Xudong Xiang

Chop Deficiency Protects Mice Against Bleomycin-induced Pulmonary Fibrosis by Attenuating M2 Macrophage Production

C/EBP homologous protein (Chop) has been shown to have altered expression in patients with idiopathic pulmonary fibrosis (IPF), but its exact role in IPF pathoaetiology has not been fully addressed. Studies conducted in patients with IPF and Chop(-/-) mice have dissected the role of Chop and endoplasmic reticulum (ER) stress in pulmonary fibrosis pathogenesis. The effect of Chop deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis were affected by the altered Chop expression and ER stress. In particular, Chop deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of Chop significantly attenuated transforming growth factor β (TGF-β) production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that Chop deficiency repressed the M2 program in macrophages, which then attenuated TGF-β secretion. Specifically, loss of Chop promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which Chop deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that Chop and ER stress are implicated in IPF pathoaetiology, involving at least the induction and differentiation of M2 macrophages.

Aloperine protects mice against ischemia reperfusion (IR)-induced renal injury by regulating PI3K/AKT/mTOR signaling and AP-1 activity.

Aloperine is a quinolizidine alkaloid extracted from the leaves of Sophora plants. It has been recognized with the potential to treat inflammatory and allergic diseases as well as tumors. In this report, we demonstrate that pretreatment with aloperine provided protection for mice against ischemia-reperfusion (IR)-induced acute renal injury as manifested by the attenuated inflammatory infiltration, reduced tubular apoptosis, and well-preserved renal function. Mechanistic studies revealed that aloperine selectively repressed IL-1β and IFN-γ expression by regulating PI3K/Akt/mTOR signaling and NF-κB transcriptional activity. However, aloperine did not show a perceptible impact on IL-6 and TGF-β expression and the related Jak2/Stat3 signaling. It was also noted that aloperine regulates AP-1 activity, through which it not only enhances SOD expression to increase reactive oxygen species (ROS) detoxification but also promotes the expression of antiapoptotic Bcl-2, thereby preventing tubular cells from IR-induced apoptosis. Collectively, our data suggest that administration of aloperine prior to IR insults, such as renal transplantation, could be a viable approach to prevent IR-induced injuries.

Blockade of dopamine D1-like receptor signalling protects mice against OVA-induced acute asthma by inhibiting B-cell activating transcription factor signalling and Th17 function

Previous studies have consistently demonstrated that dopamine D1‐like receptor (D1‐like‐R) signalling is implicated in the pathogenesis of experimental autoimmune encephalomyelitis and type I diabetes. Given that allergic asthma shares certain disease aetiology similarities with autoimmune diseases, we conducted studies in OVA‐induced mice aiming to address the impact of D1‐like‐R signalling on the pathogenesis of allergic asthma. It was noted that blockade of D1‐like‐R signalling provided protection for mice against OVA‐induced acute asthma. Particularly, treatment of OVA‐induced mice with SCH23390, a D1‐like‐R antagonist, significantly attenuated inflammatory infiltration in the airways along with repressed goblet cell hyperplasia and mucus production, as well as airway resistance. By contrast, administration of SKF83959, a D1‐like‐R agonist, displayed the opposite effect. Blockade of D1‐like‐R signalling impaired Th17 function, as manifested by a significant reduction of Th17 cells in the spleen and bronchoalveolar lavage fluid. Mechanistic studies revealed that D1‐like‐R signalling enhances B‐cell activating transcription factor activity, which then transcribes the expression of RORγt, a Th17 transcription factor; accordingly, D1‐like‐R signalling regulates Th17 differentiation to promote the development of allergic asthma. Taken together, the data obtained in the present suggest that blockade of D1‐like‐R signalling could be an effective therapeutic strategy for the prevention and treatment of allergic asthma in clinical practice.

Comparative analysis of the alveolar macrophage proteome in ALI/ARDS patients between the exudative phase and recovery phase

BackgroundDespite decades of extensive studies, the morbidity and mortality for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remained high. Particularly, biomarkers essential for its early diagnosis and prognosis are lacking.MethodsRecent studies suggest that alveolar macrophages (AMs) at the exudative phase of ALI/ARDS initiate, amplify and perpetuate inflammatory responses, while they resolve inflammation in the recovery phase to prevent further tissue injury and perpetuated inflammation in the lung. Therefore, proteins relevant to this functional switch could be valuable biomarkers for ALI/ARDS diagnosis and prognosis. We thus conducted comparative analysis of the AM proteome to assess its dynamic proteomic changes during ALI/ARDS progression and recovery.Results135 proteins were characterized to be differentially expressed between AMs at the exudative and recovery phase. MALDI-TOF-MS and peptide mass fingerprint (PMF) analysis characterized 27 informative proteins, in which 17 proteins were found with a marked increase at the recovery phase, while the rest of 10 proteins were manifested by the significantly higher levels of expression at the exudative phase.ConclusionsGiven the role of above identified proteins played in the regulation of inflammatory responses, cell skeleton organization, oxidative stress, apoptosis and metabolism, they have the potential to serve as biomarkers for early diagnosis and prognosis in the setting of patients with ALI/ARDS.

The effect of pollutional haze on pulmonary function.

