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2.
Rev. esp. patol. torac ; 35(3): 214-216, oct. 2023. ilus
Artigo em Espanhol | IBECS | ID: ibc-227391

RESUMO

La toxicidad pulmonar es un efecto adverso poco frecuente de la amiodarona cuyo diagnóstico es una tarea complicada ya que debe tenerse una alta sospecha clínica y descartar otras patologías que pueden confundirse con este proceso. Es importante que el diagnóstico sea precoz para poder instaurar un tratamiento temprano y evitar la progresión a fibrosis pulmonar. Presentamos un caso que manifiesta la importancia de un diagnóstico preciso y la buena evolución del mismo tras la retirada del fármaco y la instauración de tratamiento. (AU)


Pulmonary toxicity is a rare adverse effect of amiodarone, the diagnosis of which is a complicated task since a high clinical suspicion must be maintained and other pathologies that may be confused with this process must be ruled out. It is important that the diagnosis is early to be able to establish early treatmentand avoid progression to pulmonary fibrosis. We present a case that shows the importance of an accurate diagnosis and its good evolution after drug withdrawal and treatment initiation. (AU)


Assuntos
Humanos , Masculino , Idoso , Amiodarona/efeitos adversos , Amiodarona/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Pneumopatias
4.
Pulm Pharmacol Ther ; 82: 102243, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37454870

RESUMO

PURPOSE: Chronic lung allograft dysfunction (CLAD) was a common complication following lung transplantation that contributed to long-term morbidity and mortality. Statin therapy had been suggested to attenuate recipient inflammation and immune response, potentially reducing the risk and severity of CLAD. This study aimed to evaluate the impact of statin use and in vivo exposure on the incidence of CLAD in lung transplant recipients (LTRs), as well as their effects on immune cells and inflammatory factors. METHODS: A retrospective cohort study was conducted on patients who underwent lung transplantation between January 2017 and December 2020. The incidence of CLAD, as per the 2019 ISHLT criteria, was assessed as the clinical outcome. The plasma concentrations of statin were measured using a validated UPLC-MS/MS method, while inflammation marker levels were determined using ELISA kits. RESULTS: The statin group exhibited a significantly lower rate of CLAD (P = 0.002). Patients receiving statin therapy showed lower CD4+ T-cell counts, total T-lymphocyte counts, and IL-6 levels (P = 0.017, P = 0.048, and P = 0.038, respectively). Among the CLAD groups, the atorvastatin level (2.51 ± 1.31 ng/ml) was significantly lower than that in the non-CLAD group (OR = 1.438, 95%CI (1.007-2.053), P = 0.046). CONCLUSION: Statin therapy significantly reduced the incidence of CLAD, as well as immune cell counts and inflammatory cytokine levels in LTRs. Although the statin exposure was significantly lower in CLAD patients, it was not associated with the incidence of CLAD.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Transplante de Pulmão , Disfunção Primária do Enxerto , Humanos , Aloenxertos/efeitos dos fármacos , Aloenxertos/imunologia , Cromatografia Líquida , População do Leste Asiático , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Transplante de Pulmão/efeitos adversos , Estudos Retrospectivos , Espectrometria de Massas em Tandem , Transplantados , Disfunção Primária do Enxerto/etiologia , Disfunção Primária do Enxerto/imunologia , Disfunção Primária do Enxerto/prevenção & controle , Fatores de Risco
5.
Chem Biol Interact ; 382: 110613, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37353135

RESUMO

Lung toxicity of carbon nanotubes (CNTs) is matter of concern since very long time. However, their mechanism of toxicity is still not yet well defined. In this work, the role of structural defects as organic stressors of CNTs able to trigger their potential toxicity is investigated. Four commercial CNTs, with different carbon purity grade, are morphologically characterized by transmission electron microscopy (TEM) and the relative amount of structural defects are estimated through Raman spectroscopy, by measuring the intensity ratio D/G (ID/IG). The oxidative potential of CNTs is evaluated with cytochrome-C assay and reactive oxygen species (ROS) detection. Data show that CNTs with larger amounts of structural defects (higher ID/IG ratio) induce an increased ROS generation and consequent cytotoxicity and cellular damage, shown by TEM images of CNTs-cells interaction. Raman analyses of cells exposed to CNTs point out that the spectra of the CNTs inside the cells show no differences with respect of the signal recorded for cell-free CNTs, evidencing their biopersistence in lung cells. Raman spectra cannot provide direct indication of the existence of metals as impurity. It follows that the intensity ratio ID/IG can be taken as a predictive marker of the toxicity of a given CNT.


