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1.
Int Immunopharmacol ; 77: 105973, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31677992

RESUMO

Sepsis is a syndrome of life-threatening organ dysfunction caused by dysregulated host responses to infection. Macrophage polarization is a key process involved in the pathogenesis of sepsis. Recent evidence has demonstrated that autophagy participates in the regulation of macrophage polarization in different phases of inflammation. Here, we investigated whether trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the macrophage M2 phenotype by enhancing autophagy to counteract excessive inflammation in a cecal ligation and puncture (CLP) mouse model. TSA stimulation increased the proportions of M2 marker (CD206, CD124 and CD23)-labeled RAW264.7 macrophages. Furthermore, with increasing TSA doses, autophagy was enhanced gradually. Interestingly, the autophagy activator rapamycin (Rap), also known as an mTOR inhibitor, unexpectedly decreased the proportions of M2 marker-labeled macrophages. However, TSA treatment reversed the Rap-induced decreases in CD206-labeled macrophages. Next, we stimulated different groups of RAW264.7 cells with the autophagy inhibitors MHY1485 or 3-methyladenine (3-MA). Inhibition of autophagy at any stage in the process suppressed TSA-induced macrophage M2 polarization, but the effect was not associated with mTOR activity. In vivo, TSA administration promoted peritoneal macrophage M2 polarization, increased LC3 II expression, attenuated sepsis-induced organ (lung, liver and kidney) injury, and altered systemic inflammatory cytokine secretion. However, 3-MA abolished the protective effects of TSA in CLP mice and decreased the number of M2 peritoneal macrophages. Therefore, TSA promotes the macrophage M2 phenotype by enhancing autophagy to reduce systemic inflammation and ultimately improves the survival of mice with polymicrobial sepsis.


Assuntos
Autofagia/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Inflamação/tratamento farmacológico , Macrófagos Peritoneais/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Inibidores de Histona Desacetilases/farmacologia , Inflamação/metabolismo , Ligadura/métodos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Punções/métodos , Células RAW 264.7 , Sepse/metabolismo
2.
Lab Invest ; 99(8): 1143-1156, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30911150

RESUMO

Acute respiratory distress syndrome (ARDS) is a uniform progression of overwhelming inflammation in lung tissue with extensive infiltration of inflammatory cells. Neutrophil apoptosis is thought to be a significant process in the control of the resolution phase of inflammation. It has been proved that 5-Aza-2'-deoxycytidine (Aza) can inhibit cancer by activating death-associated protein kinase 1 (DAPK1) to promote apoptosis. However, the effect of DAPK1 on neutrophil apoptosis is unclear, and research on the role of Aza in inflammation is lacking. Here, we investigated whether Aza can regulate DAPK1 expression to influence the fate of neutrophils in ARDS. In vitro, we stimulated neutrophil-like HL-60 (dHL-60) cells with different concentrations of Aza for different durations and used RNA interference to up- or downregulate DAPK1 expression. We observed that culturing dHL-60 cells with Aza increased apoptosis by inhibiting NF-κB activation to modulate the expression of Bcl-2 family proteins, which was closely related to the levels of DAPK1. In vivo, ARDS was evoked by intratracheal instillation of lipopolysaccharide (LPS; 3 mg/kg). One hour after LPS administration, mice were treated with Aza (1 mg/kg, i.p.). To inhibit DAPK1 expression, mice were intraperitoneally injected with a DAPK1 inhibitor. Aza treatment accelerated inflammatory resolution in LPS-induced ARDS by suppressing pulmonary edema, alleviating lung injury and decreasing the infiltration of inflammatory cells in bronchoalveolar lavage fluid (BALF). Moreover, Aza reduced the production of proinflammatory cytokines. However, administration of the DAPK1 inhibitor attenuated the protective effects of Aza. Similarly, the proapoptotic function of Aza was prevented when DAPK1 was inhibited either in vivo or in vitro. In summary, Aza promotes neutrophil apoptosis by activating DAPK1 to accelerate inflammatory resolution in LPS-induced ARDS. This study provides the first evidence that Aza prevents LPS-induced neutrophil survival by modulating DAPK1 expression.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas Quinases Associadas com Morte Celular , Inflamação/metabolismo , Neutrófilos/efeitos dos fármacos , Síndrome do Desconforto Respiratório/metabolismo , Animais , Citocinas/metabolismo , Proteínas Quinases Associadas com Morte Celular/metabolismo , Proteínas Quinases Associadas com Morte Celular/farmacologia , Decitabina/metabolismo , Decitabina/farmacologia , Modelos Animais de Doenças , Células HL-60 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
Int Immunopharmacol ; 69: 289-298, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30753968

