ABSTRACT
Acute lung injury (ALI) is an urgent respiratory disease without effective treatment. Mesencephalic astrocyte-derived neurotrophic factor (MANF)has been demonstrated to play a suppressive role in some inflammatory conditions. However, the effect of MANF on ALI has not yet been reported. In this study, we collected bronchoalveolar lavage fluid (BALF) from the patients with or without pulmonary inflammation, and used lipopolysaccharide (LPS) to induce mice ALI model. Mono-macrophage-specific MANF knockout (MKO) mice were constructed and recombinant human MANF protein was used to ALI mice. We found that the endogenous MANF protein in both human BALF and mice lung tissues was increased in inflammatory conditions. MANF level in the macrophages of inflammatory lung was higher than that in normal controls in both human and mice. MANF deficiency in macrophages induced lung inflammation and aggravated LPS-induced lung injury. MANF lowered LPS-induced lung injury, inhibited macrophage polarization to M1 functional type. Meanwhile, MANF inhibited-LPS induced activation of NF-κB signal pathway by down regulating phosphorylated p65in lung tissue and macrophages. These results indicate that MANF acts as a suppressor in ALI via negatively regulating NF-κB activation and macrophages polarization, which may be a novel potential target and shed light on ALI therapy.
Subject(s)
Acute Lung Injury , Lipopolysaccharides , Macrophages , Nerve Growth Factors , Acute Lung Injury/genetics , Acute Lung Injury/immunology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Animals , Astrocytes/metabolism , Astrocytes/pathology , Disease Models, Animal , Humans , Lipopolysaccharides/pharmacology , Lung , Macrophage Activation , Macrophages/immunology , Macrophages/pathology , Mice , Mice, Knockout , NF-kappa B/metabolism , Nerve Growth Factors/genetics , Nerve Growth Factors/immunology , Nerve Growth Factors/metabolismABSTRACT
Asthma is characterized by chronic airway inflammation, which is the underlying cause of airway remodeling featured by goblet cell hyperplasia, subepithelial fibrosis, and proliferation of smooth muscle. Sevoflurane has been used to treat life-threatening asthma and our previous study shows that sevoflurane inhibits acute lung inflammation in ovalbumin (OVA)-induced allergic mice. However, the effect of sevoflurane on airway remodeling in the context of chronic airway inflammation and the underlying mechanism are still unknown. Here, female C57BL/6 mice were used to establish chronic airway inflammation model. Hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), and Sirius red (SR) staining were used to evaluate airway remodeling. Protein levels of α-SMA, VEGF, and TGF-ß1 in lung tissues were detected by western blotting analyses and immunohistochemistry staining. Results showed that inhalation of sevoflurane inhibited chronic airway inflammation including inflammatory cell infiltration and pro-inflammatory cytokine production in BALF of the OVA-challenged mice. Meanwhile, sevoflurane suppressed airway thickening, goblet cell hyperplasia, smooth muscle hyperplasia, collagen deposition, and fiber hyperplasia in the lung tissues of the mice with airway remodeling. Most notably, sevoflurane inhibited the OVA-induced expressions of VEGF and TGF-ß1. These results suggested that sevoflurane effectively inhibits airway remodeling in mouse model of chronic airway inflammation, which may be due to the downregulation of VEGF and TGF-ß1in lung tissues. Therefore, our results indicate a potential role of sevoflurane in inhibiting airway remodeling besides its known suppression effect on airway inflammation, and support the use of sevoflurane in treating severe asthma in ICU.
Subject(s)
Airway Remodeling/drug effects , Asthma/drug therapy , Inflammation/immunology , Sevoflurane/pharmacology , Transforming Growth Factor beta1/metabolism , Vascular Endothelial Growth Factor A/metabolism , Anesthetics, Inhalation/pharmacology , Animals , Asthma/pathology , Down-Regulation/drug effects , Female , Inflammation/chemically induced , Inflammation/prevention & control , Mice , OvalbuminABSTRACT
To investigate the suppressive effects of xanthatin on glioma growth in a nude mouse xenograft model and rat orthotopic implantation model using magnetic resonance imaging (MRI) to dynamically monitor the antitumour growth and antiangiogenesis effects of xanthatin. The nude mouse xenograft tumour model and rat orthotopic implantation model were established to observe the antitumour effects of xanthatin in vivo. In the rat orthotopic implanted tumour model, MRI scanning was used to dynamically monitor the antitumour growth effect and evaluate the antiangiogenesis effect of xanthatin. We found that xanthatin at a dose of 0.4 mg/10 g dramatically decreased the growth of xenograft tumours in nude mice. The antiangiogenesis effect of xanthatin C6 glioma was evaluated by dynamic contrast-enhanced (DCE) MRI via comparison of the volume transfer constant (Ktrans ) value, a parameter that reflects vessel permeability. We found that xanthatin at the doses of 8 and 16 mg/kg significantly decreased the Ktrans value, which suggests that xanthatin has antiangiogenesis effects. These data demonstrate the suppressive effects of xanthatin on C6 glioma occur via antiangiogenesis. Meanwhile, this study also provides evidence for the application of quantitative parameters of DCE-MRI for dynamically evaluating the growth and angiogenesis of intracranial tumours and for experimental and clinical research.
