RESUMO
Angiotensin (Ang) II plays an important role in the process of endothelial dysfunction in acute lung injury (ALI) and is degraded by angiotensin-converting enzyme2 (ACE2). However, treatments that target ACE2 to injured endothelium and promote endothelial repair of ALI are lacking. Mesenchymal stem cells (MSCs) are capable of homing to the injured site and delivering a protective gene. Our study aimed to evaluate the effects of genetically modified MSCs, which overexpress the ACE2 protein in a sustained manner via a lentiviral vector, on Ang II production in endothelium and in vitro repair of lipopolysaccharide (LPS)-induced endothelial injury. We found that the efficiency of lentiviral vector transduction of MSCs was as high as 97.8% and was well maintained over 30 passages. MSCs modified with ACE2 showed a sustained high expression of ACE2 mRNA and protein. The modified MSCs secreted soluble ACE2 protein into the culture medium, which reduced the concentration of Ang II and increased the production of Ang 1-7. MSCs modified with ACE2 were more effective at restoring endothelial function than were unmodified MSCs, as shown by the enhanced survival of endothelial cells; the downregulated production of inflammatory mediators, including ICAM-1, VCAM-1, TNF-α, and IL-6; reduced paracellular permeability; and increased expression of VE-cadherin. These data demonstrate that MSCs modified to overexpress the ACE2 gene can produce biologically active ACE2 protein over a sustained period of time and have an enhanced ability to promote endothelial repair after LPS challenge. These results encourage further testing of the beneficial effects of ACE2-modified MSCs in an ALI animal model.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Angiotensina II/metabolismo , Células-Tronco Mesenquimais/metabolismo , Peptidil Dipeptidase A/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Angiotensina I/genética , Angiotensina II/genética , Enzima de Conversão de Angiotensina 2 , Animais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Terapia Genética , Células HEK293 , Humanos , Lipopolissacarídeos/toxicidade , Células-Tronco Mesenquimais/citologia , Camundongos , Fragmentos de Peptídeos/genética , Peptidil Dipeptidase A/genética , Sistema Renina-AngiotensinaRESUMO
INTRODUCTION: The effect of mean arterial pressure titration to a higher level on microcirculation in septic shock patients with previous hypertension remains unknown. Our goal is to assess the effect of mean arterial pressure titration to a higher level on microcirculation in hypertensive septic shock patients. METHODS: This is a single-center, open-label study. Hypertensive patients with septic shock for less than 24 hours after adequate fluid resuscitation and requiring norepinephrine to maintain a mean arterial pressure of 65 mmHg were enrolled. Mean arterial pressure was then titrated by norepinephrine from 65 mmHg to the normal level of the patient. In addition to hemodynamic variables, sublingual microcirculation was evaluated by sidestream dark field imaging. RESULTS: Nineteen patients were enrolled in the study. Increasing mean arterial pressure from 65 mmHg to normal levels was associated with increased central venous pressure (from 11 ± 4 to 13 ± 4 mmHg, P = 0.002), cardiac output (from 5.4 ± 1.4 to 6.4 ± 2.1 l/minute, P = 0.001), and central venous oxygen saturation (from 81 ± 7 to 83 ± 7%, P = 0.001). There were significant increases in small perfused vessel density (from 10.96 ± 2.98 to 11.99 ± 2.55 vessels/mm(2), P = 0.009), proportion of small perfused vessels (from 85 ± 18 to 92 ± 14%, P = 0.002), and small microvascular flow index (from 2.45 ± 0.61 to 2.80 ± 0.68, P = 0.009) when compared with a mean arterial pressure of 65 mmHg. CONCLUSIONS: Increasing mean arterial pressure from 65 mmHg to normal levels is associated with improved microcirculation in hypertensive septic shock patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01443494; registered 28 September 2011.
