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1.
Biomed Pharmacother ; 131: 110643, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32846329

RESUMO

Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-α using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and imipenem efficiently suppressed the release of inflammatory cytokines by partly intervention of NF-κB activity. The acute lung injury was also alleviated and the survival time was prolonged in mice. In addition, entecavir and imipenem inhibited the release of TNF-α and IL-10 in human peripheral blood mononuclear cells (hPBMCs). Collectively, we proposed that entecavir and imipenem might be candidates for the treatment of CSS.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Guanina/análogos & derivados , Imipenem/farmacologia , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/virologia , Animais , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Reposicionamento de Medicamentos , Guanina/farmacologia , Humanos , Interleucina-10/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Pneumonia Viral/complicações , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
2.
Paediatr Respir Rev ; 35: 20-24, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32653469

RESUMO

Since the initial description in 2019, the novel coronavirus SARS-Cov-2 infection (COVID-19) pandemic has swept the globe. The most severe form of the disease presents with fever and shortness of breath, which rapidly deteriorates to respiratory failure and acute lung injury (ALI). COVID-19 also presents with a severe coagulopathy with a high rate of venous thromboembiolism. In addition, autopsy studies have revealed co-localized thrombosis and inflammation, which is the signature of thromboinflammation, within the pulmonary capillary vasculature. While the majority of published data is on adult patients, there are parallels to pediatric patients. In our experience as a COVID-19 epicenter, children and young adults do develop both the coagulopathy and the ALI of COVID-19. This review will discuss COVID-19 ALI from a hematological perspective with discussion of the distinct aspects of coagulation that are apparent in COVID-19. Current and potential interventions targeting the multiple thromboinflammatory mechanisms will be discussed.


Assuntos
Lesão Pulmonar Aguda/sangue , Infecções por Coronavirus/sangue , Inflamação/sangue , Pneumonia Viral/sangue , Trombose/sangue , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/fisiopatologia , Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Betacoronavirus , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/imunologia , Transtornos da Coagulação Sanguínea/fisiopatologia , Capilares/imunologia , Capilares/fisiopatologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Inibidores do Fator Xa/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Pandemias , Ativação Plaquetária , Inibidores da Agregação de Plaquetas/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Embolia Pulmonar/sangue , Embolia Pulmonar/imunologia , Embolia Pulmonar/fisiopatologia , Trombina/imunologia , Trombina/metabolismo , Trombose/tratamento farmacológico , Trombose/imunologia , Trombose/fisiopatologia
3.
Gene ; 759: 144969, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32712064

RESUMO

Sepsis-induced acute lung injury (ALI) remains one of the most common disorders in hospitals. The aim of this research was to explore the underlying characteristics and mechanisms of artesunate (AS) in protecting rat lungs from sepsis. The sepsis-induced ALI model was generated in SD rats by the intratracheal administration of lipopolysaccharide (LPS, 5 mg/kg) for 24 h. The rats were randomly assigned into 4 groups: Sham, LPS, LPS + AS, and LPS + AS + LY294002. Pathological evaluation of the lungs was conducted by HE staining, immunofluorescence, and TUNEL assay, and the MPO activity and the W/D ratio of each group were evaluated. The levels of inflammatory mediators (TNF-α and IL-6) were measured by immunoblotting, immunofluorescence and real-time PCR. Western blotting was used to determine the protein levels of PI3K, cleaved Caspase-3, p-mTOR, mTOR, p-Akt, and Akt in the lungs. The MPO activity, W/D ratio and lung injury score were obviously elevated after induction of ALI by LPS. Nevertheless, these alterations could be inhibited by AS. In addition, sepsis decreased the levels of p-mTOR, p-Akt, and PI3K and elevated the expression of cl-caspase-3, TNF-α, and IL-6 in the lungs. After AS administration, these alterations were obviously decreased, but treatment with the PI3K antagonist LY294002 inhibited the function of AS. AS could partially protect against LPS-induced ALI by inhibiting apoptosis and inflammatory mediator production, and this function is perhaps associated with the regulation of the mTOR/AKT/PI3K axis. These findings suggest that AS may possess certain beneficial characteristics in protecting the lungs from sepsis.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Artesunato/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sepse/complicações , Serina-Treonina Quinases TOR/metabolismo , Lesão Pulmonar Aguda/etiologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Artesunato/farmacologia , Interleucina-6/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
4.
Am J Respir Cell Mol Biol ; 63(5): 571-590, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32640172

