transcription­quantitative polymerase chain reaction, western blotting and immunohistochemistry. The results indicated that the combined treatment exhibited a similar effect to DEX, both of which attenuated lung structural injuries, downregulated the expressions of IL­6, TNF­α, MPO and MDA, and upregulated that of GSH. Furthermore, the combined treatment and DEX inhibited NF­κB p65 activation. The present study revealed that combined treatment with matrine and lycopene exhibited protective effects on an LPS­induced mouse model of ALI, suggesting that they may serve as a potential alternative to glucocorticoid therapy for ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Alcaloides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Licopeno/uso terapêutico , Quinolizinas/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Sinergismo Farmacológico , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
15.
Int Immunopharmacol ; 74: 105658, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177016

RESUMO

The acute respiratory distress syndrome (ARDS), a devastating clinical syndrome, is one of the most severe complications of acute lung injury (ALI). Despite of decades of clinical trials and supportive ventilation strategies, the incidence and mortality of ALI/ARDS remain high. DL-3-n-butylphthalide (NBP) is a synthesized raceme of L-3-n-butylphthalide which has been approved to possess various activities. In the current study, we aimed to investigate the effect of NBP on ALI in lipopolysaccharide (LPS)-treated mice. We found that 10 mg/kg and 50 mg/kg NBP significantly prevented LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. Sirtuin 1 (SIRT1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was increased by NBP in lung of LPS-treated mice. Knockout of SIRT1 significantly aggravated LPS-induced ALI. Moreover, the absence of SIRT1 notably inhibited NBP-induced protective effects against LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. However, knockout of SIRT1 did not completely inhibit NBP-induced upregulation of Nrf2 and attenuation of ALI. The results demonstrated that NBP could activate Nrf2 antioxidant signaling in a SIRT1-dependent and SIRT1-independent manner, resulting in the amelioration of oxidative stress, inflammation and pulmonary edema. The data highlights the importance of SIRT1/Nrf2 signaling in the protective effects of NBP.


Assuntos
Lesão Pulmonar Aguda/imunologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Benzofuranos/farmacologia , Fator 2 Relacionado a NF-E2/imunologia , Sirtuína 1/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Benzofuranos/uso terapêutico , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/imunologia , Edema Pulmonar/patologia , Sirtuína 1/genética
16.
Drug Des Devel Ther ; 13: 1763-1772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213766

RESUMO

Background and aim: A potent and selective vascular endothelial growth factor receptor (VEGFR) inhibitor SU5416, has been developed for the treatment of solid human tumors. The binding of VEGF to VEGFR plays a crucial role in the pathophysiology of respiratory disorders. However, the impact of SU5416 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Thus, this study aimed to illuminate the biofunction of SU5416 in the mouse model of ALI. Methods: Wild-type (WT) and toll-like receptor 4 (TLR4)-deficient (TLR4-/-) C57BL/6 mice were used to establish LPS-induced ALI model. The primary pulmonary microvascular endothelial cell (PMVEC) was extracted for detection of endothelial barrier function. Results: LPS significantly increased the number of inflammatory cells and inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In addition, LPS increased alveolar epithelial cells injury, inflammation infiltration and vascular permeability of PMVEC in WT and TLR4-/- mice. Western blotting experiment indicated VEGF/VEGFR and TLR4/NF-κB pathways were involved in the progression of LPS-stimulated ALI. Consistent with previous research, dexamethasone treatment appeared to be an effective therapeutic for mice with ALI. Moreover, treatment with SU5416 dramatically attenuated LPS-induced immune responses in mice lung tissues via inhibiting VEGF/VEGFR and TLR4/NF-κB pathways. Finally, SU5416 also decreased vascular permeability of PMVEC in vitro. Conclusion: SU5416 ameliorated alveolar epithelial cells injury and histopathological changes in mice lung via inhibiting VEGF/VEGFR and TLR4/NF-κB signaling pathways. We also confirmed that SU5416 could restrain vascular permeability in PMVEC through improving the integrity of endothelial cell. These findings suggested that SU5416 may serve as a potential agent for the treatment of patients with ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Indóis/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Pirróis/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/metabolismo
17.
Biomed Res Int ; 2019: 2193706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205936

RESUMO

The regulation of intracellular mitochondria degradation is mediated by mitophagy. While studies have shown that mitophagy can lead to mitochondrial dysfunction and cell damage, the role of Mdivi-1 and mitophagy remains unclear in acute lung injury (ALI) pathogenesis. In this study, we demonstrated that Mdivi-1, which is widely used as an inhibitor of mitophagy, ameliorated acute lung injury assessed by HE staining, pulmonary microvascular permeability assay, measurement of wet/dry weight (W/D) ratio, and oxygenation index (PaO2/FiO2) analysis. Then, the mitophagy related proteins were evaluated by western blot. The results indicated that LPS-induced activation of mitophagy was inhibited by Mdivi-1 treatment. In addition, we found that Mdivi-1 protected A549 cells against LPS-induced mitochondrial dysfunction. We also found that Mdivi-1 reduced pulmonary cell apoptosis in the LPS-challenged rats and protected pulmonary tissues from oxidative stress (represented by the content of superoxide dismutase, malondialdehyde and lipid peroxides in lung). Moreover, Mdivi-1 treatment ameliorated LPS-induced lung inflammatory response and cells recruitment. These findings indicate that Mdivi-1 mitigates LPS-induced apoptosis, oxidative stress, and inflammation in ALI, which may be associated with mitophagy inhibition. Thus, the inhibition of mitophagy may represent a potential therapy for treating ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Mitocôndrias/metabolismo , Quinazolinonas/farmacologia , Células A549 , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos/toxicidade , Masculino , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
Inhal Toxicol ; 31(3): 107-118, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31039646