Assuntos
Pressão Arterial/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Microcirculação/efeitos dos fármacos , Choque Séptico/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Hidratação , Hemodinâmica/efeitos dos fármacos , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Soalho Bucal/irrigação sanguínea , Norepinefrina/administração & dosagem , Norepinefrina/farmacologia , Estudos Prospectivos , Respiração Artificial/métodos , Choque Séptico/fisiopatologia , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacologiaRESUMO
The Wnt pathways have been shown to be critical for the fate of mesenchymal stem cells (MSCs) in vitro, but their roles in MSCs in vivo remain poorly characterized due to the lack of stable alterations in their signaling. In the present study, we constructed long-term and stable mMSCs lines with activated and inactivated ß-catenin (the key molecule of the canonical Wnt signaling pathway) or ROR2 (the key molecule of the noncanonical Wnt5a/ROR2 signaling pathway) modifications with lentiviral vectors. We found that the transduction efficiencies mediated by the lentiviral vectors were 92.61-97.04% and were maintained over 20 passages of mMSCs. Transfection by lentiviral vectors not only regulated the mRNA and protein expression of ß-catenin or ROR2 but also regulated nuclear ß-catenin accumulation or the Wnt5a/JNK and Wnt5a/PKC pathways belonging to the canonical Wnt and noncanonical Wnt5a/ROR2 pathways, respectively. ß-Catenin or ROR2 gene overexpression promoted mMSC proliferation, migration and differentiation into osteoblasts, while inhibiting the adipogenic differentiation of mMSCs. In contrast, inactivation of the ß-catenin or ROR2 genes resulted in the opposite effects. Therefore, these results confirm that lentiviral vector transduction can facilitate sustained and efficient gene modification of the Wnt pathway in mMSCs. This study provides a method to investigate the effects of the Wnt pathway on the fate of mMSCs in vivo and for the further improvement of MSC-based therapies.
Assuntos
Células-Tronco Mesenquimais/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismo , Adipócitos/citologia , Adipócitos/fisiologia , Animais , Diferenciação Celular , Movimento Celular , Proliferação de Células , Lentivirus , Camundongos , Osteogênese/fisiologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Transdução de Sinais , Via de Sinalização Wnt/genética , beta Catenina/genéticaRESUMO
INTRODUCTION: Glutamine supplementation is supposed to reduce mortality and nosocomial infections in critically ill patients. However, the recently published reducing deaths due to oxidative stress (REDOX) trials did not provide evidence supporting this. This study investigated the impact of glutamine-supplemented nutrition on the outcomes of critically ill patients using a meta-analysis. METHODS: We searched for and gathered data from the Cochrane Central Register of Controlled Trials, MEDLINE, Elsevier, Web of Science and ClinicalTrials.gov databases reporting the effects of glutamine supplementation on outcomes in critically ill patients. We produced subgroup analyses of the trials according to specific patient populations, modes of nutrition and glutamine dosages. RESULTS: Among 823 related articles, eighteen Randomized Controlled Trials (RCTs) met all inclusion criteria. Mortality events among 3,383 patients were reported in 17 RCTs. Mortality showed no significant difference between glutamine group and control group. In the high dosage subgroup (above 0.5 g/kg/d), the mortality rate in the glutamine group was significantly higher than that of the control group (relative risk (RR) 1.18; 95% confidence interval (CI), 1.02 to 1.38; P = 0.03). In 15 trials, which included a total of 2,862 patients, glutamine supplementation reportedly affected the incidence of nosocomial infections in the critically ill patients observed. The incidence of nosocomial infections in the glutamine group was significantly lower than that of the control group (RR 0.85; 95% CI, 0.74 to 0.97; P = 0.02). In the surgical ICU subgroup, glutamine supplementation statistically reduced the rate of nosocomial infections (RR 0.70; 95% CI, 0.52 to 0.94; P = 0.04). In the parental nutrition subgroup, glutamine supplementation statistically reduced the rate of nosocomial infections (RR 0.83; 95% CI, 0.70 to 0.98; P = 0.03). The length of hospital stay was reported in 14 trials, in which a total of 2,777 patients were enrolled; however, the patient length of stay was not affected by glutamine supplementation. CONCLUSIONS: Glutamine supplementation conferred no overall mortality and length of hospital stay benefit in critically ill patients. However, this therapy reduced nosocomial infections among critically ill patients, which differed according to patient populations, modes of nutrition and glutamine dosages.
