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1.
Redox Biol ; 28: 101356, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704583

RESUMO

Airway remodeling is one of the characteristics for chronic obstructive pulmonary disease (COPD). The mechanism underlying airway remodeling is associated with epithelial-mesenchymal transition (EMT) in the small airways of smokers and patients with COPD. Sirtuin 1 (SIRT1) is able to reduce oxidative stress, and to modulate EMT. Here, we investigated the effects and mechanisms of hydrogen sulfide (H2S) on pulmonary EMT in vitro and in vivo. We found that H2S donor NaHS inhibited cigarette smoke (CS)-induced airway remodeling, EMT and collagen deposition in mouse lungs. In human bronchial epithelial 16HBE cells, NaHS treatment also reduced CS extract (CSE)-induced EMT, collagen deposition and oxidative stress. Mechanistically, NaHS upregulated SIRT1 expression, but inhibited activation of TGF-ß1/Smad3 signaling in vivo and in vitro. SIRT1 inhibition by a specific inhibitor EX527 significantly attenuated or abolished the ability of NaHS to reverse the CSE-induced oxidative stress. SIRT1 inhibition also abolished the protection of NaHS against CSE-induced EMT. Moreover, SIRT1 activation attenuated CSE-induced EMT by modifying TGF-ß1-mediated Smad3 transactivation. In conclusion, H2S prevented CS-induced airway remodeling in mice by reversing oxidative stress and EMT, which was partially ameliorated by SIRT1 activation. These findings suggest that H2S may have therapeutic potential for the prevention and treatment of COPD.

2.
Aging (Albany NY) ; 11(24): 11844-11864, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31881011

RESUMO

Hydrogen sulfide (H2S), an endogenous gaseous signal molecule, regulates many pathologies related to aging. Sirtuin 1 (SIRT1) has been shown to protect against mitochondrial dysfunction and other pathological processes, including premature senescence. This study was aimed to investigate whether and how H2S attenuates senescence and apoptosis of alveolar epithelial cells via a SIRT1-dependent mechanism. Our results showed that treatment with sodium hydrosulfide (NaHS), a donor of H2S, attenuated cigarette smoke extract (CSE)-induced oxidative stress, mitochondrial dysfunction, cellular senescence and apoptosis in A549 cells. This was associated with SIRT1 upregulation. SIRT1 activation by a pharmacological activator, SRT1720, attenuated CSE-induced oxidative stress and mitochondrial dysfunction in A549 cells. While SIRT1 inhibition by EX 527 or silencing by siRNA transfection significantly attenuated or abolished the ability of NaHS to reverse the CSE-induced oxidative stress, mitochondrial dysfunction and the imbalance of mitochondrial fusion and fission. Also, SIRT1 inhibition or silencing abolished the protection of NaHS against CSE-induced cellular senescence and apoptosis. In conclusion, H2S attenuates CSE-induced cellular senescence and apoptosis by improving mitochondrial function and reducing oxidative stress in alveolar epithelial cells in a SIRT1-dependent manner. These findings provide novel mechanisms underlying the protection of H2S against cigarette smoke-induced COPD.

3.
Int Immunopharmacol ; : 105979, 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31771816

RESUMO

Chronic obstructive pulmonary fibrosis (COPD) is a chronic and fatal lung disease with few treatment options. Sodium hydrosulfide (NaHS), a donor of hydrogen sulfide (H2S), was found to alleviate cigarette smoke (CS)-induced emphysema in mice, however, the underlying mechanisms have not yet been clarified. In this study, we investigated its effects on COPD in a CS-induced mouse model in vivo and in cigarette smoke extract (CSE)-stimulated alveolar epithelial A549 cells in vitro. The results showed that NaHS not only relieved emphysema, but also improved pulmonary function in CS-exposed mice. NaHS significantly increased the expressions of tight junction proteins (i.e., ZO-1, Occludin and claudin-1), and reduced apoptosis and secretion of pro-inflammatory cytokines (i.e., TNF-α, IL-6 and IL-1ß) in CS-exposed mouse lungs and CSE-incubated A549 cells, indicating H2S inhibits CS-induced inflammation, injury and apoptosis in alveolar epithelial cells. NaHS also upregulated prolyl hydroxylase (PHD)2, and suppressed hypoxia-inducible factor (HIF)-1α expression in vivo and in vitro, suggesting H2S inhibits CS-induced activation of PHD2/HIF-1α axis. Moreover, NaHS inhibited CS-induced phosphorylation of ERK, JNK and p38 MAPK in vivo and in vitro, and treatment with their inhibitors reversed CSE-induced ZO-1 expression and inflammation in A549 cells. These results suggest that NaHS may prevent emphysema via the suppression of PHD2/HIF-1α/MAPK signaling pathway, and subsequently inhibition of inflammation, epithelial cell injury and apoptosis, and may be a novel strategy for the treatment of COPD.