Assuntos
Pulmão , Nanotubos de Carbono , Nanotubos de Carbono/química , Nanotubos de Carbono/toxicidade , Nanotubos de Carbono/ultraestrutura , Análise Espectral Raman , Microscopia Eletrônica de Transmissão , Humanos , Linhagem Celular , Pulmão/citologia , Pulmão/efeitos dos fármacos , Animais
6.
JAMA ; 329(18): 1567-1578, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-37159034

RESUMO

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.


Assuntos
Fibrose Pulmonar Idiopática , Medicamentos para o Sistema Respiratório , Idoso , Humanos , Masculino , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Resultado do Tratamento , Ensaios Clínicos Fase III como Assunto , Estudos Multicêntricos como Assunto , Administração Oral , Pessoa de Meia-Idade , Feminino , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Medicamentos para o Sistema Respiratório/farmacologia , Medicamentos para o Sistema Respiratório/uso terapêutico
7.
Int. j. morphol ; 41(2): 539-547, abr. 2023. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1440313

RESUMO

SUMMARY: A great deal of attention of air pollution on respiratory health is increasing, particularly in relation to haze days. It is that exposure to cigarette smoke augments the toxicity of common air contaminants, thereby increasing the complexity of respiratory diseases. Although there are various mechanisms involved to respiratory diseases caused or worsen by cigarette smoking, in which the role of AQPs in the lung with regard to fluid homeostasis still remains elusive. In this paper, we copied the rat models based on smoke generator, and investigated the morphological changes of mucosa and related functions depending on the balance of lining liquid of alveoli via AQPs expression. Compared with normal group, weak labelling of AQP1 and AQP5 protein abundance were clearly detected in the corresponding part of smoke exposure groups compared with normal group. Hence, it is suggested that the contribution of AQPs in the lung is diminished, thereby causing perturbed balancing between resorptive and secretory fluid homeostasis under cigarette smoking.


Cada vez se presta más atención a la contaminación del aire en la salud respiratoria, particularmente, en relación con los días de neblina. En consecuencia la exposición al humo del cigarrillo aumenta la toxicidad de los contaminantes comunes del aire, lo que además aumenta la complejidad de las enfermedades respiratorias. Aunque existen varios mecanismos involucrados en las enfermedades respiratorias causadas o empeoradas por el tabaquismo, en las que el papel de las AQP en el pulmón respecto a la homeostasis de líquidos sigue siendo difícil de alcanzar. En este artículo, copiamos los modelos de rata basados en el generador de humo e investigamos los cambios morfológicos de la mucosa y las funciones relacionadas según el equilibrio del líquido de revestimiento de los alvéolos a través de la expresión de AQP. En comparación con el grupo normal, se detectó claramente un etiquetado débil de la abundancia de proteínas AQP1 y AQP5 en la parte correspondiente de los grupos de exposición al humo en comparación con el grupo control. Por lo tanto, se sugiere que la contribución de las AQP en el pulmón está disminuida, provocando así un equilibrio perturbado entre la homeostasis del líquido secretor y de reabsorción bajo el hábito de fumar cigarrillos.


Assuntos
Animais , Ratos , Sistema Respiratório/patologia , Fumar Cigarros/efeitos adversos , Sistema Respiratório/efeitos dos fármacos , Líquidos Corporais/metabolismo , Imuno-Histoquímica , Microscopia Eletrônica , Ratos Sprague-Dawley , Aquaporinas/metabolismo , Homeostase , Pulmão/efeitos dos fármacos , Pulmão/patologia
8.
Appl Biochem Biotechnol ; 195(12): 7338-7378, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37000353