RESUMO

PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/virologia , Animais , Antivirais/efeitos adversos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Pulmão/enzimologia , Pulmão/virologia , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Transdução de Sinais/efeitos dos fármacos
5.
Adv Clin Exp Med ; 29(7): 813-817, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32725973

RESUMO

BACKGROUND: Acute lung injury (ALI) is a common critical respiratory disease that seriously threatens human health. Ketamine has good anti-inflammatory and immune-regulating properties that can delay the lung injury process. OBJECTIVES: High mobility group box protein 1 (HMGB1) plays an important role in the occurrence, development and treatment of ALI. Toll-like receptor 4 (TLR4) is the receptor for HMGB1. The aim of this study was to determine the role of the HMGB1 TLR4 signaling pathway in the treatment of ALI using ketamine. MATERIAL AND METHODS: A total of 30 healthy, male, 8-week-old Sprague-Dawley rats were randomly, equally divided into a control group, an lipopolysaccharide (LPS) group and a ketamine group. In order to establish a rat ALI model, 15 mg/kg of LPS was injected into the femoral veins. Ketamine was intravenously injected (10 mg/kg) into the experimental group rats. The rats were euthanized 24 h after modeling and lung tissue samples were collected. Western blot was used to test TLR4, MyD88, TRAF-6, LOX-1, and HMGB1 protein expression in the lung tissue. Real-time polymerase chain reaction (RT-PCR) was performed to detect TLR4, MyD88, TRAF-6, LOX-1, and HMGB1 mRNA levels. RESULTS: Compared with the controls, the LPS group had significantly higher TLR4, MyD88, TRAF-6, LOX-1, and HMGB1 mRNA and protein levels (p < 0.05). These levels were significantly lower after ketamine intervention in comparison with the LPS group (p < 0.05). A positive correlation was found between TLR4 and HMGB1 expression in the LPS and ketamine groups (r = 0.952, p < 0.001; r = 0.941, p < 0.001). CONCLUSIONS: Ketamine attenuates HMGB1-induced ALI, possibly by regulating the TLR4 signaling pathway.


Assuntos
Lesão Pulmonar Aguda , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Proteína HMGB1 , Ketamina/farmacologia , Lipopolissacarídeos/toxicidade , Pulmão/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like/genética
6.
Med Hypotheses ; 143: 109906, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32505910

RESUMO

Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1ß and a remarkably reduced lung edema compared to wild type. IL-1ß is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1ß. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1ß and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Armadilhas Extracelulares/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Infecções por Coronavirus/imunologia , Armadilhas Extracelulares/imunologia , Retroalimentação Fisiológica , Humanos , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pandemias , Pneumonia Viral/imunologia
7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(3): 371-375, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32543145