4.
Front Cell Neurosci ; 12: 285, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210304

RESUMO

The ventrolateral medulla (VLM), including the lateral paragigantocellular nucleus (LPGi) and rostral VLM (RVLM), is commonly considered to be a chemosensitive region. However, the specific mechanism of chemoreception in the VLM remains elusive. Acid-sensing ion channels (ASICs), a family of voltage-independent proton-gated cation channels, can be activated by an external pH decrease to cause Na+ entry and induce neuronal excitability. TWIK-related acid-sensitive potassium channels (TASKs) are members of another group of pH-sensitive channels; in contrast to AISICs, they can be stimulated by pH increases and are inhibited by pH decreases in the physiological range. Our previous study demonstrated that ASICs take part in chemoreception. The aims of this study are to explore whether TASKs participate in the acid sensitivity of neurons in the VLM, thereby cooperating with ASICs. Our research demonstrated that TASKs, including TASK1 and TASK3, are colocalized with ASIC1 in VLM neurons. Blocking TASKs by microinjection of the non-selective TASK antagonist bupivacaine (BUP), specific TASK1 antagonist anandamide (AEA) or specific TASK3 antagonist ruthenium red (RR) into the VLM increased the integrated phrenic nerve discharge (iPND), shortened the inspiratory time (Ti) and enhanced the respiratory drive (iPND/Ti). In addition, microinjection of artificial cerebrospinal fluid (ACSF) at a pH of 7.0 or 6.5 prolonged Ti, increased iPND and enhanced respiratory drive, which were inhibited by the ASIC antagonist amiloride (AMI). By contrast, microinjection of alkaline ACSF decreased iPND and respiratory drive, which were inhibited by AEA. Taken together, our data suggest that TASK1 and TASK3 are coexpressed with ASIC1 in the VLM. Moreover, TASK1 and TASK3 contribute to the central regulation of breathing by coordinating with each other to perceive local pH changes; these results indicate a novel chemosensitive mechanism of the VLM.

5.
J Thorac Dis ; 10(7): E511-E515, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30174922

RESUMO

Anthracofibrosis, which was defined as a luminal narrowing associated with overlying anthracotic mucosa on bronchoscopy, has been infrequently reported. Recently, we have identified a case of patient who had a history of pulmonary tuberculosis (TB), manifested left main bronchial stenosis and hyperpigmentation. Despite repeated and multiple cryotherapy, the condition was still progressing. Given to the potential relationship between active endobronchial tuberculosis (EBTB) and anthracofibrosis, the patient received a diagnostic anti-tuberculosis (anti-TB) treatment due to initial failed cryotherapy, resulting in improvement of hyperpigmentation and stenosis of the left main bronchus. Eventually, the patient recovered well with regular anti-TB combined with intermittent cryotherapy. Our study suggests that even without etiological evidence, there might be an indication of therapeutic trial of anti-TB medication in case of repeated bronchial stenosis due to anthracofibrosis in patients with past history of TB and other causes are excluded. Yet, the recommendation of aggressive treatment should reply on the effect of diagnostic treatment and further research.