RESUMO

The pathophysiology of lung cancer is dependent on the dysregulation in the apoptotic and autophagic pathways. The intricate link between apoptosis and autophagy through shared signaling pathways complicates our understanding of how lung cancer pathophysiology is regulated. As drug resistance is the primary reason behind treatment failure, it is crucial to understand how cancer cells may respond to different therapies and integrate crosstalk between apoptosis and autophagy in response to them, leading to cell death or survival. Thus, in this study, we have tried to evaluate the crosstalk between autophagy and apoptosis in A549 lung cancer cell line that could be modulated by employing a combination therapy of metformin (6 mM), an anti-diabetic drug, with gedunin (12 µM), an Hsp90 inhibitor, to provide insights into the development of new cancer therapeutics. Our results demonstrated that metformin and gedunin were cytotoxic to A549 lung cancer cells. Combination of metformin and gedunin generated ROS and promoted MMP loss and DNA damage. The combination further increased the expression of AMPKα1 and promoted the nuclear localization of AMPKα1/α2. The expression of Hsp90 was downregulated, further decreasing the expression of its clients, EGFR, PIK3CA, AKT1, and AKT3. Inhibition of the EGFR/PI3K/AKT pathway upregulated TP53 and inhibited autophagy. The combination was promoting nuclear localization of p53; however, some cytoplasmic signals were also detected. Further increase in the expression of caspase 9 and caspase 3 was observed. Thus, we concluded that the combination of metformin and gedunin upregulates apoptosis by inhibiting the EGFR/PI3K/AKT pathway and autophagy in A549 lung cancer cells.


Assuntos
Antineoplásicos , Apoptose , Autofagia , Limoninas , Neoplasias Pulmonares , Metformina , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Humanos , Células A549 , Apoptose/efeitos dos fármacos , Metformina/farmacologia , Limoninas/farmacologia , Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Linhagem Celular , Citotoxinas/farmacologia , Sinergismo Farmacológico , Espécies Reativas de Oxigênio/metabolismo , Combinação de Medicamentos , Dano ao DNA/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Núcleo Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo
9.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675165

RESUMO

Acute lung injury is a complex cascade process that develops in response to various damaging factors, which can lead to acute respiratory distress syndrome. Within this study, based on bioinformatics reanalysis of available full-transcriptome data of acute lung injury induced in mice and humans by various factors, we selected a set of genes that could serve as good targets for suppressing inflammation in the lung tissue, evaluated their expression in the cells of different origins during LPS-induced inflammation, and chose the tissue inhibitor of metalloproteinase Timp1 as a promising target for suppressing inflammation. We designed an effective chemically modified anti-TIMP1 siRNA and showed that Timp1 silencing correlates with a decrease in the pro-inflammatory cytokine IL6 secretion in cultured macrophage cells and reduces the severity of LPS-induced acute lung injury in a mouse model.


Assuntos
Lesão Pulmonar Aguda , RNA Interferente Pequeno , Animais , Humanos , Camundongos , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Fenótipo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo
10.
Nature ; 615(7950): 134-142, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36470304

RESUMO

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Receptores Virais , Ácido Ursodesoxicólico , Animais , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/prevenção & controle , Receptores Virais/genética , Receptores Virais/metabolismo , Estudos Retrospectivos , SARS-CoV-2/metabolismo , Tratamento Farmacológico da COVID-19 , Cricetinae , Transcrição Gênica , Ácido Ursodesoxicólico/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Organoides/efeitos dos fármacos , Organoides/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Sistema de Registros , Reprodutibilidade dos Testes , Transplante de Fígado
11.
Pharmacol Res ; 187: 106577, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36435270

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with high mortality and limited effective therapy. Herein, we reported that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), used in depression and anxiety treatment, also exhibited therapeutic activities in IPF. Fluvoxamine inhibited cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), restrained the activation of their downstream targets, including PERK/ eIF2α/ c-Myc/ miR-9-5p/ TBPL1 and TBK1/ YAP/ JNK1/2/ Bnip3/ CaMKII/ cofilin signaling, thus attenuated the activation and migration of fibroblasts upon TGF-ß1 challenge. Fluvoxamine dose-dependently improved pulmonary function, decreased the expression of inflammatory factors, reduced excessive production of extracellular matrix, and thus alleviated bleomycin (BLM)-induced lung fibrosis in mice. Moreover, fluvoxamine at a dose of 10 mg/ kg showed similar efficacy as pirfenidone (PFD) at a dose of 30 mg/kg in a mice model of lung fibrosis. In summary, our results suggest that fluvoxamine is an effective anti-fibrotic agent for IPF.