RESUMO

Objective: To observe the effect of ginsenoside Rg1 on the acute lung injury of sepsis in combination with the antibiotic imipenem in a mouse model of sepsis that induced by cecal puncture. Methods: C57BL/6 mice were used to establish the model of sepsis. The model mice were randomly divided into model group, imipenem group, ginsenoside Rg1 group, and ginsenoside Rg1+imipenem group, 10 mice in each group. Another 10 mice were set as control group. Sham operation was performed in the mice of control group. Each mice was intraperitoneally injected the corresponding drug in 2 h, 26 h and 50 h after surgery for three times. They were 2 h after surgery, 26 h after surgery and 50 h after surgery. 2 h after the last administration, the oxygenation index of the arterial blood was measured, the lung tissue was taken to measure lung wet/dry ratio (W/D), and HE staining was used to observe the lung inflammation. The ELISA kits were used to detect the levels of interleukin (IL)- 1ß, IL-6, tumor necrosis factor (TNF)-α and nuclear factor-kappa B (NF-κB) inalveolar lavage fluid. Western blot and immunohistochemical staining were used to detect NF-κB p65 expression in lung tissues. Results: The drug-administered groups significantly reduced the W/D of the lungs in the septic mice and increased the oxygenation index in the blood ( P<0.01), and decreased the inflammation in lung and the levels of IL-1ß, IL-6, TNF-α and NF-κB in the alveolar lavage fluid ( P<0.01), and decreased the expression of NF-κB p65 in lung tissue ( P<0.01). When ginsenoside Rg1 was combined with imipenem, the above indicators were closer to the control group than that in the ginsenoside Rg1 and imipenem groups. Conclusion: Rg1 can significantly inhibit lung inflammation in septic mice. It has a better therapeutic effect when combined with antibiotics.


Assuntos
Lesão Pulmonar Aguda , Ginsenosídeos , Sepse , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Antibacterianos/uso terapêutico , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B , Sepse/complicações , Sepse/tratamento farmacológico , Fator de Necrose Tumoral alfa
8.
Life Sci ; 254: 117766, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32418895

RESUMO

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common critical disease which can be caused by multiple pathological factors in clinic. However, feasible and effective treatment strategies of ALI/ARDS are limited. At present, the beneficial effect of stem cells (SCs)-based therapeutic strategies for ALI/ARDS can be attributed to paracrine. Exosomes, as a paracrine product, are regarded as a critical regulatory mediator. Furthermore, substantial evidence has indicated that exosomes from SCs can transmit bioactive components including genetic material and protein to the recipient cells and provide a protective effect. The protective role is played through a series of process including inflammation modulation, the reconstruction of alveolar epithelium and endothelium, and pulmonary fibrosis prevention. Therefore, SCs derived exosomes have the potential to be used for therapeutic strategies for ALI/ARDS. In this review, we discuss the present understanding of SCs derived exosomes related to ALI/ARDS and provide insights for developing a cell-free strategy for treating ALI/ARDS.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Exossomos/transplante , Síndrome do Desconforto Respiratório do Adulto/terapia , Lesão Pulmonar Aguda/metabolismo , Células Epiteliais Alveolares/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Dispneia , Endotélio/metabolismo , Exossomos/metabolismo , Humanos , Inflamação , Síndrome do Desconforto Respiratório do Adulto/patologia , Transplante de Células-Tronco/métodos , Células-Tronco/metabolismo
9.
Life Sci ; 254: 117773, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32418896

RESUMO

The disturbance of the immune homeostasis caused by infection is decisive for multiple organ dysfunction caused by sepsis. Both the th17 cell and the regulatory cell(Tregs) are important components of the immune system and play a crucial role in maintaining immune homeostasis. In this study, we explored the effect of Maresin1, an emerging specific pro-inflammatory mediator, on the balance of Th17/Treg in sepsis, and investigated the underlying mechanism. We used the male C57BL/6 mice to establish the model of sepsis-induced lung injury by cecal ligation and puncture to verify the protective effect of Maresin1. Our study showed that Maresin1 could significantly inhibit the excessive inflammatory response and promote the inflammation regression in the process of sepsis-induced acute lung injury, thereby reducing lung damage and improving lung function. These effects were accompanied with the regulation of Maresin1 on the Th17/Treg balance in the early stages of sepsis. We demonstrated that Maresin1 has a certain effect on increasing the number of Treg and decreasing the number of Th17 cells in the early stages of sepsis, which is consistent with its effect on STAT3/RORγt and STAT5/Foxp3 signal pathways. Our study elucidated for the first time the relationship between Maresin1 and Th17/Treg balance in sepsis-induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Ácidos Docosa-Hexaenoicos/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Distribuição Aleatória , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT5/imunologia , Sepse/tratamento farmacológico , Sepse/imunologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
10.
J Toxicol Sci ; 45(5): 293-304, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32404561

