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1.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32968029

RESUMO

In this report, we describe the case of a 17-year-old boy with progressive respiratory failure requiring extracorporeal support who met clinical criteria for a presumptive diagnosis of electronic cigarette or vaping-associated acute lung injury (EVALI), with clinical, pathologic, and laboratory evidence of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). The patient in our report had a history of tetrahydrocannabinol and nicotine electronic cigarette use for months leading up to his presentation of fever, headache, emesis, and weight loss with respiratory distress. Multiple potential diagnoses were explored, and the patient's respiratory status improved, and he was initially discharged from the hospital. Roughly one week later, the patient was readmitted for worsening respiratory distress. The patient then met sufficient criteria for a potential diagnosis of HLH and MAS (elevated ferritin level, inflammatory markers, and cytopenia) to warrant a bone marrow aspirate, which revealed rare hemophagocytic cells. Given the severity of his symptoms and laboratory evidence of HLH and MAS, the patient was started on a course of steroids and anakinra. Although laboratory markers improved after treatment, the patient's respiratory failure worsened, ultimately progressing to a need for mechanical ventilation and extracorporeal support and leading to worsening multiorgan system failure and, ultimately, death. To the best of our knowledge, this is the first report of a patient with a presumptive diagnosis of EVALI with evidence of HLH and MAS, raising the possibility that macrophage activation may play a role in the pathogenesis of EVALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Sistemas Eletrônicos de Liberação de Nicotina , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Vaping/efeitos adversos , Adolescente , Evolução Fatal , Humanos , Síndrome de Ativação Macrofágica/induzido quimicamente , Masculino , Insuficiência de Múltiplos Órgãos/etiologia
2.
J Toxicol Sci ; 45(8): 423-434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741895

RESUMO

Paraquat (PQ) as a non-selective heterocyclic herbicide, has been applied worldwide for over a few decades. But PQ is very harmful to humans and rodents. The lung is the main target organ of PQ poisoning. It is an important event that lung epithelial cells are injured during PQ-induced acute lung injury and pulmonary fibrosis. As a regulator of mRNA expression, microRNA (miRNA) may play an important role in the progress. Our study was to investigate the mechanisms of PQ-induced injury of pulmonary epithelial cells through analyzing the profiling of miRNAs and their target genes. As a result, 11 differentially expressed miRNAs were screened, including 1 upregulated miRNA and 10 downregulated miRNAs in PQ-treated murine lung alveolar epithelial cells (MLE-12 cells). The bioinformatic analyses suggested that the target genes of these miRNAs were involved in mitochondrial apoptosis pathway and DNA methylation, and participated in the regulation of PI3K-Akt, mTOR, RAS, TNF, MAPK and other signal pathways which related to oxidative stress and apoptosis. This indicated that miRNAs were an important regulator of oxidative stress and apoptosis during PQ-induced injury of murine lung alveolar epithelial cells. The findings would deepen our understanding of the mechanisms of PQ-induced pulmonary injury and might provide new treatment targets for this disease.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Apoptose/genética , Células Epiteliais/efeitos dos fármacos , Perfilação da Expressão Gênica , Expressão Gênica , Herbicidas/toxicidade , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo/genética , Paraquat/toxicidade , Alvéolos Pulmonares/citologia , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Metilação de DNA/genética , Camundongos , MicroRNAs/fisiologia , Mitocôndrias/patologia
4.
Exp Cell Res ; 394(2): 112101, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32474064