Assuntos
Antifibróticos , Fluvoxamina , Fibrose Pulmonar Idiopática , Animais , Camundongos , Bleomicina , Fibroblastos/metabolismo , Fluvoxamina/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Nucleotidiltransferases , Fator de Crescimento Transformador beta1/metabolismo , Antifibróticos/uso terapêutico
12.
Ecotoxicol Environ Saf ; 249: 114355, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36508822

RESUMO

The plasticizer di- (2-ethylhexyl) phthalate (DEHP) is considered a risk factor for allergic diseases and has attracted public attention for its adverse effects on health. However, respiratory adverse effects after DEHP exposure in food allergies have rarely been reported. MiRNAs are considered to be key regulators in the complex interrelationships between the host and microbiome and may be a potential factor involved in DEHP-induced pulmonary toxicity. To investigate the adverse effects of DEHP on the lung during sensitization, we established an ovalbumin (OVA)-sensitized mouse model exposed to DEHP and performed 16S rDNA gene sequencing, miRNA sequencing, and correlation analysis. Our results showed that DEHP aggravated the immune disorder in OVA-sensitized mice, which was mainly characterized by an increase in the proportion of Th2 lymphocytes, and further enhanced OVA-induced airway inflammation without promoting pulmonary fibrosis. Compared with the OVA group, DEHP interfered with the lung microbial community, making Proteobacteria the dominant phylum, while Bacteroidetes were significantly reduced. Differentially expressed miRNAs were enriched in the PI3K/AKT pathway, which was closely related to immune function and airway inflammation. The expression of miR-146b-5p was elevated in the DEHP group, which was positively correlated with the proportion of Th2 cells and significantly negatively correlated with the abundance of Bacteroidetes. The results indicate that DEHP may interfere with the expression of miR-146b-5p, affect the composition of the lung microbiota, induce an imbalance in T cells, and lead to immune disorders and airway inflammation. The current study uses multi-omics to reveal the potential link between the plasticizer DEHP and allergic diseases and provides new insights into the ecotoxicology of environmental exposures to DEHP.


Assuntos
Dietilexilftalato , Hipersensibilidade , Pulmão , MicroRNAs , Plastificantes , Animais , Camundongos , Dietilexilftalato/toxicidade , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Inflamação/induzido quimicamente , Pulmão/efeitos dos fármacos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , Multiômica , Ovalbumina , Fosfatidilinositol 3-Quinases/metabolismo , Plastificantes/toxicidade
13.
Mar Drugs ; 20(12)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36547913

RESUMO

Airborne particulate matter (PM) originating from industrial processes is a major threat to the environment and health in East Asia. PM can cause asthma, collateral lung tissue damage, oxidative stress, allergic reactions, and inflammation. The present study was conducted to evaluate the protective effect of eckmaxol, a phlorotannin isolated from Ecklonia maxima, against PM-induced inflammation in MH-S macrophage cells. It was found that PM induced inflammation in MH-S lung macrophages, which was inhibited by eckmaxol treatment in a dose-dependent manner (21.0−84.12 µM). Eckmaxol attenuated the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in PM-induced lung macrophages. Subsequently, nitric oxide (NO), prostaglandin E-2 (PGE-2), and pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) were downregulated. PM stimulated inflammation in MH-S lung macrophages by activating Toll-like receptors (TLRs), nuclear factor-kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. Eckmaxol exhibited anti-inflammatory properties by suppressing the activation of TLRs, downstream signaling of NF-κB (p50 and p65), and MAPK pathways, including c-Jun N-terminal kinase (JNK) and p38. These findings suggest that eckmaxol may offer substantial therapeutic potential in the treatment of inflammatory diseases.