6.
J Thorac Dis ; 10(6): 3232-3243, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30069319

RESUMO

Background: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease with limited treatment options. Hydrogen (H2) has been shown to be anti-oxidative and anti-inflammatory. This study aimed to evaluate the beneficial effects of H2 inhalation on COPD development in mice. Methods: A COPD mouse model was established in male C57BL mice by cigarette smoke (CS) exposure. The H2 intervention was administered by atomisation inhalation. Lung functions were assessed by using Buxco lung function measurement system. The inflammatory cells were counted and the levels of IL-6 and KC in BALF were assayed with ELISA. The lung tissue was subjected to H&E or PAS or Masson's trichrome stain. Furthermore, 16HBE cells were used to evaluate the effects of H2 on signaling change caused by hydrogen peroxide (H2O2). H2O2 was used to treat 16HBE cells with or without H2 pretreatment. The IL-6 and IL-8 levels in cell culture medium were measured. The levels of phosphorylated ERK1/2 and nucleic NF-κB in lungs and 16HBE cells were determined. Results: H2 ameliorated CS-induced lung function decline, emphysema, inflammatory cell infiltration, small-airway remodelling, goblet-cell hyperplasia in tracheal epithelium and activated ERK1/2 and NF-κB in mouse lung. In 16HBE airway cells, H2O2 increased IL-6 and IL-8 secretion in conjunction with ERK1/2 and NF-κB activation. These changes were reduced by H2 treatment. Conclusions: These findings demonstrated that H2 inhalation could inhibit CS-induced COPD development in mice, which is associated with reduced ERK1/2 and NF-κB-dependent inflammatory responses.

7.
Front Pharmacol ; 9: 263, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29765317

RESUMO

Aberrant activation of hypoxia-inducible factor (HIF)-1α is frequently encountered and promotes oxidative stress and inflammation in chronic obstructive pulmonary disease (COPD). The present study investigated whether sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, can mediate its effect through inhibiting HIF-1α-induced oxidative stress and inflammation in cigarette smoke (CS)-induced COPD in mice. Here, we found that STS improved pulmonary function, ameliorated emphysema and decreased the infiltration of inflammatory cells in the lungs of CS-exposed mice. STS reduced CS- and cigarette smoke extract (CSE)-induced upregulation of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the lungs and macrophages. STS also inhibited CSE-induced reactive oxygen species (ROS) production, as well as the upregulation of heme oxygenase (HO)-1, NOX1 and matrix metalloproteinase (MMP)-9 in macrophages. In addition, STS suppressed HIF-1α expression in vivo and in vitro, and pretreatment with HIF-1α siRNA reduced CSE-induced elevation of TNF-α, IL-1ß, and HO-1 content in the macrophages. Moreover, we found that STS inhibited CSE-induced the phosphorylation of ERK, p38 MAPK and JNK in macrophages, and inhibition of these signaling molecules significantly repressed CSE-induced HIF-1α expression. It indicated that STS inhibits CSE-induced HIF-1α expression likely by blocking MAPK signaling. Furthermore, STS also promoted HIF-1α protein degradation in CSE-stimulated macrophages. Taken together, these results suggest that STS prevents COPD development possibly through the inhibition of HIF-1α signaling, and may be a novel strategy for the treatment of COPD.

8.
Mol Clin Oncol ; 8(1): 38-46, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29387395

RESUMO

Increasing evidence supports a key role for the bone morphogenetic protein (BMP) signaling pathway in lung vasculogenesis and angiogenesis. Genetic variations in BMP genes have been found to be correlated with cancer risk. In particular, the mutation in the 3'-untranslated region of BMPs may significantly affect gene function, leading to cancer susceptibility. The aim of the present study was to determine whether genetic variations in the components of the BMP family are associated with lung cancer risk. A total of 314 tag single-nucleotide polymorphisms were identified in 18 genes, which are considered to either compose or regulate BMPs, and their association with lung cancer risk was evaluated in a two-stage case-control study with 4,680 cases and controls. A consistently significant association of SMAD5 rs12719482 with elevated lung cancer risk was observed in the three types of sources of populations (adjusted additive model in the combined population: Odds ratio=1.32, 95% confidence interval: 1.16-1.51). The lung cancer risk statistically significantly increased with the increasing number of variant alleles of SMAD5 rs12719482 in a dose-dependent pattern (P for trend=4.9×10-5). Consistent evidence was identified for a significant interaction between the rs12719482 and cigarette smoking, performed as either a continuous or discrete variable. These findings indicated that SMAD5 rs12719482 may be a possible candidate marker for susceptibility to lung cancer in the Chinese population.