RESUMO

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) are common lung disorders characterized by alveolar-capillary barrier disruption and dyspnea, which can cause substantial morbidity and mortality. Currently, a cluster of acute respiratory illnesses, known as novel coronavirus (2019-nCoV)-infected pneumonia (NCIP), which allegedly originally occurred in Wuhan, China, has increased rapidly worldwide. The critically ill patients with ARDS have high mortality in subjects with comorbidities. Previously, the excessive recruitment and activation of neutrophils (polymorphonuclear leukocytes [PMNs]), accompanied by neutrophil extracellular traps (NETs) formation were reported being implicated in the pathogenesis of ALI/ARDS. However, the direct visualization of lung epithelial injuries caused by NETs, and the qualitative and quantitative evaluations of this damage are still lacking. Additionally, those already reported methods are limited for their neglect of the pathological role exerted by NETs and focusing only on the morphological features of NETosis. Therefore, we established a cell-based assay for detecting NETs during lung epithelial cells-neutrophils co-culture using the xCELLigence system, a recognized real-time, dynamic, label-free, sensitive, and high-throughput apparatus. Our results demonstrated that lung epithelial injuries, reflected by declines in cell index (CI) values, could be induced by lipopolysaccharide (LPS)-activated PMNs, or NETs in a time and dose-dependent manner. NETs generation was verified to be the major contributor to the cytotoxicity of activated PMNs; protein components of NETs were the prevailing cytotoxic mediators. Moreover, this cell-based assay identified that PMNs from severe pneumonia patients had a high NETs formative potential. Additionally, acetylsalicylic acid (ASA) and acetaminophen (APAP) were discovered alleviating NETs formation. Thus, this study not only presents a new methodology for detecting the pathophysiologic role of NETs but also lays down a foundation for exploring therapeutic interventions in an effort to cure ALI/ARDS in the clinical setting of severe pneumonia, including the emerging of NCIP.


Assuntos
Lesão Pulmonar Aguda/sangue , Infecções por Coronavirus/sangue , Armadilhas Extracelulares/diagnóstico por imagem , Neutrófilos/metabolismo , Pneumonia Viral/sangue , Síndrome do Desconforto Respiratório do Adulto/sangue , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/diagnóstico por imagem , Lesão Pulmonar Aguda/virologia , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Armadilhas Extracelulares/virologia , Humanos , Lipopolissacarídeos/toxicidade , Pulmão/diagnóstico por imagem , Pulmão/virologia , Masculino , Neutrófilos/virologia , Pandemias , Pneumonia/sangue , Pneumonia/diagnóstico por imagem , Pneumonia/virologia , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Síndrome do Desconforto Respiratório do Adulto/virologia
5.
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
6.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(3): 376-381, 2020 Mar 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376590

RESUMO

OBJECTIVE: To investigate the changes in phagocytic function of alveolar macrophages (AMs) in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explore the possible mechanism. METHODS: Kunming mice were randomly divided into normal control group and ALI (induced by LPS instillation in the airway) model group. AMs were obtained from bronchoalveolar lavage fluid in both groups, and phagocytosis of the AMs was observed using flow cytometry and fluorescence microscopy. Western blotting and ELISA were used to detect the expression and secretion of IL-33 in the lung tissue of the mice. We also detected the secretion of IL-33 by an alveolar epithelial cell line MLE-12 in response to stimulation with different concentrations of LPS. The AMs from the normal control mice were treated with different concentrations of LPS and IL-33, and the changes in the phagocytic activity of the cells were observed. RESULTS: Compared with those in normal control group, the percentage of AMs phagocytosing fluorescent microspheres was significantly decreased, and the expression of IL-33 in lung tissue and IL-33 level in the bronchoalveolar lavage fluid were significantly increased in ALI mice (P < 0.01). LPS (100-1000 ng/mL) obviously promoted the secretion of IL-33 in cultured MLE-12 cells (P < 0.01). Both LPS (10-500 ng/mL) and IL-33 (100 ng/mL) significantly inhibited the phagocytic activity of the AMs from normal control mice (P < 0.01). CONCLUSIONS: The phagocytic activity of AMs is weakened in ALI mice possibly due to direct LPS stimulation and the inhibitory effect of the alarmin IL-33 produced by LPS-stimulated alveolar epithelial cells.