RESUMO

Acute exposure to hydrogen sulfide (H2S) can cause fatal acute lung injury (ALI). However, the mechanisms of H2S-induced ALI are still not fully understood. This study aims to investigate the role of the tight junction protein claudin-5 in H2S-induced ALI. In our study, Sprague-Dawley (SD) rats were exposed to H2S to establish the ALI model, and in parallel, human pulmonary microvascular endothelial cells (HPMECs) were incubated with NaHS (a H2S donor) to establish a cell model. Lung immunohistochemistry and electron microscopy assays were used to identify H2S-induced ALI, and the expression of claudin-5, p-AKT/t-AKT and p-FoxO1/t-FoxO1 was detected. Our results show that H2S promoted the formation of ALI by morphological investigation and decreased claudin-5 expression. Dexamethasone (Dex) could partly attenuate NaHS-mediated claudin-5 downregulation, and the protective effects of Dex could be partially blocked by LY294002, a PI3K/AKT/FoxO1 pathway antagonist. Moreover, as a consequence of the altered phosphorylation of AKT and FoxO1, a change in claudin-5 with the same trend was observed. Therefore, the tight junction protein claudin-5 might be considered a therapeutic target for the treatment of ALI induced by H2S and other hazardous gases.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Claudina-5/metabolismo , Claudina-5/fisiologia , Sulfeto de Hidrogênio/toxicidade , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/genética , Animais , Células Cultivadas , Claudina-5/genética , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Terapia de Alvo Molecular , Ratos Sprague-Dawley
11.
Surgery ; 168(3): 478-485, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32439208

RESUMO

BACKGROUND: Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS: Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS: Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION: Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.


Assuntos
Intestinos/irrigação sanguínea , Fragmentos de Peptídeos/uso terapêutico , Proteínas de Ligação a RNA/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , Proteínas de Ligação a RNA/imunologia , Proteínas de Ligação a RNA/farmacologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo
12.
Int J Nanomedicine ; 15: 2287-2302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280221

RESUMO

Background: Mitochondrial dysfunction played a vital role in the pathogenesis of various diseases, including acute lung injury (ALI). However, few strategies targeting mitochondria were developed in treating ALI. Recently, we fabricated a porous Se@SiO2 nanoparticles (NPs) with antioxidant properties. Methods: The protective effect of Se@SiO2 NPs was assessed using confocal imaging, immunoblotting, RNA-seq, mitochondrial respiratory chain (MRC) activity assay, and transmission electron microscopy (TEM) in airway epithelial cell line (Beas-2B). The in vivo efficacy of Se@SiO2 NPs was evaluated in a lipopolysaccharide (LPS)-induced ALI mouse model. Results: This study demonstrated that Se@SiO2 NPs significantly increased the resistance of airway epithelial cells under oxidative injury and shifted lipopolysaccharide-induced gene expression profile closer to the untreated controls. The cytoprotection of Se@SiO2 was found to be achieved by maintaining mitochondrial function, activity, and dynamics. In an animal model of ALI, pretreated with the NPs improved mitochondrial dysfunction, thus reducing inflammatory responses and diffuse damage in lung tissues. Additionally, RNA-seq analysis provided evidence for the broad modulatory activity of our Se@SiO2 NPs in various metabolic disorders and inflammatory diseases. Conclusion: This study brought new insights into mitochondria-targeting bioactive NPs, with application potential in curing ALI or other human mitochondria-related disorders.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Selênio/farmacologia , Dióxido de Silício/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Citoproteção , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Humanos , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Mitocôndrias/metabolismo , Nanopartículas/uso terapêutico , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Porosidade , Selênio/química , Dióxido de Silício/química
13.
Life Sci ; 250: 117551, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32179075