9.
Sci Rep ; 8(1): 376, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29321495

RESUMO

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by abnormal inflammation, persistent and progressive lung function decline. The anti-inflammatory actions of tanshinone IIA, which is the most important active component from Chinese herbal medicine Danshen, have been well studied. However, it remains unknown whether sodium tanshinone IIA sulfonate (STS) protects against the development of COPD. Here we found that STS inhalation (5 mg/kg, 30 min per session, twice a day) significantly attenuated lung function decline, airspace enlargement, mucus production, bronchial collagen deposition, inflammatory responses and oxidative stress caused by cigarette smoke (CS) and lipopolysaccharide (LPS) exposures in mice. Moreover, treatment with STS (10 µg/ml) reduced CS extract (CSE)-induced IL-6 and IL-8 secretion in human bronchial epithelial (16HBE) cells. The anti-inflammatory actions of STS were associated with inhibition of ERK1/2 and NF-κB activations. Interestingly, STS inhibited CS-induced reduction of cystic fibrosis transmembrane conductance regulator (CFTR) in mouse lungs and in 16HBE cells. Treatment with a specific CFTR inhibitor CFTR-Inh172 augmented CSE-induced ERK1/2 and NF-κB-dependent inflammatory responses, but abolished the inhibitory action of STS on IL-6 and IL-8 secretion in 16HBE cells. These results demonstrate that CS-induced COPD and down-regulation of CFTR are prevented by STS.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fenantrenos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Linhagem Celular , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Camundongos , Fenantrenos/farmacologia , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/metabolismo , Testes de Função Respiratória
10.
Int Immunopharmacol ; 54: 210-220, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29156356

RESUMO

Chronic obstructive pulmonary disease (COPD) is a chronic, progressive and lethal lung disease with few treatments. Limax, a mollusk with lung, has been widely used to control phlegm and cough in China, yet whether Limax has a positive effect on COPD is unknown. This study investigated the effects of water-soluble extract from Limax on COPD development and the underlying mechanisms. The results showed that Limax extract improved lung function, relieved emphysema and suppressed the inflammation in the lungs of CS-challenged mice, as evidenced by diminished release of IL-6, KC, TNF-α, IFN-γ, Muc5AC, IL-17 and diminished mRNA expression of Muc5B. Moreover, Limax extract also inhibited phosphorylation of P38 and ERK and increased the expression of PPARγ. More interestingly, Limax extract (0.1µg/ml) inhibited CSE-induced release of IL-6 in vitro, which was substantially abrogated by heat treatment, and filtrate obtained from the deproteinized Limax extract with the 100KD ultrafiltration membrane, inhibited the secretion of IL-6. Taken together, these results suggest that, Limax extract prevents COPD development via inhibition of inflammation and mucus production, thus has a potential preventive and therapeutic application in COPD.


Assuntos
Misturas Complexas/uso terapêutico , Pneumonia/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Fumar Cigarros/efeitos adversos , Citocinas/metabolismo , Modelos Animais de Doenças , Gastrópodes/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mucina-5AC/metabolismo , Mucina-5B/metabolismo , Muco/metabolismo
11.
Front Physiol ; 9: 1860, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30670978

RESUMO

The present study examined whether angiotensin II (Ang II) mediates the pressor effect through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS)-mitogen-activated protein kinase (MAPK) signaling in the glutamatergic neurons of the rostral ventrolateral medulla (RVLM) in stress-induced hypertensive rats (SIHR). The SIHR model was established using electric foot-shocks combined with noises for 15 days. We observed that Ang II type 1 receptor (AT1R) and the glutamatergic neurons co-localized in the RVLM of SIHR. Furthermore, glutamate levels in the intermediolateral column of the spinal cord were higher in SIHR than in controls. Microinjection of Ang II into the RVLM of SIHR activated stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK), extracellular signal-regulated protein kinase (ERK) 1/2, and p38MAPK. Compared with controls, the activation of SAPK/JNK, ERK1/2, p38MAPK, and ROS in the RVLM were higher in SIHR, an effect that was blocked by an NADPH oxidase inhibitor (apocynin) and an AT1R antagonist (candesartan). RVLM microinjection of apocynin or a SAPK/JNK inhibitor (SP600125), but not an ERK1/2 inhibitor (U0126) or a p38MAPK inhibitor (SB203580), decreased AT1R mRNA and mean arterial blood pressure (MABP) in SIHR. The increase of AT1R protein expression and MABP was inhibited by intracerebroventricular infusion (ICV), for 14 days, of SP600125, but not U0126 or SB203580 in SIHR. We conclude that Ang II modulates the pressor effect through AT1R-dependent ROS-SAPK/JNK signaling in glutamatergic neurons in the RVLM of SIHR.