Assuntos
Lesão Pulmonar Aguda , Macrófagos Alveolares , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Lipopolissacarídeos , Pulmão , Camundongos , Fagocitose
7.
Artigo em Chinês | MEDLINE | ID: mdl-32306680

RESUMO

Objective: To investigate the CT features of lung injury induced by paraquat poisoning and its relationship with prognosis, and to provide reference for the judgment of the condition and prognosis of paraquat poisoning. Methods: 146 cases of paraquat poisoning patients were treated in the Third People's Hospital of Xuzhou City from January 2013 to April 2016. The cases were divided into mild group, moderate-severe group and fulminant group according to the concentration of paraquat in urine. The clinical data and CT imaging findings were analyzed and reconstructed in three-dimensional reconstruction. The extent of the lesion was observed and the relationship between CT and prognosis was explored. Results: Paraquat lung injury has many manifestations on CT images, and it's performance can be intersecting at the same time. Early lesions lighter cases, late CT imaging lesions can be completely absorbed or residual fibrosis, the prognosis was good; the early lesion was pulmonary consolidation, pleural effusion cases, the late CT image was usually pleural thickening and bronchiectasis, the prognosis was relatively good; early lesions were large patches of ground glass opacity cases, finally, pulmonary fibrosis was common, the mortality rate of 56.57%. There were significant differences in the extent of lung injury between different groups (P<0.001) , and the difference in mortality was statistically significant when the lung injury was different (P<0.001) . Multivariate stepwise Logistic regression analysis showed that ground-glass opacity (OR value=2.013) , interstitial lung fibrosis (OR=3.779) and mediastinal emphysema (OR=33.118) were risk factors for death of lung injury caused by paraquat poisoning (P<0.05) . Conclusion: There were many manifestations on CT images of paraquat lung injury, and the manifestations of paraquat lung injury can be intersecting at the same time. The pulmonary manifestations and outcomes of different paraquat types were different. The CT manifestations of lung injury in paraquat poisoning were mainly exudative changes at early stage, and can be gradually absorbed or evolved into interstitial changes at later stage. The cumulative damage range can be used as a reference for evaluating the prognosis. Ground-glass opacity, interstitial pulmonary fibrosis and mediastinal emphysema are the risk factors for death of lung injury caused by paraquat poisoning.


Assuntos
Lesão Pulmonar Aguda/diagnóstico por imagem , Paraquat/envenenamento , Lesão Pulmonar Aguda/induzido quimicamente , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Prognóstico , Tomografia Computadorizada por Raios X
8.
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
9.
J Toxicol Sci ; 45(3): 177-186, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32147640

RESUMO

MECP2 (Methyl-CpG-binding protein 2) has been shown to have a critical role in regulating DNA methylation against smoke exposed lung injury. However, the biological function of MECP2 and the underlying molecular mechanism remains elusive. Human bronchial epithelial (16HBE) and alveolar type II epithelial cells (AECII) were exposed to increasing concentrations of cigarette smoke extracts (CSE) solution to establish CSE-induced lung epithelial cell injury models. Our findings revealed that MECP2 was down-regulated, while CYP1B1 was up-regulated in CSE-induced lung epithelial cell injury models by quantitative real time PCR, western blotting and immunofluorescence staining. Down-regulated CYP1B1 was ascribed to the demethylation of its promoter by methylation-specific PCR (MSP). The in vitro experiments further showed that MECP2 overexpression significantly attenuated CSE-triggered cell growth attenuation, cell cycle arrest, apoptosis and ROS generation in lung epithelial cells by CCK-8 and flow cytometry assays. In molecular level, we further demonstrated that MECP2 overexpression obviously suppressed the expression of CYP1B1 through enhancing DNA methylation. Therefore, our data suggest that MECP2 protects against CSE-induced lung epithelial cell injury possibly through down-regulating CYP1B1 expression via elevating its methylation status.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Fumar Cigarros/efeitos adversos , Citocromo P-450 CYP1B1/metabolismo , Metilação de DNA , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Expressão Gênica , Pulmão/citologia , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Extratos Vegetais/efeitos adversos , Tabaco/química , Lesão Pulmonar Aguda/patologia , Células Cultivadas , Citocromo P-450 CYP1B1/genética , Humanos , Extratos Vegetais/isolamento & purificação
10.
Artigo em Inglês | MEDLINE | ID: mdl-32129084

