Protective effects of progesterone on pulmonary artery smooth muscle cells stimulated with Interleukin 6 via blocking the shuttling and transcriptional function of STAT3.

BACKGROUND: Sex hormone paradox is a crucial but unresolved issue in the field of pulmonary artery hypertension (PAH), and is thought to be related to different pathogenic factors. Inflammation is one of pathological mechanisms of PAH development. However, effects of sex hormones on the pulmonary vasculature under the condition of inflammation are still elusive. METHODS: Interleukin-6 (IL-6) was used as a representative inflammatory stimulator. Effects of 17ß-estradiol or progesterone on human pulmonary artery smooth muscle cells (PASMCs) were measured under the condition of IL-6. Cell functions of proliferation and migration were measured by Alarmar Blue, EdU assay, wound-healing assay and transwell chambers. We explored further mechanisms using western blot, immunofluorescence, co-immunoprecipitation, qPCR and chromatin immunoprecipitation. RESULTS: Our results revealed that IL-6 promoted the proliferation of PASMCs, but progesterone could reverse the adverse effect of IL-6. The protective effect was dependent on progesterone receptor (PGR). By interacting with signal transducer and activator of transcription 3 (STAT3), activated PGR could reduce the IL-6-induced nuclear translocation of STAT3 and prevent STAT3-chromatin binding in PASMCs, leading to the decreased transcription of downstream CCND1 and BCL2. Alternatively, progesterone slightly decreased the phosphorylation of pro-proliferative Erk1/2 and Akt kinases and upregulated the anti-proliferative pSmad1-Id1/2 axis in IL-6-incubated PASMCs. CONCLUSIONS: Progesterone played a protective role on PASMCs in the context of IL-6, by blocking the functions of STAT3. Our findings might assist in explaining the clinical phenomenon of better prognosis for women with PAH.

High flow nasal cannula versus conventional oxygen therapy in postoperative patients at high risk for pulmonary complications: A systematic review and meta-analysis.

BACKGROUND: The effects of high flow nasal cannula (HFNC) on postoperative patients at high risk for pulmonary complications(PC) are controversial. We aimed to further determine the effectiveness of HFNC in postoperative patients at high risk for PC by comparison to conventional oxygen therapy (COT). METHODS: We performed a comprehensive search that compared HFNC with COT in postoperative patients at high risk for PC. The main outcomes were length of hospital stay (hospital LOS) and respiratory complications. RESULTS: Six trials with a total of 733 patients were pooled in our final studies. Except for Hospital LOS (I2  = 53%, χ2  = 8.51, P = .07) and rate of intubation or non-invasive ventilation (NIV) for respiratory failure (RF) (I2  = 49%, χ2  = 1.97, P = .16) between HFNC and COT, no significant heterogeneity was found in outcome measures. Compared with COT, HFNC was associated with a lower rate of intubation or NIV for RF (RR 0.23, 95% CI 0.08-0.66, P = .006) and rate of hypercapnia (RR 0.37, 95% CI 0.20-0.68, P = .002). As for the Hospital LOS, ICU LOS, rate of requirement of O2 after discontinuous and hypoxemia, HFNC did not show any advantage over COT. Trial Sequential Analysis (TSA) for Hospital LOS showed that monitoring boundaries were finally not surpassed and required information size (RIS) was not met. CONCLUSIONS: The available randomised controlled trials (RCTs) suggest that, among the postoperative patients at high risk for PC, HFNC therapy compared with the COT significantly reduces rate of incubation or NIV for RF and rate of hypercapnia, meanwhile is safely administered. Further large-scale, multicenter, randomised and controlled studies are needed to confirm our results.

Heterozygous SOD2 deletion deteriorated chronic intermittent hypoxia-induced lung inflammation and vascular remodeling through mtROS-NLRP3 signaling pathway.