12.
Cell Physiol Biochem ; 44(4): 1337-1351, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29183030

RESUMO

BACKGROUND/AIMS: Extracellular ATP performs multiple important functions via activation of P2 receptors on the cell surface. P2Y receptors play critical roles in ATP evoked response in human lung adenocarcinoma cells (A549 cells). Emodin is an anthraquinone derivative originally isolated from Chinese rhubarb, possesses anticancer properties. In this study we examined the inhibiting effects of emodin on proliferation, migration and epithelial-mesenchymal transition (EMT) by suppressing P2Y receptors-dependent Ca2+ increase and nuclear factor-κB (NF-KB) signaling in A549 cells. METHODS: A549 cells were pretreated with emodin before stimulation with ATP for the indicated time. Then, intracellular Ca2+ concentration ([Ca2+]i) was measured by Fluo-8/AM staining. Cell proliferation and cell cycle progression were tested by CCK8 assay and flow cytometry In addition, wound healing and western blot were performed to determine cell migration and related protein levels (Bcl-2, Bax, claudin-1, NF-κB). RESULTS: Emodin blunted ATP/UTP-induced increase of [Ca2+]i and cell proliferation concentration-dependently Meanwhile, it decreased ATP-induced cells accumulation in the S phase. Furthermore, emodin altered protein abundance of Bcl-2, Bax and claudin-1 and attenuated EMT caused by ATP. Such ATP-induced cellular reactions were also inhibited by a nonselective P2Y receptors antagonist, suramin, in a similar way to emodin. Besides, emodin could inhibit activation of NF-κB, thus suppressed ATP-induced proliferation, migration and EMT. CONCLUSION: Our results demonstrated that emodin inhibits ATP-induced proliferation, migration, EMT by suppressing P2Y receptors-mediated [Ca2+]i increase and NF-κB signaling in A549 cells.


Assuntos
Trifosfato de Adenosina/farmacologia , Proliferação de Células/efeitos dos fármacos , Emodina/toxicidade , Receptores Purinérgicos P2Y/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células A549 , Adenocarcinoma , Adenocarcinoma de Pulmão , Caderinas/metabolismo , Cálcio/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Claudina-1/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares , Microscopia de Fluorescência , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Antagonistas do Receptor Purinérgico P2Y/toxicidade , Receptores Purinérgicos P2Y/química , Receptores Purinérgicos P2Y/genética , Suramina/toxicidade , Proteína X Associada a bcl-2/metabolismo
13.
J Neuroinflammation ; 14(1): 169, 2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28835252

RESUMO

BACKGROUND: Neuroinflammation plays hypertensive roles in the uninjured autonomic nuclei of the central nervous system, while its mechanisms remain unclear. The present study is to investigate the effect of neuroinflammation on autophagy in the neurons of the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside. METHODS: Stress-induced hypertension (SIH) was induced by electric foot-shock stressors with noise interventions in rats. Systolic blood pressure (SBP) and the power density of the low frequency (LF) component of the SAP spectrum were measured to reflect sympathetic vasomotor activity. Microglia activation and pro-inflammatory cytokines (PICs (IL-1ß, TNF-α)) expression in the RVLM were measured by immunoblotting and immunostaining. Autophagy and autophagic vacuoles (AVs) were examined by autophagic marker (LC3 and p62) expression and transmission electron microscopy (TEM) image, respectively. Autophagy flux was evaluated by RFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors transfected into the RVLM. Tissue levels of glutamate, gamma aminobutyric acid (GABA), and plasma levels of norepinephrine (NE) were measured by using high-performance liquid chromatography (HPLC) with electrochemical detection. The effects of the cisterna magna infused minocycline, a microglia activation inhibitor, on the abovementioned parameters were analyzed. RESULTS: SIH rats showed increased SBP, plasma NE accompanied by an increase in LF component of the SBP spectrum. Microglia activation and PICs expression was increased in SIH rats. TEM demonstrated that stress led to the accumulation of AVs in the RVLM of SIH rats. In addition to the Tf-LC3 assay, the concurrent increased level of LC3-II and p62 suggested the impairment of autophagic flux in SIH rats. To the contrary, minocycline facilitated autophagic flux and induced a hypotensive effect with attenuated microglia activation and decreased PICs in the RVLM of SIH rats. Furthermore, SIH rats showed higher levels of glutamate and lower level of GABA in the RVLM, while minocycline attenuated the decrease in GABA and the increase in glutamate of SIH rats. CONCLUSIONS: Collectively, we concluded that the neuroinflammation might impair autophagic flux and induced neural excitotoxicity in the RVLM neurons following SIH, which is involved in the development of SIH.