RESUMO

Clinical studies have established that the capacity of removing excess fluid from alveoli is impaired in most patients with acute respiratory distress syndrome. Impaired alveolar fluid clearance (AFC) correlates with poor outcomes. Adenosine A2B receptor (A2BAR) has the lowest affinity with adenosine among four adenosine receptors. It is documented that A2BAR can activate adenylyl cyclase (AC) resulting in elevated cAMP. Based on the understanding that cAMP is a key regulator of epithelial sodium channel (ENaC), which is the limited step in sodium transport, we hypothesized that A2BAR signaling may affect AFC in acute lung injury (ALI) through regulating ENaC via cAMP, thus attenuating pulmonary edema. To address this, we utilized pharmacological approaches to determine the role of A2BAR in AFC in rats with endotoxin-induced lung injury and further focused on the mechanisms in vitro. We observed elevated pulmonary A2BAR level in rats with ALI and the similar upregulation in alveolar epithelial cells exposed to LPS. A2BAR stimulation significantly attenuated pulmonary edema during ALI, an effect that was associated with enhanced AFC and increased ENaC expression. The regulatory effects of A2BAR on ENaC-α expression were further verified in cultured alveolar epithelial type II (ATII) cells. More importantly, activation of A2BAR dramatically increased amiloride-sensitive Na+ currents in ATII cells. Moreover, we observed that A2BAR activation stimulated cAMP accumulation, whereas the cAMP inhibitor abolished the regulatory effect of A2BAR on ENaC-α expression, suggesting that A2BAR activation regulates ENaC-α expression via cAMP-dependent mechanism. Together, these findings suggest that signaling through alveolar epithelial A2BAR promotes alveolar fluid balance during endotoxin-induced ALI by regulating ENaC via cAMP pathway, raising the hopes for treatment of pulmonary edema due to ALI.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Células Epiteliais Alveolares/metabolismo , AMP Cíclico/metabolismo , Alvéolos Pulmonares/metabolismo , Receptor A2B de Adenosina/metabolismo , Transdução de Sinais/fisiologia , Lesão Pulmonar Aguda/induzido quimicamente , Adenosina/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Animais , Endotoxinas/farmacologia , Canais Epiteliais de Sódio/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Alvéolos Pulmonares/efeitos dos fármacos , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
11.
Oxid Med Cell Longev ; 2020: 6579696, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32148654

RESUMO

Mitophagy is involved in sepsis-induced acute lung injury (ALI). Bcl-2 family proteins play an important role in mitochondrial homeostasis. However, whether targeting Bcl-2 proteins (Bcl-2 and Bad) could influence mitophagy in ALI remains unclear. In this study, lipopolysaccharide (LPS) was used to induce injury in A549 cells and ALI in mice. LPS treatment resulted in elevated cell apoptosis, enhanced mitophagy, decreased Bcl-2 expression, increased Bad expression, and activation of PINK1/Parkin signaling in cells and lung tissues. Both Bcl-2 overexpression and Bad knockdown attenuated LPS-induced injury, inhibited cell apoptosis and mitophagy, and improved survival. Atg5 knockout (KO) inhibited LPS-induced cell apoptosis. Furthermore, Bcl-2 proteins regulated mitophagy by modulating the recruitment of Parkin from the cytoplasm to mitochondria via direct protein-protein interactions. These results were further confirmed in Park2 KO cells and Park2-/- mice. This is the first study to demonstrate that Bcl-2 proteins regulated mitophagy in LPS-induced ALI via modulating the PINK1/Parkin signaling pathway, promoting new insights into the mechanisms and investigation of therapeutic strategies for a septic patient with ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lipopolissacarídeos/efeitos adversos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ubiquitina-Proteína Ligases/genética , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Mitofagia , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo
13.
Pneumologie ; 74(2): 77-87, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-32016924