Detrimental health effects of atmospheric exposure to ambient particulate matter (PM) have been investigated in numerous studies. Exposure to pollutional haze, the carrier of air pollutants such as PM and nitrogen dioxide (NO2) has been linked to lung and cardiovascular disease, resulting increases in both hospital admissions and mortality. This review focuses on the constituents of pollutional haze and its effects on pulmonary function. The article presents the available information and seeks to correlate pollutional haze and pulmonary function.

Role of C/EBP homologous protein and endoplasmic reticulum stress in asthma exacerbation by regulating the IL-4/signal transducer and activator of transcription 6/transcription factor EC/IL-4 receptor α positive feedback loop in M2 macrophages

Background: C/EBP homologous protein (Chop), a marker of endoplasmic reticulum (ER) stress, exhibits aberrant expression patterns during asthma development. However, its exact role in asthma pathogenesis is not fully understood. Objectives: We aimed to determine the function and mechanism of Chop in the pathogenesis of allergic asthma in patients and animals. Methods: Studies were conducted in asthmatic patients and Chop−/− mice to dissect the role of Chop and ER stress in asthma pathogenesis. An ovalbumin (OVA)–induced allergic airway inflammation model was used to address the effect of Chop deficiency on asthma development. Next, the effect of Chop deficiency on macrophage polarization and related signaling pathways was investigated to demonstrate the underlying mechanisms. Results: Asthmatic patients and mice after OVA induction exhibited aberrant Chop expression along with ER stress. Specifically, Chop was noted to be specifically overexpressed in macrophages, and mice deficient in Chop were protected from OVA‐induced allergic airway inflammation, as manifested by attenuated airway inflammation, remodeling, and hyperresponsiveness. Chop was found to exacerbate allergic airway inflammation by enhancing M2 programming in macrophages. Mechanistic studies characterized an IL‐4/signal transducer and activator of transcription 6/transcription factor EC (Tfec)/IL‐4 receptor &agr; positive feedback regulatory loop, in which IL‐4 induces Chop expression, which then promotes signal transducer and activator of transcription 6 signaling to transcribe Tfec expression. Finally, Tfec transcribes IL‐4 receptor &agr; expression to promote M2 programming in macrophages. Conclusions: Chop and ER stress are implicated in asthma pathogenesis, which involves regulation of M2 programming in macrophages.

Effects and mechanism of dehydroepiandrosterone on epithelial–mesenchymal transition in bronchial epithelial cells

ABSTRACT Background: Chronic persistent asthma is characterized by airway remodeling, in which epithelial–mesenchymal transition (EMT) may play a significant role. Dehydroepiandrosterone (DHEA), a steroid hormone and testosterone analog, is considered as an important immunomodulating hormone. However, its role in EMT remains unclear. We sought to investigate whether transforming growth factor-β1 (TGF-β1) stimulates human bronchial epithelial cells (16HBE-14o) to undergo EMT, and whether this transition can be abrogated by DHEA. Methods: The 16HBE-14o cells were stimulated with 5 ng/ml TGF-β1 for 3 days to induce EMT, with or without DHEA pretreatment, and assayed for epithelial or mesenchymal markers using Western Blot. The involvement of phosphoinositide 3-kinase (PI3K) -mediated signaling pathway was also evaluated, the epithelial cells were also incubated with pharmacological approaches (agonists and antagonists of Akt, LY294002 or IGF-1) or flutamide, the antagonist of androgen receptor. Results were analyzed using nonparametric statistical tests. Results: Our data demonstrate that treatment of 16HBE-14o cells with TGF-β1 for 3 days induced EMT as reflected by conversion to the spindle-like morphology, loss of E-cadherin, and acquisition of a-smooth muscle actin (a-SMA). Pretreatment of 16HBE-14o cells with DHEA preserved the epithelial-like morphology, restored the expression of E-cadherin, and abolished the activation of a-SMA, and this effect is a PI3K-dependent mechanism. Conclusion: Our results indicate that TGF-β1 induces EMT in a PI3K-dependent manner in 16HBE-14o cells. DHEA inhibits the bronchial epithelial to mesenchymal transition via the inhibition of PI3K/Akt-dependent signal pathway stimulated by TGF-β1. Therefore, DHEA may be a useful therapy for asthma.

Lung ultrasound: a promising tool to monitor ventilator-associated pneumonia in critically ill patients

Ventilator-associated pneumonia (VAP) is the most frequent intensive care unit (ICU)-acquired infection that is independently associated with mortality. Accurate diagnosis and timely treatment have been shown to improve the prognosis of VAP. Chest X-ray or computed tomography imaging are used for conventional assessment of VAP, but these methods are impractical for real-time measurement in critical patients. Therefore, lung ultrasound (LUS) has been increasingly used for the assessment of VAP in the ICU. Traditionally, LUS has seemed unsuitable for the detection of lung parenchyma owing to the high acoustic impedance of air; however, the fact that the reflection and reverberation in the detection region of the ultrasound reflect the underlying pathology of lung diseases has led to the increased use of ultrasound imaging as a standard of care supported by evidence-based and expert consensus in the ICU. Considering that any type of pneumonia causes air volume changes in the lungs, accumulating evidence has shown that LUS effectively measures the presence of VAP as well as dynamic changes in VAP. This review offers evidence for ultrasound as a noninvasive, easily repeatable, and bedside means to assess VAP; in addition, it establishes a protocol for qualitative and quantitative monitoring of VAP.