Preeclampsia (PE) is one of the leading causes of maternal death worldwide. Elevated fatty acid binding protein 4 (FABP4) levels have been observed in patients with PE, however, the mechanism by which FABP4 contributes to the pathogenesis of PE remains unclear. In this study, we compared the levels of FABP4 and cytokines between 20 PE patients and 10 healthy pregnant women by using ELISA, immunohistochemistry (IHC) analysis, and flow cytometry (fluorescence-activated cell sorting, FACS). Elevated FABP4 was accompanied by regulatory T (Treg)/T helper type 17 (Th17) imbalance in PE. Knockdown of FABP4 attenuated lipopolysaccharide (LPS)-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and interleukin-17A (IL-17A) production in primary macrophages. In addition, silencing of FABP4 also suppressed Th17 differentiation via paracrine signaling. Overexpression of FABP4 promoted Th17 differentiation via increasing IL-17A/IL-23 release. Reciprocally, IL-17A upregulated FABP4 and activated the NLRP3 inflammasome in vitro and in vivo. The in vivo studies revealed that FABP4 inhibitor BMS309403 ameliorated PE clinical phenotypes, the Treg/Th17 imbalance, and NLRP3 inflammasome activation in PE mice model. In conclusion, FABP4 facilitates inflammasome activation to induce the imbalance of Treg/Th17 in PE via forming a positive feedback with IL-17A.
The new coronavirus pneumonia (COVID-19) occurred in Wuhan in December 2019. Subsequent outbreak of COVID-19 worldwide is defined by the World Health Organization (WHO) as a public health emergency of international concern. Epidemiological data showed that the severe COVID-19 patients accounted for as high as 20% or more. In addition to the impairment of respiratory system, acute kidney injury (AKI) remains one of the main complications. Immune damage mediated by cytokine storms and concomitant AKI contribute a key factor of poor prognosis. Based on the previous experience of blood purification in severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) combined with clinical front-line practice, we have developed a blood purification protocol for severe COVID-19 patients. This protocol is divided into four major steps: The first step is to assess whether patients with severe COVID-19 need blood purification; the second step is to prescribe a blood purification treatment for COVID-19 patients; the third step is to monitor and adjust the parameters of blood purification; the fourth step is to evaluate the timing of discontinue the blood purification. It is expected that blood purification will play a key role in effectively reducing the mortality of patients with severe COVID-19 through the standardized implementation of the present protocol.
Background Hydrogen sulfide (H2S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H2S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H2S in carbon tetrachloride (CCl4)-induced hepatotoxicity, cirrhosis and portal hypertension. Methods and Findings Sodium hydrosulfide (NaHS), a donor of H2S, and DL-propargylglycine (PAG), an irreversible inhibitor of cystathionine γ-lyase (CSE), were applied to the rats to investigate the effects of H2S on CCl4-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H2S, hepatic H2S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP) 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl4 significantly reduced serum levels of H2S, hepatic H2S production and CSE expression. NaHS attenuated CCl4-induced acute hepatotoxicity by supplementing exogenous H2S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), albumin, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and soluble intercellular adhesion molecule (ICAM)-1, liver histology, hepatic hydroxyproline content and α-smooth muscle actin (SMA) expression. PAG showed opposing effects to NaHS on most of the above parameters. Conclusions Exogenous H2S attenuates CCl4-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H2S may present a promising approach, particularly for its prophylactic effects, against liver cirrhosis and portal hypertension.
To investigate the changes in heme oxygenase (HO) system expression in pulmonary thromboembolism (PTE), and the influence to the pulmonary artery blood pressure as a result of the changes.In 23 healthy adult male dogs, autologous thrombus was injected through the jugular vein to reproduce the PTE model. They were divided randomly into 4 groups: A (pulmonary embolism 3 hours group), B (pulmonary embolism 8 hours group), C (pulmonary embolism 24 hours group) and D (control group). Swan-Ganz catheter was placed via the femoral vein to observe the changes in hemodynamics. Pulmonary artery was obtained to detect the expression of HO-1 using semi-quantity reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical method.The pulmonary artery mean pressure (PAMP), pulmonary artery systolic pressure (PASP) and pulmonary artery diastolic pressure (PADP) of the experimental groups were increased obviously after the pulmonary embolism as compared with those of before the embolism (all P<0.05), and were decreased obviously 1 hour after the embolism (all P<0.05). The decrease was gradual and stopped after 4-5 hours, but the pressure 8 hours after embolism was still higher than that of before embolism. HO-1 was not expressed in pulmonary artery in control group, but expressed after embolism in each experimental group. The expression was increased gradually after pulmonary embolism, and it was remarkable 24 hours after embolism (all P<0.05).The expression of HO-1 increased in PTE, and the increased pulmonary artery blood pressure decreased at the same time. The results suggest that HO-1 is related with dilatation of pulmonary artery after PTE.
Infection-associated inflammation and coagulation are critical pathologies in sepsis-induced acute lung injury (ALI). This study aimed to investigate the effects of microRNA-363-3p (miR-363-3p) on sepsis-induced ALI and explore the underlying mechanisms. A cecal ligation and puncture-induced septic mouse model was established. The results of this study suggested that miR-363-3p was highly expressed in lung tissues of septic mice. Knockdown of miR-363-3p attenuated sepsis-induced histopathological damage, the inflammation response and oxidative stress in lung tissues. Furthermore, knockdown of miR-363-3p reduced the formation of platelet-derived microparticles and thrombin generation in blood samples of septic mice. Downregulation of miR-363-3p suppressed sphingosine-1-phosphate receptor 1 (S1PR1) expression in lung tissues and subsequently inactivated the nuclear factor kappa-B ligand (NF-κB) signaling. A luciferase reporter assay confirmed that miR-363-3p directly targeted the 3'-UTR of the mouse S1pr1 mRNA. Collectively, our study suggests that inactivation of NF-κB signaling is involved in the miR-363-3p/S1PR1 axis-mediated protective effect on septic ALI.
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