RESUMO

Beginning in April of 2019, the US saw > 2,000 cases of hospitalized, often young, patients with severe acute lung injury, of which over 40 died, and the only existing connection between patients was their use of electronic cigarettes (e-cigarettes). The acronym EVALI ("e-cigarette, or vaping, product use associated lung injury") has since been established for the condition. This review article is intended to provide an overview of recent, mainly US literature on EVALI, including the case definition, epidemiology, clinical presentation, typical disease progression, as well as potential triggers. Ancillary to this, the review further provides a general overview of the basic function of e-cigarettes, the ingredients of the liquids used in these (e-liquids), as well as a brief description of the associated potential inhalation risks.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Dronabinol/efeitos adversos , Sistemas Eletrônicos de Liberação de Nicotina , Vaping/efeitos adversos , Lesão Pulmonar Aguda/epidemiologia , Canabidiol/administração & dosagem , Canabidiol/efeitos adversos , Surtos de Doenças , Dronabinol/administração & dosagem , Humanos , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Fatores de Risco
14.
Artigo em Inglês | MEDLINE | ID: mdl-32073894

RESUMO

The adaptive immune response could play a major role in the resolution of lung injury. Although regulatory T cells (Tregs) have been implicated in promoting the resolution of lung injury, therapeutic strategies to enhance Treg quantity and activity at the site of injury need further exploration. In the current study, Akt inhibition using triciribine (TCBN), given 48 h after lipopolysaccharide (LPS) administration, increased Tregs-promoted resolution of acute lung injury (ALI). TCBN treatment enhanced the resolution of LPS-induced ALI on day 7 by reducing pulmonary edema and neutrophil activity associated with an increased number of CD4+/FoxP3+/CD103+ and CTLA4+ effector Tregs, specifically in the injured lungs and not in the spleen. Treatment of EL-4 T-lymphocytes with two Akt inhibitors (TCBN and MK-2206) for 72 h resulted in increased FoxP3 expression in vitro. On the other end, Treg-specific PTEN knockout (PTENTreg KO) mice that have a higher Akt activity in its Tregs exhibited a significant impairment in ALI resolution, increased edema, and neutrophil activity associated with a reduced number of CD4+/FoxP3+/CD103+ and CTLA4+ effector Tregs as compared with the control group. In conclusion, our study identifies a potential target for the treatment of late-stage ALI by promoting resolution through effector Treg-mediated suppression of inflammation.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T Reguladores/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Transferência Adotiva/métodos , Animais , Antígenos CD/metabolismo , Antígenos CD4/metabolismo , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Cadeias alfa de Integrinas/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Baço , Linfócitos T Reguladores/efeitos dos fármacos
15.
Mol Immunol ; 120: 13-22, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32045770

RESUMO

OBJECTIVE: To investigate the impact of death-associated protein kinase 1 (Dapk1) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) via p38MAPK/NF-κB pathway. METHODS: Dapk1+/+ and Dapk1-/- mice were randomized into Control, LPS, SB203580 (a p38MAPK pathway inhibitor) + LPS, and PDTC (a NF-κB pathway inhibitor) + LPS groups. Cell counts, lung wet to dry weight ratio (W/D weight ratio), as well as indicators of oxidative stress were determined followed by the detection with HE staining, ELISA, qRT-PCR, Western blotting and Immunofluorescence. Besides, to explore whether the effect of Dapk1 on ALI directly mediated via p38MAPK/NF-κB pathway, mice were injected with TC-DAPK 6 (a Dapk1 inhibitor) with or without SB203580/PDTC before LPS administration. RESULTS: LPS induced lung injury with increased lung W/D weight ratio, which could be partly reversed by SB203580 and PDTC in LPS-induced mice with activated p38MAPK/NF-κB pathway in lung tissues, especially in Dapk1-/- mice. SB203580 and PDTC reduced total cells and neutrophils in BALF in LPS-induced mice, accompanying with decreased levels of TNF-α, IL-6, MPO, LPO and MDA and the expressions of beclin-1, Atg5 and LC3II, but with the up-regulated activities of SOD and GSH-Px, as well as p62 protein expression. Besides, TC-DAPK 6 aggravated the pathologic injury in LPS-induced ALI with more serious inflammatory response, oxidative stress and autophagy as well as the activated p38MAPK/NF-κB pathway, which were reversed by SB203580 or PDTC. CONCLUSION: Dapk1 improved oxidative stress, inhibited autophagy, and reduce inflammatory response of LPS-induced ALI mice by inhibiting p38MAPK/NF-κB pathway.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Proteínas Quinases Associadas com Morte Celular/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Autofagia , Proteínas Quinases Associadas com Morte Celular/deficiência , Proteínas Quinases Associadas com Morte Celular/genética , Imidazóis/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Estresse Oxidativo , Piridinas/farmacologia , Pirrolidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiocarbamatos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-31994907