Assuntos
Inflamação , Pulmão , Macrófagos , Material Particulado , Pneumonia , Polifenóis , Humanos , Ciclo-Oxigenase 2/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Material Particulado/toxicidade , Receptores Toll-Like/metabolismo , Polifenóis/química , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico
14.
J Nat Prod ; 85(11): 2656-2666, 2022 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-36322828

RESUMO

Asthma is a highly prevalent and heterogeneous chronic respiratory disease and is often treated with inhaled corticosteroids or in combination with a ß2-adrenergic receptor (ß2-AR) agonist. However, around 5% of asthma remains uncontrolled, and more effective antiasthmatic drugs with known mechanisms are in high demand. Herein, we immobilized ß2-AR on the polystyrene amino microsphere surface in a one-step fashion. The successful immobilization of ß2-AR was verified by scanning electron microscopy and chromatographic analysis. We screened rosmarinic acid (RA) as the bioactive compound targeting ß2-AR in Perilla frutescens (L.) Britton by mass spectroscopy. The binding constant between RA and ß2-AR was determined to be 2.95 × 104 M-1 by adsorption energy distribution and frontal analysis. The antiasthmatic effect and mechanism of RA were examined on a murine model of allergic asthma induced by ovalbumin (OVA) and aluminum hydroxide. The results showed that RA significantly reduced lung inflammatory cell numbers, the production of Th2 cytokines, and the secretion of total IgE, OVA-specific IgE, and eotaxin. The decreased inflammatory cell infiltration and mucus hypersecretion were associated with the inhibition of the NF-κB signaling pathway. Moreover, the mRNA expression levels of AMCase, CCL11, CCR3, Ym2, and E-selectin in the lung tissues were effectively reduced. It is the first time that RA was proven to target ß2-AR and be effective in counteracting allergic airway inflammation via the NF-κB signaling pathway. Therefore, the immobilized ß2-AR preserves the potential in screening antiasthmatic compounds from herbal medicine, and RA can be developed as an effective agent for the treatment of allergic asthma.


Assuntos
Agonistas Adrenérgicos beta , Antiasmáticos , Asma , Perilla frutescens , Pneumonia , Receptores Adrenérgicos beta , Animais , Camundongos , Antiasmáticos/química , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Asma/induzido quimicamente , Asma/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Ovalbumina , Perilla frutescens/química , Pneumonia/tratamento farmacológico , Transdução de Sinais , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Agonistas Adrenérgicos beta/uso terapêutico , Receptores Adrenérgicos beta/metabolismo
15.
Nature ; 611(7936): 578-584, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36323778

RESUMO

Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites<sup>1,2</sup>, although the immunoregulatory roles of most fibre diets and their microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.


Assuntos
Ácidos e Sais Biliares , Fibras na Dieta , Microbioma Gastrointestinal , Inflamação , Inulina , Animais , Humanos , Camundongos , Ácidos e Sais Biliares/metabolismo , Ácido Cólico/farmacologia , Fibras na Dieta/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Imunidade Inata , Inflamação/induzido quimicamente , Inflamação/classificação , Inflamação/patologia , Inulina/farmacologia , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Metabolômica , Pulmão/efeitos dos fármacos , Pulmão/patologia , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/patologia , Interleucina-33/metabolismo , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia
17.
Nucleic Acids Res ; 50(15): 8418-8430, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-35920332

RESUMO

The lung is a complex organ with various cell types having distinct roles. Antisense oligonucleotides (ASOs) have been studied in the lung, but it has been challenging to determine their effectiveness in each cell type due to the lack of appropriate analytical methods. We employed three distinct approaches to study silencing efficacy within different cell types. First, we used lineage markers to identify cell types in flow cytometry, and simultaneously measured ASO-induced silencing of cell-surface proteins CD47 or CD98. Second, we applied single-cell RNA sequencing (scRNA-seq) to measure silencing efficacy in distinct cell types; to the best of our knowledge, this is the first time scRNA-seq has been applied to measure the efficacy of oligonucleotide therapeutics. In both approaches, fibroblasts were the most susceptible to locally delivered ASOs, with significant silencing also in endothelial cells. Third, we confirmed that the robust silencing in fibroblasts is broadly applicable by silencing two targets expressed mainly in fibroblasts, Mfap4 and Adam33. Across independent approaches, we demonstrate that intratracheally administered LNA gapmer ASOs robustly induce gene silencing in lung fibroblasts. ASO-induced gene silencing in fibroblasts was durable, lasting 4-8 weeks after a single dose. Thus, lung fibroblasts are well aligned with ASOs as therapeutics.


