PREDICTIVE VALUE OF SOLUBLE PROGRAMMED CELL DEATH LIGAND-1 IN THE PROGRESSION OF SEPTIC PATIENTS TO CHRONIC CRITICAL ILLNESS IN THE INTENSIVE CARE UNIT: A PROSPECTIVE OBSERVATIONAL CLINICAL STUDY.

ABSTRACT: Background: As an immune marker, serum soluble programmed cell death ligand-1 (sPD-L1) is significantly increased in sepsis and is predictive of mortality. We investigated the prognostic value of sPD-L1 in postseptic immunosuppression and progression to chronic critical illness (CCI). Methods: Adults with sepsis in intensive care units (ICUs) for the first time were screened and assigned to either a CCI group (ICU stay ≥14 days with persistent organ dysfunction) or a rapid recovery (RAP) group based on clinical outcome. Data regarding basic admission information and clinical parameters were collected and compared across the two groups. Serum sPD-L1 levels were detected by enzyme-linked immunosorbent assay at admission and on the seventh day (D 7 ). Logistic regression analysis was used to determine the factors affecting septic patients' lymphocytopenia diagnosis on day 7 and CCI progression during hospitalization. The receiver operating characteristic curve and DeLong test were used to assess variable predictive power. Results: During the study period, a total of 166 septic patients were admitted to the ICU, and 91 septic patients were enrolled after screening. Compared with those in healthy individuals, the sPD-L1 levels in septic patients were significantly higher and positively correlated with traditional inflammatory markers and disease severity scores ( P < 0.05). In a multivariate regression analysis, sPD-L1 alone predicted lymphocytopenia on day 7 ( P < 0.05). In the sepsis cohort, 59 patients (64.8%) experienced RAP, and 32 patients (35.2%) developed CCI. Compared with the RAP group, the patients in the CCI group had a higher mean age, greater severity of disease, and higher mortality ( P < 0.05). D 7 -sPD-L1 remained higher in the CCI group, and the area under the curve that predicted the occurrence of CCI was equivalent to the APACHE II score, with areas under the curve of 0.782 and 0.708, respectively. Conclusions: The severity of infection and immunosuppression in sepsis may be linked to serum sPD-L1. D 7 -sPD-L1 is valuable in predicting the progression of CCI in patients.

Heparin-binding protein (HBP) worsens the severity of pancreatic necrosis via up-regulated M1 macrophages activation in acute pancreatitis mouse models.

Acute pancreatitis (AP) is one of the most widespread clinical emergencies. Macrophages are the most common immune cells in AP pancreatic tissue and are closely associated with pancreatic necrosis and recovery. The level of heparin-binding protein (HBP) is closely linked to inflammation. In this study, we assessed the effect of HBP on AP tissue necrosis severity and whether HBP is associated with M1 macrophages in pancreatic necrosis. We observed the dynamic changes of HBP levels in the pancreas during acute inflammation in the caerulein-induced AP mice model. We used hematoxylin-eosin staining to evaluate pancreatic edema and necrosis, and to detect infiltration of macrophages by immunohistochemistry. Moreover, expressions of the maker and cytokines of macrophages, including inducible nitric oxide synthase (iNOS), and arginase 1 (Arg-1), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) mRNA, were detected by real-time polymerase-chain reaction (RT-PCR). High levels of HBP in the pancreas were detected at 48 h, and heparin inhibited HBP expression in AP pancreatic tissue. Inhibiting HBP expression by injecting heparin before AP can alleviate pancreatic necrosis and inhibit F4/80 labeled M1 macrophage infiltration and IL-6, TNF-α, and iNOS mRNA expression. Clodronate liposome (CLDL) intraperitoneally treated mice showed no change in pancreatic HBP levels, but pancreatic macrophage-specific antigen F4/80 and TNF-α, IL-1ß, and IL-6 mRNA levels decreased after CLDL treatment. HBP is critical for pancreatic necrosis response in acute pancreatitis by increasing the infiltration of M1 macrophages and promoting the secretion of inflammatory factors, such as TNF-α, IL-6, IL-1ß, which can be reduced by heparin.

miR-20b suppresses mitochondrial dysfunction-mediated apoptosis to alleviate hyperoxia-induced acute lung injury by directly targeting MFN1 and MFN2.