Assuntos
Autofagia/fisiologia , Hipertensão/metabolismo , Mediadores da Inflamação/metabolismo , Bulbo/metabolismo , Neurônios/metabolismo , Estresse Psicológico/metabolismo , Animais , Hipertensão/etiologia , Hipertensão/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Bulbo/patologia , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/complicações , Estresse Psicológico/patologia
14.
Sci Rep ; 6: 38777, 2016 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-27934921

RESUMO

The role of acid-sensing ion channels (ASICs) in the ventrolateral medulla (VLM) remains uncertain. Here, we found that ASIC1a and ASIC2 are widely expressed in rat medulla, and the expression level is higher at neonatal stage as compared to adult stage. The two ASIC subunits co-localized in medualla neurons. Furthermore, pH reduction triggered typical ASIC-type currents in the medulla, including the VLM. These currents showed a pH50 value of 6.6 and were blocked by amiloride. Based on their sensitivity to psalmotoxin 1 (PcTx1) and zinc, homomeric ASIC1a and heteromeric ASIC1a/2 channels were likely responsible for acid-mediated currents in the mouse medulla. ASIC currents triggered by pH 5 disappeared in the VLM neurons from ASIC1-/-, but not ASIC2-/- mice. Activation of ASICs in the medulla also triggered neuronal excitation. Moreover, microinjection of artificial cerebrospinal fluid at a pH of 6.5 into the VLM increased integrated phrenic nerve discharge, inspiratory time and respiratory drive in rats. Both amiloride and PcTx1 inhibited the acid-induced stimulating effect on respiration. Collectively, our data suggest that ASICs are highly expressed in the medulla including the VLM, and activation of ASICs in the VLM contributes to central chemoreception.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Bulbo/metabolismo , Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Camundongos , Camundongos Knockout , Ratos
15.
Toxicol Lett ; 262: 161-172, 2016 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-27717887

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with few treatment options and poor prognosis. Emodin, extracted from Chinese rhubarb, was found to be able to alleviate bleomycin (BLM)-induced pulmonary fibrosis, yet the underlying mechanism remains largely unknown. This study aimed to further investigate the effects of emodin on the inflammation and fibrosis of BLM-induced pulmonary fibrosis and the mechanism involved in rats. Our results showed that emodin improved pulmonary function, reduced weight loss and prevented death in BLM-treated rats. Emodin significantly relieved lung edema and fibrotic changes, decreased collagen deposition, and suppressed the infiltration of myofibroblasts [characterized by expression of α-smooth muscle actin (α-SMA)] and inflammatory cells (mainly macrophages and lymphocytes). Moreover, emodin reduced levels of TNF-α, IL-6, TGF-ß1 and heat shock protein (HSP)-47 in the lungs of BLM-treated rats. In vitro, emodin profoundly inhibited TGF-ß1-induced α-SMA, collagen IV and fibronectin expression in human embryo lung fibroblasts (HELFs). Emodin also inhibited TGF-ß1-induced Smad2/3 and STAT3 activation, indicating that Smad2/3 and STAT3 inactivation mediates emodin-induced effects on TGF-ß1-induced myofibroblast differentiation. These results suggest that emodin can exert its anti-fibrotic effect via suppression of TGF-ß1 signaling and subsequently inhibition of inflammation, HSP-47 expression, myofibroblast differentiation and extracellular matrix (ECM) deposition.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Bleomicina/antagonistas & inibidores , Bleomicina/toxicidade , Emodina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Matriz Extracelular/efeitos dos fármacos , Proteínas de Choque Térmico HSP47/antagonistas & inibidores , Proteínas de Choque Térmico HSP47/biossíntese , Humanos , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Testes de Função Respiratória , Perda de Peso/efeitos dos fármacos
16.
Sci Rep ; 6: 35696, 2016 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-27774992