RESUMO

Acute respiratory distress syndrome (ARDS) is a common cause of death in the intensive care unit, with mortality rates of ~30-40%. To reduce invasive diagnostics such as bronchoalveolar lavage and time-consuming in-hospital transports for imaging diagnostics, we hypothesized that particle flow rate (PFR) pattern from the airways could be an early detection method and contribute to improving diagnostics and optimizing personalized therapies. Porcine models were ventilated mechanically. Lipopolysaccharide (LPS) was administered endotracheally and in the pulmonary artery to induce ARDS. PFR was measured using a customized particles in exhaled air (PExA 2.0) device. In contrast to control animals undergoing mechanical ventilation and receiving saline administration, animals who received LPS developed ARDS according to clinical guidelines and histologic assessment. Plasma levels of TNF-α and IL-6 increased significantly compared with baseline after 120 and 180 min, respectively. On the other hand, the PFR significantly increased and peaked 60 min after LPS administration, i.e., ~30 min before any ARDS stage was observed with other well-established outcome measurements such as hypoxemia, increased inspiratory pressure, and lower tidal volumes or plasma cytokine levels. The present results imply that PFR could be used to detect early biomarkers or as a clinical indicator for the onset of ARDS.


Assuntos
Lesão Pulmonar Aguda/patologia , Modelos Animais de Doenças , Lipopolissacarídeos/toxicidade , Troca Gasosa Pulmonar , Síndrome do Desconforto Respiratório do Adulto/patologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Gasometria , Citocinas/metabolismo , Hemodinâmica , Tamanho da Partícula , Reologia , Suínos , Volume de Ventilação Pulmonar
17.
Mol Med Rep ; 21(2): 927-935, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974595

RESUMO

Acute lung injury (ALI) is characterized by neutrophilic infiltration, uncontrolled oxidative stress and inflammatory processes. Despite various therapeutic regimes having been performed, there remains no effective pharmacotherapy available to treat ALI. Halofuginone (HF), a ketone isolated from Dichroa febrifuga, exhibits significant anti­inflammatory and antifibrotic effects. Dexamethasone (DEX), a synthetic glucocorticoid, has been routinely used as an adjuvant therapy in treating inflammatory diseases, including ALI. The present study aimed to investigate the effects of the combination of HF and DEX in the treatment of ALI. The present results suggested that the simultaneous administration of HF and DEX markedly decreased the level of pro­inflammatory cytokines and increased the level of anti­inflammatory cytokines, as assessed by western blot analysis. In addition, HF and DEX effectively decreased nuclear factor­κB activity via suppressing the phosphorylation of P65 in lipopolysaccharide (LPS)­induced human pulmonary alveolar epithelial cells (HPAEpiC) and lung tissues extracted from ALI rats, as determined by immunofluorescence. Furthermore, in vivo experiments demonstrated that the combination of HF and DEX in LPS­induced ALI rats defended against lung fibrosis, perivascular inflammation, congestion and edema of pulmonary alveoli, as assessed by histopathological analysis, TUNEL staining and immunohistochemistry assay. Taken together, the present study indicated the synergistic effect of HF and DEX on LPS­induced ALI in HPAEpiC cells and a rat model. These results offer a novel therapeutic approach for the treatment of ALI.