Supplemental oxygen is commonly used to treat severe respiratory failure, while prolonged exposure to hyperoxia can induce acute lung injury characterized by the accumulation of reactive oxygen species (ROS) and pulmonary inflammation. Dysregulation of microRNAs contributes to multiple diseases, including hyperoxia-induced acute lung injury (HALI). In this study, we explored the roles of miR-20b in mediating the response of type II alveolar epithelial cells (ACE IIs) to hyperoxia and the potential underlying mechanisms. We found that miR-20b was significantly decreased in the lung tissues of HALI models and H2O2-treated ACE IIs. Hyperoxia induced the release of TNF-α, decreased the mitochondrial membrane potential, and led to excessive ROS production and cell apoptosis. Overexpression of miR-20b suppressed the hyperoxia-induced biological effects in ACE IIs. miR-20b negatively regulated the expression levels of Mitofusin 1 (MFN1) and MFN2, the two key proteins of mitochondrial fusion, via complementarily binding to the 3'-untranslated regions of mRNAs. Furthermore, both in vivo and in vitro, upregulation of MFN1 and MFN2 aggravated lung damage and cell apoptosis that were alleviated by miR-20b overexpression. These results provided new insights into the involvement of the miR-20b/MFN1/2 signaling pathway in HALI.

Heparin-Binding Protein Enhances NF-κB Pathway-Mediated Inflammatory Gene Transcription in M1 Macrophages via Lactate.

In early-stage sepsis, glucose metabolism is increased primarily through glycolysis in the inflammatory response of M1 macrophages. Heparin-binding protein (HBP) has been linked to sepsis, which can promote macrophage activation and inflammatory factor release. However, the mechanism by which glucose metabolism regulates the inflammatory response is unclear. We show that HBP contributes to sepsis by modulating the inflammatory response via lactate-dependent glycolysis in macrophages. Peritoneal macrophages from BALB/c mouse were treated with lipopolysaccharide (LPS). The expression of M1-related proinflammatory genes was investigated by PCR array. IL-1ß, iNOS, TNF-α, and IL-6 mRNA expression was determined by qRT-PCR. Intracellular lactate levels were measured using lactate assays. Nuclear factor-kappaB (NF-κB) activity was determined by electrophoretic mobility shift assays (EMSAs). TNF-α levels were measured by qRT-PCR. HBP enhanced inflammatory gene expression in mouse peritoneal macrophages and intracellular lactate accumulation and significantly increased LPS-stimulated NF-κB transcriptional activity and TNF-α expression through lactate. Lactate was essential for the HBP-induced increase in LPS-stimulated TNF-α expression. The critical role of lactate in HBP-induced NF-κB signaling was confirmed, as α-CHCA-mediated (MCT) suppression significantly inhibited NF-κB activity and TNF-α expression. HBP plays an important role in the initial inflammatory reaction, presumably by activating M1 macrophages, increasing lactate levels, and regulating proinflammatory factor release via NF-κB pathway activation.

Research advances in myocardial injury caused by COVID-19.

Coronavirus disease 2019 (COVID-19) caused a large-scale infection in China at the end of 2019. The virus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has the characteristics of strong transmission capacity, diverse clinical manifestations, long incubation period, strong infection in incubation period, etc. With the increase of the number of cases and the continuous improvement of clinical data, we found that patients with COVID-19 have myocardial injury besides typical respiratory system manifestations. According to published data, we summarized the clinical manifestations of myocardial injury in COVID-19 patients, and discussed the probable injury mechanism, treatment methods and future research directions.

Role of M2 Macrophages in Sepsis-Induced Acute Kidney Injury.

BACKGROUND: Sepsis is a major cause of acute kidney injury (AKI), with high rates of morbidity and mortality. M2 macrophages have been shown to play important roles in the secretion of anti-inflammatory and tissue repair mediators. In this study, we investigate the role of M2 macrophages in sepsis-induced AKI by depleting these cells in vivo through the systemic administration of liposomal clodronate (LC). METHODS: Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) or sham surgery. Biochemical and histological renal damage was assessed. Macrophage infiltration and M2 macrophage depletion were assessed by immunohistochemistry. RT-PCR was used to investigate the expression of the inducible nitric oxide synthase (iNOS), arginase 1 (Arg-1), and found in inflammatory zone 1 (FIZZ1) mRNAs. Western blots were performed to assay the tissue levels of interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α). RESULTS: M2 macrophages were obviously detected 72 h after sepsis-induced AKI. Kidney injury was more severe, renal function was decreased, and blood creatinine and blood urea nitrogen (BUN) levels were higher after M2 macrophage depletion. M2 macrophage depletion significantly inhibited the proliferation of tubular cells. M2 macrophage depletion also downregulated IL-10 expression and increased TNF-α secretion during sepsis-induced AKI. CONCLUSIONS: M2 macrophages attenuate sepsis-induced AKI, presumably by upregulating IL-10 expression and suppressing TNF-α secretion.