RESUMO

AIMS: Increasing evidence indicates that FK866, a specific noncompetitive nicotinamide phosphoribosyl transferase inhibitor, exhibits a protective effect on acute lung injury (ALI). Autophagy plays a pivotal role in sepsis-induced ALI. However, the contribution of autophagy and the underlying mechanism by which FK866-confered lung protection remains elusive. Herein, we aimed to study whether FK866 could alleviate sepsis-induced ALI via the JNK-dependent autophagy. MAIN METHODS: Male C57BL/6 mice were subjected to cecal ligation and puncture (CLP) to establish the polymicrobial sepsis mice model, and treated with FK866 (10 mg/kg) at 24, 12 and 0.5 h before the CLP procedure. The lung protective effects were measured by lung histopathology, tissue edema, vascular leakage, inflammation infiltration, autophagy-related protein expression and JNK activity. A549 cells were stimulated with LPS (1000 ng/ml) to generate the ALI cell model, and pretreated with FK866 or SP600125 for 30 min to measure the autophagy-related protein expression and JNK activity. KEY FINDINGS: Our results demonstrated that FK866 reduced lung injury score, tissue edema, vascular leakage, and inflammatory infiltration, and upregulated autophagy. The protective effect of autophagy conferred by FK866 on ALI was further clarified by using 3-methyladenine (3MA) and rapamycin. Additionally, the activity of JNK was suppressed by FK866, and inhibition of JNK promoted autophagy and showed a benefit effect. SIGNIFICANCE: Our study indicates that FK866 protects against sepsis-induced ALI by induction of JNK-dependent autophagy. This may provide new insights into the functional mechanism of NAMPT inhibition in sepsis-induced ALI.


Assuntos
Acrilamidas/uso terapêutico , Lesão Pulmonar Aguda/tratamento farmacológico , Autofagia , MAP Quinase Quinase 4/metabolismo , Piperidinas/uso terapêutico , Sepse/tratamento farmacológico , Células A549 , Lesão Pulmonar Aguda/complicações , Animais , Líquido da Lavagem Broncoalveolar , Permeabilidade Capilar , Modelos Animais de Doenças , Humanos , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/complicações , Transdução de Sinais , Regulação para Cima
14.
Gene ; 741: 144562, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32169629

RESUMO

Renal Ischemia/Reperfusion (rI/R)-induced acute lung injury (ALI) is a major problem in rI/R. The objective of the current study was to explore the defensive roles of propofol (Pro), an intravenous anesthetic, on rI/R-induced ALI through mitogen-activated protein kinase (MAPK) signaling. Rats were divided into Sham, Pro (10 mg/kg), rI/R, rI/R + Pro (5 mg/kg), and rI/R + Pro (10 mg/kg) groups. Rats were treated with Pro at 1 h after rI/R treatment. Serum and lung tissues at 24 h after rI/R were collected to evaluate morphological changes and the expression of myeloperoxidase (MPO), inflammatory cytokines, and crucial proteins in the MAPK pathway. Pro attenuated the production of mediators, resulting in reduced levels of autophagy and apoptosis by restricting the MAPK pathway in rI/R-induced ALI model. Pro represses rI/R-induced pulmonary autophagy and apoptosis by decreasing the production of inflammatory molecules, and the effects of Pro are involved in the inhibition of the MAPK pathway.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Propofol/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Lesão Renal Aguda/complicações , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ratos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
15.
PLoS Pathog ; 16(3): e1008341, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32176725