RESUMO

Aberrant activation of TGF-ß1 is frequently encountered and promotes epithelial-mesenchymal transition (EMT) and fibroblast activation in pulmonary fibrosis. The present study investigated whether emodin mediates its effect via suppressing TGF-ß1-induced EMT and fibroblast activation in bleomycin (BLM)-induced pulmonary fibrosis in rats. Here, we found that emodin induced apoptosis and inhibited cellular proliferation, migration and differentiation in TGF-ß1-stimulated human embryonic lung fibroblasts (HELFs). Emodin suppressed TGF-ß1-induced EMT in a dose- and time-dependent manner in alveolar epithelial A549 cells. Emodin also inhibited TGF-ß1-induced Smad2, Smad3 and Erk1/2 activation, suggesting that Smad2/3 and Erk1/2 inactivation mediated the emodin-induced effects on TGF-ß1-induced EMT. Additionally, we provided in vivo evidence suggesting that emodin apparently alleviated BLM-induced pulmonary fibrosis and improved pulmonary function by inhibiting TGF-ß1 signaling and subsequently repressing EMT, fibroblast activation and extracellular matrix (ECM) deposition. Taken together, our data suggest that emodin mediates its effects mainly via inhibition of EMT and fibroblast activation and thus has a potential for the treatment of pulmonary fibrosis.


Assuntos
Bleomicina/farmacologia , Emodina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Células A549 , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Fibrose Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
17.
Biosci Rep ; 36(6)2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27780890

RESUMO

Extracorporeal pulsed electromagnetic field (PEMF) has shown the ability to regenerate tissue by promoting cell proliferation. In the present study, we investigated for the first time whether PEMF treatment could improve the myocardial ischaemia/reperfusion (I/R) injury and uncovered its underlying mechanisms.In our study, we demonstrated for the first time that extracorporeal PEMF has a novel effect on myocardial I/R injury. The number and function of circulating endothelial progenitor cells (EPCs) were increased in PEMF treating rats. The in vivo results showed that per-treatment of PEMF could significantly improve the cardiac function in I/R injury group. In addition, PEMF treatment also reduced the apoptosis of myocardial cells by up-regulating the expression of anti-apoptosis protein B-cell lymphoma 2 (Bcl-2) and down-regulating the expression of pro-apoptosis protein (Bax). In vitro, the results showed that PEMF treatment could significantly reduce the apoptosis and reactive oxygen species (ROS) levels in primary neonatal rat cardiac ventricular myocytes (NRCMs) induced by hypoxia/reoxygenation (H/R). In particular, PEMF increased the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS), which might be closely related to attenuated cell apoptosis by increasing the releasing of nitric oxide (NO). Therefore, our data indicated that PEMF could be a potential candidate for I/R injury.


Assuntos
Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/terapia , Animais , Apoptose/fisiologia , Campos Eletromagnéticos , Masculino , Miócitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Proteína X Associada a bcl-2/metabolismo
18.
J Appl Physiol (1985) ; 119(6): 686-95, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26205539

RESUMO

In mammals, the neural control of airway smooth muscle is dominated by a subset of airway vagal preganglionic neurons in the ventrolateral medulla. These neurons are physiologically modulated by adrenergic/noradrenergic projections, and weakened α2-adrenergic inhibition of them is indicated to participate in the pathogenesis and exacerbation of asthma. This study tests whether these neurons are modulated by α1-adrenoceptors, and if so, how. In anesthetized adult rats, microinjection of the α1A-adrenoceptor agonist A61603 (1 pmol) unilaterally into the medullary region containing these neurons caused a significant increase in airway resistance, which was prevented by intraperitoneal atropine (0.5 mg/kg). In rhythmically firing medullary slices of newborn rats, A61603 (10 nM) caused depolarization in both the inspiratory-activated and inspiratory-inhibited airway vagal preganglionic neurons that were retrogradely labeled, and a significant increase in the spontaneous firing rate. Under voltage clamp, A61603 significantly enhanced the spontaneous excitatory inputs to both types of neurons and caused a tonic inward current in the inspiratory-activated neurons along with significantly increased peak amplitude of the inspiratory inward currents. The responses in vitro were prevented by α1A-adrenoceptor antagonist RS100329 (1 µM), which alone significantly inhibited the spontaneous excitatory inputs to both types of the neurons. After pretreatment with tetrodotoxin (1 µM), A61603 (10 or 100 nM) had no effect on either type of neuron. We conclude that in rats, activation of α1-adrenoceptors in the medullary region containing airway vagal preganglionic neurons increases airway vagal tone, and that this effect is primarily mediated by facilitation of the excitatory inputs to the preganglionic neurons.


Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Bulbo/metabolismo , Neurônios/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Nervo Vago/metabolismo , Animais , Animais Recém-Nascidos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Masculino , Bulbo/efeitos dos fármacos , Bulbo/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Mecânica Respiratória/efeitos dos fármacos , Mecânica Respiratória/fisiologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo , Sistema Respiratório/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Tetrodotoxina/farmacologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia
19.
Neurosci Lett ; 587: 22-8, 2015 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-25524407

RESUMO

Several pieces of evidence indicate that the microglial P2X7 receptor (P2X7R) regulate cardiovascular activities. We explored the possible roles of microglial P2X7R in the PVN mediated sympathoexcitatory responses in acute myocardial infarction (AMI) rat. Sprague-Dawley rats underwent coronary artery ligation to induce AMI. The rats received intraperitoneal administration of the P2X7R antagonist Brilliant Blue-G (BBG, 25 or 50 mg kg(-1), once a day for 5 days) prior to myocardial ischemia. Other rats received bilateral microinjection of P2X7R-siRNA (0.015 or 0.03 nmol 0.1µl per side, once a day for 2 days) targeting P2X7R mRNA into the PVN prior to myocardial ischemia. First, we examined the ATP levels and protein expression P2X7R in the PVN in different ischemia time groups, and we found that the change of P2X7R was positive correlated with the ATP levels in a time-dependent manner. The double-immunofluorescence evidence showed that P2X7R was mainly co-localizated with the microglial marker Iba-1 in the PVN. Second, gene knockdown of P2X7R with P2X7-siRNA or inhibition of P2X7R with BBG reduce the mRNA and protein expression of IL-1ß and TNF-α in the PVN of AMI rat. Third, microinjected P2X7-siRNA also suppressed the up-regulation of P2X7R, oxytocin and vasopressin in the PVN of AMI rats. Fourth, P2X7-siRNA and BBG also attenuated the renal sympathetic nerve activity (RSNA) in the AMI rats. Our results indicate that microglial P2X7R activation in PVN mediating the production of proinflammatory cytokines that activate oxytocinergic and vasopressinergic neuron, which augmented the RSNA in the AMI rat.


Assuntos
Pressão Sanguínea , Frequência Cardíaca , Infarto do Miocárdio/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antígenos Nucleares/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Interleucina-1beta/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Infarto do Miocárdio/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Ocitocina/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Receptores Purinérgicos P2X7/genética , Corantes de Rosanilina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Vasopressinas/metabolismo
20.
PLoS One ; 9(12): e114536, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25486122

RESUMO

This study utilized magnetic resonance imaging (MRI) to monitor the real-time status of the urinary bladder in normal and diseased states following cyclophosphamide (CYP)-induced cystitis, and also examined the role of the phosphoinositide 3-kinase (PI3K) pathway in the regulation of urinary bladder hypertrophy in vivo. Our results showed that under MRI visualization the urinary bladder wall was significantly thickened at 8 h and 48 h post CYP injection. The intravesical volume of the urinary bladder was also markedly reduced. Treatment of the cystitis animals with a specific PI3K inhibitor LY294002 reduced cystitis-induced bladder wall thickening and enlarged the intravesical volumes. To confirm the MRI results, we performed H&E stain postmortem and examined the levels of type I collagen by real-time PCR and western blot. Inhibition of the PI3K in vivo reduced the levels of type I collagen mRNA and protein in the urinary bladder ultimately attenuating cystitis-induced bladder hypertrophy. The bladder mass calculated according to MRI data was consistent to the bladder weight measured ex vivo under each drug treatment. MRI results also showed that the urinary bladder from animals with cystitis demonstrated high magnetic signal intensity indicating considerable inflammation of the urinary bladder when compared to normal animals. This was confirmed by examination of the pro-inflammatory factors showing that interleukin (IL)-1α, IL-6 and tumor necrosis factor (TNF)α levels in the urinary bladder were increased with cystitis. Our results suggest that MRI can be a useful technique in tracing bladder anatomy and examining bladder hypertrophy in vivo during disease development and the PI3K pathway has a critical role in regulating bladder hypertrophy during cystitis.


Assuntos
Cistite/prevenção & controle , Hipertrofia/prevenção & controle , Imagem por Ressonância Magnética/métodos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Doenças da Bexiga Urinária/prevenção & controle , Bexiga Urinária/citologia , Animais , Western Blotting , Células Cultivadas , Cromonas/farmacologia , Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Cistite/metabolismo , Cistite/patologia , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipertrofia/etiologia , Hipertrofia/metabolismo , Hipertrofia/patologia , Masculino , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Doenças da Bexiga Urinária/etiologia , Doenças da Bexiga Urinária/metabolismo , Doenças da Bexiga Urinária/patologia
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