Assuntos
Células Endoteliais , Fibroblastos/efeitos dos fármacos , Pulmão/citologia , Oligonucleotídeos Antissenso/administração & dosagem , Animais , Fibroblastos/metabolismo , Inativação Gênica , Pulmão/efeitos dos fármacos , Camundongos , Oligonucleotídeos/administração & dosagem , Traqueia/metabolismo
19.
Int J Hyperthermia ; 39(1): 977-986, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35853732

RESUMO

OBJECTIVE: Acute lung injury (ALI) is a common complication of heat stroke (HS) and a direct cause of death. However, the mechanism underlying ALI following HS remains unclear. METHOD: To investigate whether ferroptosis is involved in HS-ALI. We established a HS model of mice and mouse lung epithelial-2 cells (MLE-2). The severity of lung injury was measured by H&E staining, the wet-to-dry lung weight ratio, and Transmission electron microscopy. Potential markers of ferroptosis Fe2+, malondialdehyde (MDA), hydroxynonenal (4-HNE) and lipid peroxidation were detected. The percentages of cell death and viability induced by HS were assessed by LDH and CCK8 assays. SLC7A11, ACSL4, GPX4, SIRT1, p53, and p53 K382 acetylation levels were measured by Western blot. RESULTS: The administration of ferroptosis inhibitor ferrostatin-1(Fer-1) could significantly ameliorate lung injury, inhibiting levels of MDA and 4-HNE, and ameliorating HS-induced increased ACSL4, decreased SLC7A11 and GPX4, suggesting ferroptosis was involved in HS-induced ALI in vivo and in vitro. Moreover, SIRT1 expression decreased, and p53 K382 acetylation levels increased in MLE-2 cells. Activation of SIRT1 could improve lung epithelial ferroptosis caused by HS in vivo ang in vitro. Besides, the activation of SIRT1 could significantly reduce the p53 K382 acetylation levels, suggesting that activation of SIRT1 could prevent ferroptosis via inhibiting p53 acetylation. CONCLUSION: These findings substantiate the vital role of the SIRT1/p53 axis in mediating ferroptosis in HS-ALI, suggesting that targeting SIRT1 may represent a novel therapeutic strategy to ameliorate ALI during HS.


Assuntos
Lesão Pulmonar Aguda , Ferroptose , Golpe de Calor , Pulmão , Sirtuína 1 , Proteína Supressora de Tumor p53 , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/etiologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Resposta ao Choque Térmico , Humanos , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo
20.
Am J Respir Cell Mol Biol ; 67(3): 309-319, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35679109

RESUMO

Pulmonary fibrosis is a devastating lung disease with few therapeutic options. CHIT1 (chitinase 1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through the regulation of TGF-ß (transforming growth factor-ß) signaling and effector function. Therefore, CHIT1 is a potential therapeutic target for pulmonary fibrosis. This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Extensive screening of small molecule libraries identified the aminoglycoside antibiotic kasugamycin (KSM) as a potent CHIT1 inhibitor. Elevated concentrations of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In in vivo bleomycin- and TGF-ß-stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that KSM inhibits fibrotic macrophage activation, fibroblast proliferation, and myofibroblast transformation. Null mutation of TGFBRAP1 (TGF-ß-associated protein 1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of KSM in in vivo lungs and in vitro fibroblasts responses. KSM inhibits the physical association between CHIT1 and TGFBRAP1, suggesting that the antifibrotic effect of KSM is mediated through regulation of TGFBRAP1, at least in part. These studies demonstrate that KSM is a novel CHIT1 inhibitor with a strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.


Assuntos
Aminoglicosídeos , Antifibróticos , Quitinases , Fibrose Pulmonar , Aminoglicosídeos/farmacologia , Aminoglicosídeos/uso terapêutico , Animais , Antifibróticos/farmacologia , Antifibróticos/uso terapêutico , Bleomicina/farmacologia , Quitinases/antagonistas & inibidores , Fibroblastos/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo
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