RESUMO

Infection with avian influenza A H5N1 virus results in acute lung injury (ALI) and has a high mortality rate (52.79%) because there are limited therapies available for treatment. Drug repositioning is an economical approach to drug discovery. We developed a method for drug repositioning based on high-throughput RNA sequencing and identified several drugs as potential treatments for avian influenza A H5N1 virus. Using high-throughput RNA sequencing, we identified a total of 1,233 genes differentially expressed in A549 cells upon H5N1 virus infection. Among these candidate genes, 79 drug targets (corresponding to 59 approved drugs) overlapped with the DrugBank target database. Twenty-two of the 41 commercially available small-molecule drugs reduced H5N1-mediated cell death in cultured A549 cells, and fifteen drugs that protected A549 cells when administered both pre- and post-infection were tested in an H5N1-infection mouse model. The results showed significant alleviation of acute lung injury by amitriptyline HCl (an antidepressant drug), flavin adenine dinucleotide (FAD; an ophthalmic agent for vitamin B2 deficiency), azacitidine (an anti-neoplastic drug) and calcitriol (an active form of vitamin D). All four agents significantly reduced the infiltrating cell count and decreased the lung injury score in H5N1 virus-infected mice based on lung histopathology, significantly improved mouse lung edema by reducing the wet-to-dry weight ratio of lung tissue and significantly improved the survival of H5N1 virus-infected mice. This study not only identifies novel potential therapies for influenza H5N1 virus-induced lung injury but also provides a highly effective and economical screening method for repurposing drugs that may be generalizable for the prevention and therapy of other diseases.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Amitriptilina/administração & dosagem , Azacitidina/administração & dosagem , Calcitriol/administração & dosagem , Influenza Humana/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/imunologia , Animais , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Feminino , Flavina-Adenina Dinucleotídeo/administração & dosagem , Humanos , Virus da Influenza A Subtipo H5N1/fisiologia , Influenza Humana/virologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
16.
Cell Mol Biol Lett ; 25: 10, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161620

RESUMO

Background: Ferroptosis is a newly recognized type of cell death, which is different from traditional necrosis, apoptosis or autophagic cell death. However, the position of ferroptosis in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored intensively so far. In this study, we mainly analyzed the relationship between ferroptosis and LPS-induced ALI. Methods: In this study, a human bronchial epithelial cell line, BEAS-2B, was treated with LPS and ferrostatin-1 (Fer-1, ferroptosis inhibitor). The cell viability was measured using CCK-8. Additionally, the levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and iron, as well as the protein level of SLC7A11 and GPX4, were measured in different groups. To further confirm the in vitro results, an ALI model was induced by LPS in mice, and the therapeutic action of Fer-1 and ferroptosis level in lung tissues were evaluated. Results: The cell viability of BEAS-2B was down-regulated by LPS treatment, together with the ferroptosis markers SLC7A11 and GPX4, while the levels of MDA, 4-HNE and total iron were increased by LPS treatment in a dose-dependent manner, which could be rescued by Fer-1. The results of the in vivo experiment also indicated that Fer-1 exerted therapeutic action against LPS-induced ALI, and down-regulated the ferroptosis level in lung tissues. Conclusions: Our study indicated that ferroptosis has an important role in the progression of LPS-induced ALI, and ferroptosis may become a novel target in the treatment of ALI patients.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Cicloexilaminas/uso terapêutico , Ferroptose/efeitos dos fármacos , Fenilenodiaminas/uso terapêutico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Aldeídos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cicloexilaminas/farmacologia , Ferroptose/imunologia , Humanos , Ferro/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenilenodiaminas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo
17.
J Nanobiotechnology ; 18(1): 38, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32101146

