Loss of lymphocytes, particularly T cell apoptosis, is a central pathological event after severe tissue injury which is associated with increased susceptibility for life-threatening infections. The precise immunological mechanisms leading to T cell death after acute injury are largely unknown. Here, we identified a monocyte-T cell interaction driving bystander cell death of T cells in ischemic stroke and burn injury. Specifically, we found that stroke induced a FasL-expressing monocyte population, which led to extrinsic T cell apoptosis. This phenomenon was driven by the AIM2 inflammasome-dependent interleukin-1 (IL-1 ) secretion after sensing cell-free DNA. Pharmacological inhibition of this pathway improved T cell survival and reduced post-stroke bacterial infections. As such, this study describes inflammasome-dependent monocyte activation as a previously unstudied cause of T cell death after injury, and challenges the current paradigms of post-injury lymphopenia.

BackgroundPrevious studies suggest applying prone position (PP) and lateral position (LP) in patients with severe acute respiratory distress syndrome (ARDS) for their efficacy in improving oxygenation and lung recruitment.This paper aims to share clinical experiences and outcome of using PP and LP in combination with oxygen therapy (OT) andNon-invasive ventilation (NIV) in severe and critical patients with COVID-19. MethodsClinical data of 48 severe and critical patients have been retrieved from medical records and reviewed. The primary outcome is the survival rate. Secondary outcome is the rate of patients requiring intubation. ResultsIn total, 25 patients were finally included in the study.The mean respiratory rate of all 25 patients decreased from 28.4 breaths/min to 21.3 breaths/min. CT results showed increase in lung recruitment. All patients tolerated PP and LP well. No deterioration or severe adverse events associated with PP and LP occurred. All patients recovered and survived without intubation. Follow-up to date showed that all patients have been discharged except one with mild symptoms and positive RNA test. Conclusion:Clinical outcomes of early application of PP and LP in combination with OT and NIV in severe and critical patients with COVID-19 indicated well tolerance of the therapy and resulted in improving patients' oxygenation in a safe and effective manner. Therefore, this strategy can be explored as an early intervention in managing patients in early stage of disease development under the context of pandemic and limited medical resources.

Background: Endoplasmic reticulum stress (ER stress) plays a critical role in the pathogenesis of liver fibrosis; thus, it can be a potential therapeutic target of fibrosis. However, the mechanism of ER stress regulation in fibrosis, particularly through sirtuin 1 (SIRT1), remains unclear. The objective of this study was to investigate the effect of SIRT1-mediated inhibition of ER stress in bile duct ligation (BDL)-induced liver fibrosis, and to explore the effect of salvianolic acid A (SalA) on BDL-induced liver fibrosis through SIRT1/heat shock factor 1 (HSF1) signaling.Materials and Methods: We explored the effects of SalA on liver fibrosis and ER stress in BDL-induced liver fibrosis in rats and the human hepatic stellate cell line LX2 cells. The LX2 cells were treated with 20 ng of platelet-derived growth factor-BB homodimer (PDGF-BB) for 24 h, and then incubated in the absence or presence of SalA (25 μM) for 24 h.Results: In vivo, SalA treatment alleviated BDL-induced liver injury and ER stress. Importantly, SalA treatment increased HSF1 expression and activity using a SIRT1-dependent mechanism. In LX2 cells, PDGF-BB induced ER stress and fibrosis were blocked by HSF1 overexpression. Furthermore, SIRT1 siRNA abrogated the SalA-mediated promotion of HSF1 deacetylation and expression, suggesting that SalA-mediated protection occurs by SIRT1 targeting HSF1 for deacetylation.Conclusion: This is the first study to identify the SIRT1/HSF1 pathway as a key therapeutic target for controlling BDL-induced liver fibrosis and to show that SalA confers protection against BDL- and PDGF-BB-induced hepatic fibrosis and ER stress through SIRT1-mediated HSF1 deacetylation.

Fibrosis reflects a progression to liver cancer or cirrhosis of the liver. Recent studies have shown that high-mobility group box-1 (HMGB1) plays a major role in hepatic injury and fibrosis. Carnosic acid (CA), a compound extracted from rosemary, has been reported to alleviate alcoholic and non-alcoholic fatty liver injury. CA can also alleviate renal fibrosis. We hypothesized that CA might exert anti-liver fibrosis properties through an HMGB1-related pathway, and the results of the present study showed that CA treatment significantly protected against hepatic fibrosis in a bile duct ligation (BDL) rat model. CA reduced the liver expression of α-smooth muscle actin (α-SMA) and collagen 1 (Col-1). Importantly, we found that CA ameliorated the increase in HMGB1 and Toll-like receptor 4 (TLR4) caused by BDL, and inhibited NF-κB p65 nuclear translocation in fibrotic livers. In vitro, CA inhibited LX2 cell activation by inhibiting HMGB1/TLR4 signaling pathway. Furthermore, miR-29b-3p decreased HMGB1 expression, and a dual-luciferase assay validated these results. Moreover, CA down-regulated HMGB1 and inhibited LX2 cell activation, and these effects were significantly counteracted by antago-miR-29b-3p, indicating that the CA-mediated inhibition of HMGB1 expression might be miR-29b-3p dependent. Collectively, the results demonstrate that a miR-29b-3p/HMGB1/TLR4/NF-κB signaling pathway, which can be modulated by CA, is important in liver fibrosis, and indicate that CA might be a prospective therapeutic drug for liver fibrosis.