Assuntos
Estado Terminal/mortalidade , Estado Terminal/terapia , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/mortalidade , Suplementos Nutricionais , Glutamina/administração & dosagem , Infecção Hospitalar/diagnóstico , Humanos , Tempo de Internação/tendências , Mortalidade/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Resultado do TratamentoRESUMO
INTRODUCTION: Prone positioning (PP) has been reported to improve the survival of patients with severe acute respiratory distress syndrome (ARDS). However, it is uncertain whether the beneficial effects of PP are associated with positive end-expiratory pressure (PEEP) levels and long durations of PP. In this meta-analysis, we aimed to evaluate whether the effects of PP on mortality could be affected by PEEP level and PP duration and to identify which patients might benefit the most from PP. METHODS: Publications describing randomized controlled trials (RCTs) in which investigators have compared prone and supine ventilation were retrieved by searching the following electronic databases: PubMed/MEDLINE, the Cochrane Library, the Web of Science and Elsevier Science (inception to May 2013). Two investigators independently selected RCTs and assessed their quality. The data extracted from the RCTs were combined in a cumulative meta-analysis and analyzed using methods recommended by the Cochrane Collaboration. RESULTS: A total of nine RCTs with an aggregate of 2,242 patients were included. All of the studies received scores of up to three points using the methods recommended by Jadad et al. One trial did not conceal allocation. This meta-analysis revealed that, compared with supine positioning, PP decreased the 28- to 30-day mortality of ARDS patients with a ratio of partial pressure of arterial oxygen/fraction of inspired oxygen ≤ 100 mmHg (n = 508, risk ratio (RR) = 0.71, 95 confidence interval (CI) = 0.57 to 0.89; P = 0.003). PP was shown to reduce both 60-day mortality (n = 518, RR = 0.82, 95% CI = 0.68 to 0.99; P = 0.04) and 90-day mortality (n = 516, RR = 0.57, 95% CI = 0.43 to 0.75; P < 0.0001) in ARDS patients ventilated with PEEP ≥ 10 cmH2O. Moreover, PP reduced 28- to 30-day mortality when the PP duration was >12 h/day (n = 1,067, RR = 0.73, 95% CI = 0.54 to 0.99; P = 0.04). CONCLUSIONS: PP reduced mortality among patients with severe ARDS and patients receiving relatively high PEEP levels. Moreover, long-term PP improved the survival of ARDS patients.
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Respiração com Pressão Positiva , Decúbito Ventral , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/terapia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Two new Mileewini leafhoppers (Hemiptera: Cicadellidae: Mileewinae), Mileewa triloba sp. nov. and Ujna cavipenis sp. nov. are described from Hainan Island, China. Habitus images and figures of both male and female genitalia are provided together with a key to species of Mileewini from Hainan.
Assuntos
Hemípteros , Animais , China , Feminino , Ilhas , MasculinoRESUMO
Three new species of Mileewini, Mileewa digitata sp. nov., M. furcata sp. nov., M. nigricincta sp. nov., from Tibet, China are described and illustrated.
Assuntos
Hemípteros , Animais , China , TibetRESUMO
A new leafhopper genus and species, Anzihelus bistriatus Yan & Yang, gen. nov. sp. nov. (Cicadellidae, Mileewinae, Mileewini) is described from Sichuan Province, China. Habitus images and figures of the male and female genitalia are provided together with a key to the genera of Mileewini from China.
RESUMO
Four new species of Mileewini, Mileewa clavata He Yang, sp. nov., Mileewa rubricosta He Yang, sp. nov., Mileewa quinquemaculata He Yang, sp. nov. and Ujna liboensis He Yang, sp. nov., are described and illustrated. A checklist of all Chinese Mileewini is provided.
Assuntos
Hemípteros , Animais , China , Hemípteros/classificação , Hemípteros/fisiologiaRESUMO
The complete mitochondrial genome (mitogenome) of Aglossa dimidiata (Lepidoptera: Pyralidae) was sequenced using high-throughput sequencing. The mitogenome of A. dimidiata was 15,225 bp in length. It comprised 37 typical genes and one control region. All protein-coding genes (PCGs) were initiated with ATN, except for COX1 (TTG). All PCGs used TAN as stop codon, except for ND5 and ND4 terminated with incomplete T. Twenty-two tRNA genes ranged from 61 to 71 bp in size. The monophyly of family Pyralidae and the sister relationship between A. dimidiata and Orthopygia glanucinalis are both supported by maximum likelihood method using the nucleotide sequences of 13 PCGs.