RESUMO

BACKGROUND: Macrophage polarization and reprogramming in the lung play a critical role in the initiation, development and progression of acute lung injury (ALI). Regulating the activation and differentiation of pulmonary macrophages may provide a potential therapeutic strategy to treat ALI. We previously developed a novel class of anti-inflammatory nanoparticles (P12) that can potently inhibit Toll-like receptor (TLR) signaling in macrophages. These bioactive nanodevices were made of gold nanoparticles (GNPs) coated with hexapeptides to not only ensure their physiological stability but also enable GNPs with TLR inhibitory activity. RESULTS: In this study, using a lipopolysaccharide (LPS) induced ALI mouse model, we showed that P12 was able to alleviate lung inflammation and damage through reducing the infiltration of inflammatory cells and increasing the anti-inflammatory cytokine (IL-10) in the lung. These results prompted us to investigate possible macrophage polarization by P12. We first confirmed that P12 primarily targeted macrophages in the lung to exert anti-inflammatory activity. We then showed that P12 could drive the polarization of mouse bone marrow-derived macrophages (BMDMs) toward anti-inflammatory M2 phenotype. Interestingly, in the ALI mouse model, P12 was able to increase the alveolar M2 macrophages and reduce both the alveolar and interstitial M1 macrophages in the bronchoalveolar lavage fluid (BALF) and lung tissues. CONCLUSION: This study demonstrated that peptide-coated GNPs could induce M2 macrophage polarization in vitro and in vivo to effectively regulate lung inflammation, protect lung from injuries and promote inflammation resolution. The ability of regulating macrophage polarization together with TLR inhibition made such a bioactive nanodevice a new generation of potent therapeutics to treat ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Ouro/farmacologia , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Ouro/química , Interleucina-10/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/tratamento farmacológico
18.
BMC Complement Med Ther ; 20(1): 40, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32033557

RESUMO

BACKGROUND: Guettarda speciosa is mainly found in tropical areas in Asia. Although G. speciosa is traditionally used to treat some of the inflammatory disorders, the experimental evidence supporting the anti-inflammatory effect of G. speciosa is limited. Here, we sought to obtain evidence that G. speciosa has anti-inflammatory activity using an acute lung injury (ALI) mouse model and to explore possible underlying mechanisms for the activity. METHODS: The methanol extract of G. speciosa Linn. (MGS) was fingerprinted by HPLC. Cytotoxicity was determined by MTT and flow cytometer. As for an ALI mouse model, C57BL/6 mice received an intratracheal (i.t.) injection of lipopolysaccharide (LPS). The effects of MGS on lung inflammation in the ALI mice were assessed by differential cell counting and FACS of inflammatory cells and hematoxylin and eosin staining of lung tissue. Proteins were analyzed by immunoprecipitation and immunoblotting, and gene expression was by real-time qPCR. Neutrophil elastase activity was measured by ELISA. RESULTS: MGS did not cause metabolic disarray or produce reactive oxygen species that could induce cytotoxicity. Similar to ALI patients, C57BL/6 mice that received an i.t. LPS developed a high level of neutrophils, increased pro-inflammatory cytokines, and inflicted tissue damage in the lung, which was suppressed by i.t. MGS administered at 2 h after LPS. Mechanistically, MGS activated Nrf2, which was related to MGS interrupting the ubiquitin-dependent degradation of Nrf2. MGS suppressed the nuclear localization of NF-κB induced by LPS, suggesting the inhibition of NF-κB activity. Furthermore, MGS inhibited the enzymatic activity of neutrophil elastase. CONCLUSION: MGS could suppress lung inflammation in an ALI mouse model, the effect of which could be attributed to multiple mechanisms, including the activation of Nrf2 and the suppression of NF-κB and neutrophil elastase enzymatic activity by MGS.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Extratos Vegetais/farmacologia , Pneumonia/tratamento farmacológico , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Citometria de Fluxo , Elastase de Leucócito/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Masculino , Metanol , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Rubiaceae/química
19.
Sci Rep ; 10(1): 2947, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076015