Assuntos
Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares/patologia , Dexametasona/farmacologia , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Células Epiteliais Alveolares/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Inflamação/patologia , Lipopolissacarídeos , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
18.
Thorax ; 75(3): 253-261, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31915307

RESUMO

INTRODUCTION: Zinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested. METHODS: 64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well. RESULTS: Injecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail. CONCLUSION: Zinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/prevenção & controle , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , Zinco/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Proteínas de Transporte de Cátions/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/genética , Homeostase , Humanos , Selectina L/metabolismo , Lipopolissacarídeos , Masculino , Metalotioneína/genética , Metalotioneína/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro , Receptores de Complemento 3b/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Zinco/metabolismo , Zinco/uso terapêutico
19.
J Biochem Mol Toxicol ; 34(3): e22434, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31860763

RESUMO

The purpose of this paper is to observe the protective action and its effective mechanism of eriodictyol on lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, our results indicated that eriodictyol could dramatically suppress the inflammatory mediators, including interleukin-6 (IL-6), IL-1ß, prostaglandin E2, and tumor necrosis factor-α in bronchoalveolar lavage fluid of LPS-challenged mice. Eriodictyol also alleviated the wet/dry ratio and improved pathological changes of the lung. In addition, eriodictyol significantly decreased myeloperoxidase activity and malondialdehyde content as well as increased superoxide dismutase activity. Moreover, eriodictyol inhibited the COX-2/NLRP3/NF-κB signaling pathway in the lung tissues of ALI mice. In conclusion, our observations validated that eriodictyol processed the protective effects on ALI mice, which was related to the regulation of the COX-2/NLRP3/NF-κB signaling pathway.


Assuntos
Lesão Pulmonar Aguda , Ciclo-Oxigenase 2/metabolismo , Flavanonas/farmacologia , Lipopolissacarídeos/toxicidade , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
20.
Eur J Pharmacol ; 869: 172893, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31883915

RESUMO

Organosulfur compounds, such as L-cysteine, allicin and other sulfur-containing organic compounds in Allium species, have been proposed to possess many important physiological and pharmacological functions. A novel L-cysteine derivative, t-Butyl S-allylthio-L-cysteinate (5P39), was designed and synthesized by combining L-cysteine derivative and allicin pharmacophore through a disulfide bond. This study aimed to explore the effects and mechanisms of 5P39 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. At the experimental concentration (5, 10 and 20 µM), 5P39 suppressed the excessive secretion of nitric oxide (NO) and interleukin-6 (IL-6) in mice peritoneal macrophages stimulated by LPS. A mouse model of ALI was established by tracheal instillation of LPS for 2 h before 5P39 (30 and 60 mg/kg) administration. The results showed that 5P39 treatment down-regulated the wet/dry weight ratio (W/D ratio) of lungs and reduced the protein concentration, the number of total cells as well as the myeloperoxidase (MPO) activity in bronchoalveolar lavage fluid (BALF). 5P39 administration improved the histopathological changes of lungs in ALI mice with the decreased levels of pro-inflammatory cytokines in BALF. The inhibitory effects of 5P39 on the toll-like receptor 4 (TLR4) expression and macrophages accumulation in lung tissues were observed by immunohistochemistry. Additionally, 5P39 significantly attenuated the LPS-activated high expression of key proteins in TLR4/MyD88 signaling pathway. Taken together, the present study showed that 5P39 effectively alleviate the severity of ALI, and its mechanism might relate to the inhibition of LPS-activated TLR4/MyD88 signaling pathway, demonstrating a promising potential for further development into an anti-inflammatory drug candidate.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Cisteína/farmacologia , Cisteína/uso terapêutico , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cisteína/análogos & derivados , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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