RESUMO
Background: Tumor necrosis factor-alpha (TNF-α) is a major proinflammatory cytokine that has been posited to be involved in the development of chronic pancreatitis (CP). Several studies have been carried out that explored the association between the TNF-α -308A/G polymorphism and CP; however, conflicting results have emerged. The aim of this study was to perform a meta-analysis to provide a more precise assessment of the relationship between the TNF-α -308A/G polymorphism and CP risk. Methods: Case-control studies were identified using PubMed, Embase, Web of Science, Cochrane Library, and Chinese National Knowledge Infrastructure through January 2019 from which seven were identified that met all inclusion criteria. Results: This meta-analysis included 695 CP cases and 742 controls. A positive association was found between the A allele and the risk of CP using the additive model (OR [odds ratio] = 1.83, 95% CI [confidence interval] = 1.08-3.10). We also found, after excluding the Hardy-Weinberg equilibrium-violating studies, that the AA genotype was significantly associated with CP in both the additive and recessive models (OR = 2.28, 95% CI = 1.27-4.07; OR = 2.19, 95% CI = 1.26-3.81). Conclusion: This meta-analysis indicates that the A allele of the TNF-α -308A/G polymorphism increases the risk of CP.
Assuntos
Pancreatite Crônica/genética , Fator de Necrose Tumoral alfa/genética , Alelos , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fator de Necrose Tumoral alfa/metabolismo , População Branca/genéticaRESUMO
Although mesenchymal stem cells (MSCs) transplantation has been shown to promote the lung respiration in acute lung injury (ALI) in vivo, its overall restorative capacity appears to be restricted mainly because of low retention in the injured lung. Angiotensin II (Ang II) are upregulated in the injured lung. Our previous study showed that Ang II increased MSCs migration via Ang II type 2 receptor (AT2R). To determine the effect of AT2R in MSCs on their cell migration after systemic injection in ALI mice, a human AT2R expressing lentiviral vector and a lentivirus vector carrying AT2R shRNA were constructed and introduced into human bone marrow MSCs. A mouse model of lipopolysaccharide-induced ALI was used to investigate the migration of AT2R-regulated MSCs and the therapeutic potential in vivo. Overexpression of AT2R dramatically increased Ang II-enhanced human bone marrow MSC migration in vitro. Moreover, MSC-AT2R accumulated in the damaged lung tissue at significantly higher levels than control MSCs 24 and 72 hours after systematic MSC transplantation in ALI mice. Furthermore, MSC-AT2R-injected ALI mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti-inflammatory effects. In contrast, there were less lung retention in MSC-ShAT2R-injected ALI mice compared with MSC-Shcontrol after transplantation. Thus, MSC-ShAT2R-injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. Our results demonstrate that overexpression of AT2R enhance the migration of MSCs in ALI mice and may provide a new therapeutic strategy for ALI. Stem Cells Translational Medicine 2018;7:721-730.