RESUMO

Sepsis is associated with exacerbated inflammatory response which subsequently results in multiple organ dysfunction. Sepsis accounts for high mortality and morbidity among newborns worldwide. Narciclasine is a plant alkaloid which has shown to possess anti-inflammatory properties. In this study we investigated the effect and mechanism of action of narciclasine in neonatal sepsis rat models. The excessive release of S100A8/A9 or calprotectin in neonatal sepsis could be detrimental as it could exacerbate the inflammatory responses. We found that narciclasine significantly reduced the plasma levels of S100A8/A9 and also suppressed its expression in the liver and lung. The systemic and local bacterial load was also reduced in the narciclasine treated rats. The systemic and local production of pro-inflammatory cytokines in plasma and organs (liver and lungs) was significantly reduced in the narciclasine treated rats. The histopathological studies showed that narciclasine prevents the organ damage associated with sepsis and improved the survival of neonatal rats. Sepsis increased the phosphorylated NF-κß p65 protein expression in the liver. Narciclasine suppressed the phosphorylation of NF-κß p65 and the degradation of NF-κß inhibitory protein alpha. It could also suppress the expression of adaptor proteins of the toll like receptor signaling pathway viz., myeloid differentiation factor 88 (MyD88), Interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6). These results suggest that narciclasine protects against sepsis in neonatal rats through the inhibition of calprotectin, pro-inflammatory cytokines and suppression of NF-κß signaling pathway.


Assuntos
Alcaloides de Amaryllidaceae/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , Complexo Antígeno L1 Leucocitário/metabolismo , Fenantridinas/uso terapêutico , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Alcaloides de Amaryllidaceae/farmacologia , Anemia/complicações , Animais , Animais Recém-Nascidos , Carga Bacteriana , Inflamação/sangue , Inflamação/complicações , Mediadores da Inflamação/sangue , Interleucina-6/metabolismo , Fígado/lesões , Fígado/patologia , Fenantridinas/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Proteínas S100/sangue , Proteínas S100/metabolismo , Sepse/sangue , Sepse/complicações , Sepse/microbiologia , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
20.
Sci Rep ; 10(1): 1790, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019966

RESUMO

Paraquat (PQ) is a non-selective herbicide and is exceedingly toxic to humans. The mechanism of PQ toxicity is very complex and has not been clearly defined. There is no specific antidote for PQ poisoning. 5-hydroxy-1-methylhydantoin (HMH) is an intrinsic antioxidant and can protect against renal damage caused by PQ. The mechanism of PQ toxicology and the possible effects of HMH on PQ-induced lung injury were determined in this study. It was found that PQ decreased superoxide dismutase (SOD) activity and elevated the level of malondialdehyde (MDA), while HMH elevated SOD activity and decreased the level of MDA. Based on metabolomics, the citrate cycle, glutathione metabolism, taurine and hypotaurine metabolism, regulation of lipolysis in adipocytes, inflammatory mediator regulation of TRP channels, purine and pyrimidine metabolism, aldosterone synthesis and secretion, and phenylalanine metabolism were changed in the PQ group. Compared with the PQ group, the levels of N-acetyl-l-aspartic acid, L-glutamic acid, L-aspartic acid, mesaconic acid, adenosine 5' monophosphate, methylmalonic acid, cytidine, phosphonoacetic acid, hypotaurine, glutathione (reduced) and cysteinylglycine increased, while the levels of corticosterone, xanthine, citric acid, prostaglandin G2, 4-pyridoxic acid and succinyl proline decreased in the HMH group. These metabolites revealed that HMH can alleviate inflammation caused by PQ and elevate the activity of intrinsic antioxidants. In conclusion, our results revealed PQ toxicology and the pharmacology underlying the protective effect of HMH on lung injury due to PQ. Toxicity caused by PQ results in lipid peroxidation and an increase in reactive oxygen species (ROS), nitric oxide (NO), damage to the biliary system, gastrointestinal system and nervous system, in addition to lungs, kidneys, and the liver. HMH is a good antioxidant and protects against lung injury caused by PQ. In summary, HMH efficiently reduced PQ-induced lung injury in mice.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Herbicidas/toxicidade , Hidantoínas/uso terapêutico , Paraquat/toxicidade , Substâncias Protetoras/uso terapêutico , Lesão Pulmonar Aguda/metabolismo , Glutationa/metabolismo , Humanos , Peroxidação de Lipídeos/fisiologia , Malondialdeído/metabolismo , Metabolômica , Superóxido Dismutase/metabolismo , Taurina/metabolismo
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