RESUMO

Objective: To establish a rat model with respiratory and pulmonary responses caused by inhalation exposure to non-lethal concentrations of ammonia (NH3) that can be used for evaluation of new medical countermeasure strategies for NH3-induced acute lung injury (ALI). This is of great value since no specific antidotes of NH3-induced injuries exist and medical management relies on supportive and symptomatically relieving efforts. Methods: Female Sprague-Dawley rats (8-9 weeks old, 213g ± 2g) were exposed to NH3 using two different exposure regimens; nose-only inhalation or intratracheal instillation. The experiment was terminated 5 h, 24 h, 14 and 28 days post-exposure. Results: Nose-only inhalation of NH3 (9000-15 000 ppm) resulted in increased salivation and labored breathing directly post-exposure. Exposure did not increase inflammatory cells in bronchoalveolar lavage fluid but exposure to 12 000 ppm NH3 during 15 min reduced body weight and induced coagulation abnormalities by increasing serum fibrinogen levels. All animals were relatively recovered by 24 h. Intratracheal instillation of NH3 (1%) caused early symptoms of ALI including airway hyperresponsiveness, neutrophilic lung inflammation and altered levels of coagulation factors (increased fibrinogen and PAI-1) and early biomarkers of ALI (IL-18, MMP-9, TGFß) which was followed by increased deposition of newly produced collagen 14 days later. Histopathology analysis at 5 h revealed epithelial desquamation and that most lesions were healed after 14 days. Conclusions: This study demonstrates that intratracheal instillation can reproduce several early hallmarks of ALI. Our findings therefore support that the intratracheal instillation exposure regimen can be used for new medical countermeasure strategies for NH3-induced ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Amônia/administração & dosagem , Amônia/toxicidade , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Colágeno/metabolismo , Feminino , Fibrina/metabolismo , Fibrinogênio/análise , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/fisiopatologia , Nariz , Ratos Sprague-Dawley , Mecânica Respiratória/efeitos dos fármacos , Traqueia
19.
Molecules ; 24(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067702

RESUMO

PM2.5 is particulate matter with a diameter of 2.5 µm or less. Airway macrophages are the key players regulating PM2.5-induced inflammation. High molecular weight hyaluronan (HMW-HA) has previously been shown to exert protective effects on PM2.5-induced acute lung injury and inflammation. However, little is known about the detailed mechanism. In this study, we aimed to determine whether HMW-HA alleviates PM2.5-induced pulmonary inflammation by modulating macrophage polarization. The levels of M1 biomarkers TNF-α, IL-1ß, IL-6, CXCL1, CXCL2, NOS2 and CD86, as well as M2 biomarkers IL-10, MRC1, and Arg-1 produced by macrophages were measured by ELISA, qPCR, and flow cytometry. In addition, the amount of M1 macrophages in lung tissues was examined by immunofluorescence of CD68 and NOS2. We observed a decline in PM2.5-induced M1 polarization both in macrophages and lung tissues when HMW-HA was administered simultaneously. Meanwhile, western blot analysis revealed that PM2.5-induced JNK and p38 phosphorylation was suppressed by HMW-HA. Furthermore, in vitro and in vivo studies showed that co-stimulation with HMW-HA and PM2.5 promoted the expression and release of IL-10, but exhibited limited effects on the transcription of MRC1 and ARG1. In conclusion, our results demonstrated that HMW-HA ameliorates PM2.5-induced lung inflammation by repressing M1 polarization through JNK and p38 pathways and promoting the production of pro-resolving cytokine IL-10.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Ácido Hialurônico/administração & dosagem , Interleucina-10/genética , Pneumonia/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Animais , Arginase/genética , Biomarcadores , Polaridade Celular/efeitos dos fármacos , Citocinas/genética , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Glicoproteínas de Membrana/genética , Peso Molecular , Material Particulado/efeitos adversos , Fosforilação/efeitos dos fármacos , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/patologia , Ratos
20.
Int Immunopharmacol ; 73: 312-320, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129418

RESUMO

Progressive lung injury and pulmonary inflammation can be induced by an intraperitoneal injection of lipopolysaccharide (LPS). Interleukin-1ß (IL-1ß) is a key pro-inflammatory cytokine that can further exaggerate inflammation, which is cleaved and activated by the NALP3 inflammasome. Although the nuclear receptor Rev-erbα attenuates the level of LPS-induced pulmonary inflammation, the mechanism remains unclear. In this study, we investigated the influence of LPS-induced production of IL-1ß and Rev-erbα on the development of lung inflammation. Herein, we demonstrate that Rev-erbα reduces IL-1ß production and lung injury following an intraperitoneal injection of LPS, which is dependent on the NF-κB/NALP3 pathway. Thus, Rev-erbα is able to decrease the extent of acute lung injury by regulating IL-1ß production. This mechanism may represent a potential novel therapeutic approach for lung injury.


Assuntos
Lesão Pulmonar Aguda/imunologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Glicina/análogos & derivados , Glicina/farmacologia , Interleucina-1beta/imunologia , Isoquinolinas/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Células RAW 264.7 , Transdução de Sinais , Tiofenos/farmacologia
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