Assuntos
Lesão Pulmonar Aguda/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Movimento Celular , Citocinas/análise , Modelos Animais de Doenças , Contagem de Leucócitos , Lipopolissacarídeos/toxicidade , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Neutrófilos/citologia , Receptor Tipo 2 de Angiotensina/genéticaRESUMO
BACKGROUND: Mesenchymal stem cells (MSCs) migrate via the bloodstream to sites of injury and are possibly attracted by inflammatory factors. As a proinflammatory mediator, angiotensin II (Ang II) reportedly enhances the migration of various cell types by signaling via the Ang II receptor in vitro. However, few studies have focused on the effects of Ang II on MSC migration and the underlying mechanisms. METHODS: Human bone marrow MSCs migration was measured using wound healing and Boyden chamber migration assays after treatments with different concentrations of Ang II, an AT1R antagonist (Losartan), and/or an AT2R antagonist (PD-123319). To exclude the effect of proliferation on MSC migration, we measured MSC proliferation after stimulation with the same concentration of Ang II. Additionally, we employed the focal adhesion kinase (FAK) inhibitor PF-573228, RhoA inhibitor C3 transferase, Rac1 inhibitor NSC23766, or Cdc42 inhibitor ML141 to investigate the role of cell adhesion proteins and the Rho-GTPase protein family (RhoA, Rac1, and Cdc42) in Ang II-mediated MSC migration. Cell adhesion proteins (FAK, Talin, and Vinculin) were detected by western blot analysis. The Rho-GTPase family protein activities were assessed by G-LISA and F-actin levels, which reflect actin cytoskeletal organization, were detected by using immunofluorescence. RESULTS: Human bone marrow MSCs constitutively expressed AT1R and AT2R. Additionally, Ang II increased MSC migration in an AT2R-dependent manner. Notably, Ang II-enhanced migration was not mediated by Ang II-mediated cell proliferation. Interestingly, Ang II-enhanced migration was mediated by FAK activation, which was critical for the formation of focal contacts, as evidenced by increased Talin and Vinculin expression. Moreover, RhoA and Cdc42 were activated by FAK to increase cytoskeletal organization, thus promoting cell contraction. Furthermore, FAK, Talin, and Vinculin activation and F-actin reorganization in response to Ang II were prevented by PD-123319 but not Losartan, indicating that FAK activation and F-actin reorganization were downstream of AT2R. CONCLUSIONS: These data indicate that Ang II-AT2R regulates human bone marrow MSC migration by signaling through the FAK and RhoA/Cdc42 pathways. This study provides insights into the mechanisms by which MSCs home to injury sites and will enable the rational design of targeted therapies to improve MSC engraftment.
Assuntos
Angiotensina II/farmacologia , Movimento Celular/efeitos dos fármacos , Quinase 1 de Adesão Focal/metabolismo , Células-Tronco Mesenquimais/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Quinase 1 de Adesão Focal/antagonistas & inibidores , Humanos , Células-Tronco Mesenquimais/citologia , Proteína rhoA de Ligação ao GTP/antagonistas & inibidoresRESUMO
There are some limitations to the therapeutic effects of mesenchymal stem cells (MSCs) on acute respiratory distress syndrome (ARDS) due to their low engraftment and differentiation rates in lungs. We found previously that noncanonical Wnt5a signaling promoted the differentiation of mouse MSCs (mMSCs) into type II alveolar epithelial cells (AT II cells), conferred resistance to oxidative stress, and promoted migration of MSCs in vitro. As receptor tyrosine kinase-like orphan receptor 2 (ROR2) is an essential receptor for Wnt5a, it was reasonable to deduce that ROR2 might be one of the key molecules for the therapeutic effect of MSCs in ARDS. The mMSCs that stably overexpressed ROR2 or the green fluorescent protein (GFP) control were transplanted intratracheally into the ARDS mice [induced by intratracheal injection of lipopolysaccharide (LPS)]. The results showed that ROR2-overexpressing mMSCs led to more significant effects than the GFP controls, including the retention of the mMSCs in the lung, differentiation into AT II cells, improvement of alveolar epithelial permeability, improvement of acute LPS-induced pulmonary inflammation, and, finally, reduction of the pathological impairment of the lung tissue. In conclusion, MSCs that overexpress ROR2 could further improve MSC-mediated protection against epithelial impairment in ARDS.