Oxidative stress caused by chronic intermittent hypoxia (CIH) is the hallmark of obstructive sleep apnea (OSA). Among the first line of defense against oxidative stress is the dismutation of superoxide radicals, which in the mitochondria is carried out by manganese superoxide dismutase (SOD2). In this study, wild-type (WT) and SOD2-heterozygous knockout (SOD2+/-) mice were exposed to CIH or normoxic (Nor) conditions. After 4 weeks, pulmonary artery pressure was measured, and the mice were processed to harvest either serum for cytokine assays or lungs for flow cytometry and histopathological studies. Herein, we showed that heterozygous deletion of SOD2 markedly deteriorated pulmonary remodeling and increased the oxidative stress, especially promoted the infiltration of macrophages in the lungs of CIH mouse. Moreover, in the intermittent hypoxia (IH)-treated RAW264.7 cells, SOD2 knockdown increased the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation accompanied with the IL-1ß elevation and caspase-1 activity. Additionally, mitochondrial ROS (mtROS) scavenger mito-TEMPO abolished NLRP3 inflammasome activation in IH-treated RAW264.7 cells. Collectively, our results supported that SOD2 contributed to the pathogenesis of CIH-induced lung remodeling. Meanwhile, SOD2 knockdown exacerbates oxidative damage through assembly and activation of NLRP3 inflammasome in macrophages. SOD2 may be a novel therapeutic target for CIH-induced pulmonary inflammation and arteriole remodeling.

Low Dose of Cyanidin-3-O-Glucoside Alleviated Dextran Sulfate Sodium-Induced Colitis, Mediated by CD169+ Macrophage Pathway.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic disease of the intestinal tract in which excessive activation of inflammatory response is correlated. Cyanidin-3-O-glucoside (C3G) is a powerful anti-inflammatory agent, widely existing in fruits and vegetables. However, the role of C3G has rarely been investigated in dextran sulfate sodium (DSS)-induced colitis. METHODS: In an attempt to elucidate the possible mechanism of IBD and develop new efficient therapeutic methods for colitis, we evaluated the effects of C3G on DSS-induced colitis. DSS-induced colitic C57BL/6 mice were intraperitoneal injected with 1ug C3G or phosphate buffer every 2 days, a total of 3 times; the changes in macrophages and regular T cells were analyzed by flow cytometry and immunofluorescence. Cytokines and chemokines were measured by real-time quantitative polymerase chain reaction. RESULTS: The results showed that C3G treatment did not cause changes in body weight and colon length as much as those of DSS-treated mice only. Cytokine expression levels such as interleukin (IL)- 6, IL-1ß, IL-18, tumor necrosis factor α, interferon γ (IFN γ) in colons and mesenteric lymph nodes (mLNs) from C3G-treated mice were lower than those from colitic mice. Meanwhile, C3G injection inhibited the decrease in CCL22 levels and Tregs induction in colitic mice. Furthermore, the activation of macrophages by LPS and increase of CD169+ cells induced by type I IFN could be inhibited by C3G directly in vitro. CONCLUSIONS: The study is the first to demonstrate strong effects of C3G to alleviate DSS-induced colonic damage in mice. The effect of C3G on DSS-induced colitis clearly showed a decrease of CD169+ macrophages in both the colon and mLNs. An increase of CD169+ cells induced by type I IFN could be inhibited by C3G. All these data suggest that the role of C3G in colitic inflammation was mediated at least partially by CD169+ cells and the type I IFN pathway.

Diagnostic value of (1 → 3)-ß-D-glucan in bronchoalveolar lavage fluid for invasive fungal disease: A meta-analysis.

BACKGROUND: The serum (1 â†’ 3)-ß-D-glucan (BG) assay has been approved for diagnosing invasive fungal diseases (IFDs). However, the performance of (1 â†’ 3)-ß-D-glucan assay in bronchoalveolar lavage (BAL) fluid is various among studies. The present study aimed to assess the accuracy of (1 â†’ 3)-ß-D-glucan assay in bronchoalveolar lavage fluid for the diagnosis of invasive fungal diseases by means of meta-analysis and systematic review of relevant studies. METHOD: The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (OR) and a summary receiver-operating characteristic curve of BAL-BG for diagnosing invasive fungal diseases were pooled using meta-analysis. We also performed meta-regression analysis. RESULTS: A total of 838 patients (138 with proven or probable invasive fungal diseases), included in 6 studies, were analyzed. The pooled sensitivity, specificity, PLR, NLR and diagnostic odds ratio were 0.52 (95%CI, 0.38-0.53), 0.58 (95%CI, 0.55-0.61), 1.34 (95%CI, 1.08-1.66), 0.82 (95% CI, 0.63-1.07) and 1.71 (95%CI, 1.01-2.92) respectively. The area under the summary receiver operating characteristic curve, with 95% confidence intervals was 0.61 (95%CI, 0.67-0.55). CONCLUSION: The accuracy of (1 â†’ 3)-ß-D-glucan test in bronchoalveolar lavage fluid is marginal, so that the results should not be interpreted alone but can be used as a part of full assessment with clinical features, image findings and other laboratory results for the diagnosis of invasive fungal diseases.