RESUMO

The timely resolution of pulmonary inflammation coordinated by endogenous pro-resolving mediators helps limit lung tissue injury, but few endogenous pro-resolving mediators that are normally operative during acute inflammation. The protective effects of BML-111 (5(S)-6(R)-7-trihydroxyheptanoic acid methyl ester), a potent commercially available anti-inflammatory and pro-resolving mediator, on ventilation-induced lung injury (VILI) have been extensively studied, but its characteristics as a pro-resolving mediator have not. Here, anesthetized Sprague-Dawley rats were ventilated with a high tidal volume (20 mL/kg, HVT) for 1 h and randomly allocated to recover for 6, 12, 24, 48, 72, 96 or 168 h; BML-111 was administered at the peak of inflammation to evaluate its pro-resolving effect on VILI. The one-hour HVT induced a maximal pulmonary inflammatory response at 12 h that was largely resolved by 72 h. BML-111 largely resolved the maximal inflammatory response at 48 h; the resolution interval (Ri) was shortened by 26 h. Similarly, HVT elicited a time course of changes in histopathology and pulmonary edema, and BML-111 alleviates these changes. Mechanistically, neutrophil apoptosis was significantly increased in BML-111-treated rats subjected to HVT. The apoptosis inhibitor z-VAD-fmk partially reversed the proapoptotic actions of BML-111 on neutrophil and the resolving effects of BML-111 on VILI but had no effect alone. Importantly, the HVT treatment activated the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1) and NF-κB signaling pathways in the lung tissue, and BML-111 further induced Nrf2 and HO-1 expression but inhibited the NF-κB pathway. Intriguingly, when we inhibited the Nrf2/HO-1 pathway with the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), Nrf2 expression was further increased, but the inhibitory effects of BML-111 on the NF-κB pathway and on the subsequent inflammatory response, and the proapoptotic actions on neutrophil were reversed. The results suggest that BML-111 promotes the resolution of HVT-induced inflammation to mitigate VILI in rats, perhaps by modulating the Nrf2/HO-1 and NF-κB pathways and subsequently increasing neutrophil apoptosis.


Assuntos
Ácidos Heptanoicos/uso terapêutico , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Neutrófilos/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Animais , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Humanos , Pulmão/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Protoporfirinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
4.
Exp Ther Med ; 16(2): 1433-1441, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30116392

RESUMO

The current study aimed to investigate the changes and regulatory mechanism of cluster of differentiation (CD)4+CD25high forkhead box protein 3 (Foxp3+) regulatory T cells (Tregs) in childhood B-cell acute lymphocytic leukemia (B-ALL). A total of 18 children with B-ALL and 15 age-matched healthy children were included. Reverse-transcription quantitative polymerase chain reaction was used to evaluate the mRNA levels of Foxp3, cytotoxic T-lymphocyte associated protein 4 (CTLA4), glucocorticoid-induced tumor necrosis factor receptor (GITR), lymphocyte activation gene 3 (LAG3), interleukin (IL)-2 receptor (R)ß/γ, IL-6Rα/ß, mothers against decapentaplegic homolog (Smad)3/4 and runt-related transcription factor (RUNX)1/3 in CD4-positive cells. The concentration of cytokines in plasma were measured using a cytometric bead array. Additionally, the proportion of CD4+CD25highFoxp3+ Tregs and levels of associated proteins was analyzed using flow cytometry. The results demonstrated that the proportion of CD4+CD25highFoxp3+ and expression of Foxp3 in children with B-ALL was significantly higher compared with healthy controls (P<0.05) and that transcription levels of CTLA4, GITR and LAG3 were also significantly elevated (P<0.05). Compared with healthy controls, the expression of IL-2Rα/ß and its downstream molecule phosphorylated signal transducer and activator of transcription 5 (pSTAT5) in CD4-positive cells significantly increased (P<0.05); however, no significant difference of IL-2Rγ levels was identified between the two groups. Correlation analysis demonstrated a significant positive correlation between the expression of phosphorylated (p) signal transducer and activator of transcription factor (STAT)5 and CD4+CD25highFoxp3+ Tregs in children with B-ALL (r=0.17; P<0.05). The plasma concentration of TGF-ß, the expression of its receptor TGF-ßRI/II and downstream molecules Smad3/4 were significantly upregulated in children with B-ALL (P<0.05), whereas the expression of RUNX1/3 was lower compared with healthy controls (P<0.05). Furthermore, the expression of Smad3 and RUNX1 was positively correlated with CD4+CD25highFoxp3+ Tregs in children with B-ALL (r=0.87 and 0.60, respectively; P<0.05). Additionally, the expression of pSTAT3 in CD4-positive cells decreased significantly in pediatric patients with B-ALL when compared with healthy controls; however, plasma concentrations of IL-6 was significantly higher (P<0.05). Furthermore, a negative correlation was identified between pSTAT3 and CD4+CD25highFoxp3+ Tregs in pediatric patients with B-ALL (r=-0.39; P<0.05). However, no significant differences in IL-6Rα/ß expression were identified between the two groups. The results demonstrated that the excessive activation of IL-2/pSTAT5 and TGF-ß/Smad signaling, and insufficiency of pSTAT3 may be correlated with increased CD4+CD25highFoxp3+ Tregs in pediatric B-ALL.

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