Assuntos
Lesão Pulmonar Aguda/terapia , Células-Tronco Mesenquimais/citologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Síndrome do Desconforto Respiratório/terapia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Proteínas de Fluorescência Verde , Lipopolissacarídeos/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
INTRODUCTION: Mesenchymal stem cells (MSCs) have potential for re-epithelization and recovery in acute respiratory distress syndrome (ARDS). In a previous in vitro study, the results showed that the canonical Wnt/ß-catenin pathway promoted the differentiation of MSCs into type II alveolar epithelial cells, conferred resistance to oxidative stress, and promoted their migration, suggesting that the Wnt/ß-catenin pathway might be one of the key mechanisms underling the therapeutic effect of mouse MSCs in ARDS. METHODS: Mouse MSCs stable transfected with ß-catenin or green fluorescent protein control were transplanted intratracheally into the ARDS mice induced by lipopolysaccharide. Lung tissue injury and repair assessment were examined using haematoxylin and eosin staining, lung injury scoring, Masson's trichrome staining and fibrosis scoring. Homing and differentiation of mouse MSCs were assayed by labelling and tracing MSCs using NIR815 dye, immunofluorescent staining, and Western immunoblot analysis. The inflammation and permeability were evaluated by detecting the cytokine and protein measurements in bronchoalveolar lavage fluid using enzyme-linked immunosorbent assay. RESULTS: In this study, ß-catenin-overexpressing MSC engraftment led to more significant effects than the GFP controls, including the retention of the MSCs in the lung, differentiation into type II alveolar epithelial cells, improvement in alveolar epithelial permeability, and the pathologic impairment of the lung tissue. CONCLUSION: These results suggest that the activation of canonical Wnt/ß-catenin pathway by mouse MSCs by overexpressing ß-catenin could further improve the protection of mouse MSCs against epithelial impair and the therapeutic effects of mouse MSCs in ARDS mice.
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Lesão Pulmonar Aguda/terapia , Células Epiteliais/citologia , Alvéolos Pulmonares/metabolismo , Síndrome do Desconforto Respiratório/terapia , Mucosa Respiratória/citologia , Via de Sinalização Wnt/fisiologia , Animais , Diferenciação Celular/fisiologia , Movimento Celular , Terapia Baseada em Transplante de Células e Tecidos , Células Cultivadas , Lipopolissacarídeos , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologia , Alvéolos Pulmonares/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMO
OBJECTIVE: To review the study of estrogen receptor modulator and correlative Chinese herbs. METHOD: Based on to the documents in the world, the estrogen receptor modulator and correlative Chinese herbs summarized. RESULT AND CONCLUSION: Estrogen receptor modulator is biological compounds in botany. It can exert faint estrogen-like effects by low affinity with estrogen receptor. Some of the Chinese herbs have the estrogen-like activity, but further and more systemic research work are to be done.
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Medicamentos de Ervas Chinesas/farmacologia , Plantas Medicinais/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Envelhecimento/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Genisteína/isolamento & purificação , Genisteína/farmacologia , Humanos , Lignanas/isolamento & purificação , Lignanas/farmacologia , Moduladores Seletivos de Receptor Estrogênico/isolamento & purificaçãoRESUMO
Conventional dendritic cells (cDCs) have been reported to participate in the pathophysiology of acute lung injury (ALI). Fms-like tyrosine kinase 3 (FLT3) signaling represents a highly specific pathway for the manipulation of cDCs in vivo. The purpose of this study was to clarify the effect of FLT3 signaling on the accumulation and maturation of pulmonary cDCs, and whether inhibition of FLT3 signaling may attenuate acute lung inflammation and lung injury. C57BL/6 mice were pretreated with FLT3-ligand (FLT3L) and lestaurtinib separately for five consecutive days. A murine model of ALI was subsequently generated by intra-tracheal instillation of lipopolysaccharide (LPS) and lung specimens were harvested 24 h later. Flow cytometry was conducted to measure the accumulation and maturation of pulmonary cDCs. IL-6, IFN-γ, IL-4, MPO activity and transcription factor T-bet/GATA-3 mRNA ratio were quantified to evaluate lung inflammation. Lung injury was estimated by lung wet weight/body weight ratio (LWW/BW) and histopathological analysis. LPS challenge resulted in rapid accumulation and maturation of pulmonary cDCs. FLT3L pretreatment further stimulated the accumulation and maturation of pulmonary cDCs, leading to a markedly increased LWW/BW and aggravated lung histopathology. Meanwhile, lung MPO activity, T-bet/GATA-3 mRNA ratio and concentrations of IL-6 and IFN-γ were elevated by FLT3L administration. In contrast, lestaurtinib pretreatment inhibited the accumulation and maturation of pulmonary cDCs, leading to a significantly decreased LWW/BW and improved lung histopathology. Lestaurtinib administration also suppressed lung MPO activity, T-bet/GATA-3 mRNA ratio and production of IL-6 and IFN-γ. Our findings show that FLT3 signaling ameliorates ALI by regulating the accumulation and maturation of pulmonary cDCs, suggesting an innovative pharmacotherapy for ALI.