Edema fluid resorption is critical for gas exchange, and both alveolar epithelial sodium channel (ENaC) and Na,K-ATPase are accredited with key roles in the resolution of pulmonary edema. Alveolar fluid clearance (AFC) was measured in in situ ventilated lungs by instilling isosmolar 5% BSA solution with Evans Blue-labeled albumin tracer (5 ml/kg) and measuring the change in Evans Blue-labeled albumin concentration over time. Treatment with lipoxin A4 and lipoxin receptor agonist (5(S), 6(R)-7-trihydroxymethyl 17 heptanoate) significantly stimulated AFC in oleic acid (OA)-induced lung injury, with the outcome of decreased pulmonary edema. Lipoxin A4 and 5(S), 6(R)-7-trihydroxymethyl 17 heptanoate not only up-regulated the ENaC α and ENaC γ subunits protein expression, but also increased Na,K-ATPase α1 subunit protein expression and Na,K-ATPase activity in lung tissues. There was no significant difference of intracellular cAMP level between the lipoxin A4 treatment and OA group. However, the intracellular cGMP level was significantly decreased after lipoxin A4 treatment. The beneficial effects of lipoxin A4 were abrogated by butoxycarbonyl-Phe-Leu-Phe-Leu-Ph (lipoxin A4 receptor antagonist) in OA-induced lung injury. In primary rat alveolar type II epithelial cells stimulated with LPS, lipoxin A4 increased ENaC α and ENaC γ subunits protein expression and Na,K-ATPase activity. Lipoxin A4 stimulated AFC through activation of alveolar epithelial ENaC and Na,K-ATPase.
Several investigators have sought risk factors for mortality in acute kidney injury (AKI). However, no epidemiological studies have investigated the impact of red blood cell distribution width (RDW) on prognosis for critically ill patients with AKI. The aim of this study was to investigate the association of RDW with mortality in these patients.We analyzed data from the MIMIC-III. RDW was measured upon ICU admission. The association between RDW and mortality of AKI was determined using a multivariate logistic regression and was expressed as the adjusted odds ratio with associated 95% confidence interval (CI). We also conducted subgroup analyses to determine the consistency of this association.A total of 14,078 critically ill patients with AKI were eligible for this analysis. In multivariate analysis, adjusted for age and gender and compared with the reference group (RDW 11.1-13.4%) related to hospital mortality, the adjusted ORs (95% CIs) for RDW levels 13.5-14.3%, 14.4-15.6%, and 15.7-21.2% were 1.22 (1.05, 1.43), 1.56 (1.35, 1.81), and 2.66 (2.31, 3.06), respectively. After adjusting for confounding factors, with high RDW linked to an increase in mortality (RDW 15.7-21.2% versus 11.1-13.4%: OR, 1.57; 95% CI, 1.22 to 2.01; P trend <0.0001). A similar trend was observed for 30-day mortality.RDW appeared to be an independent prognostic marker in critically ill patients with AKI and higher RDW was associated with increased risk of mortality in these patients.
The majority of the coronavirus disease 2019 (COVID-19) non-survivors meet the criteria for disseminated intravascular coagulation (DIC). Although timely monitoring of clotting hemorrhagic development during the natural course of COVID-19 is critical for understanding pathogenesis, diagnosis, and treatment of the disease, however, limited data are available on the dynamic processes of inflammation/coagulopathy/fibrinolysis (ICF).We monitored the dynamic progression of ICF in patients with moderate COVID-19. Out of 694 COVID-19 inpatients from 10 hospitals in Wenzhou, China, we selected 293 adult patients without comorbidities. These patients were divided into different daily cohorts according to the COVID-19 onset-time. Furthermore, data of 223 COVID-19 patients with comorbidities and 22 critical cases were analyzed. Retrospective data were extracted from electronic medical records.The virus-induced damages to pre-hospitalization patients triggered two ICF fluctuations during the 14-day course of the disease. C-reactive protein (CRP), fibrinogen, and D-dimer levels increased and peaked at day 5 (D) 5 and D9 during the 1st and 2nd fluctuations, respectively. The ICF activities were higher during the 2nd fluctuation. Although 12-day medication returned high CRP concentrations to normal and blocked fibrinogen increase, the D-dimer levels remained high on days 17 ± 2 and 23 ± 2 days of the COVID-19 course. Notably, although the oxygenation index, prothrombin time and activated partial thromboplastin time were within the normal range in critical COVID-19 patients at administration, 86% of these patients had a D-dimer level > 500 μg/L.COVID-19 is linked with chronic DIC, which could be responsible for the progression of the disease. Understanding and monitoring ICF progression during COVID-19 can help clinicians in identifying the stage of the disease quickly and accurately and administering suitable treatment.
If age boundaries are arbitrarily or roughly defined, age-related analyses can result in questionable findings. Here, we aimed to delineate the uniquely age-dependent immune features of coronavirus disease 2019 (COVID-19) in a retrospective study of 447 patients, stratified according to age distributions of COVID-19 morbidity statistics into well-defined age-cohorts (2–25y, 26–38y, 39–57y, 58–68y, and 69–79y). Age-dependent susceptibilities and severities of the disease were observed in COVID-19 patients. A comparison of the lymphocyte counts among the five age-groups indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection led to age-dependent lymphopenia. Among the lymphocyte subsets, the CD8+ T cell count alone was significantly and age-dependently decreased (520, 385, 320, 172, and 139 n/μl in the five age-groups, respectively). In contrast, the CD4+ T cell, B cell, and natural killer cell counts did not differ among age-cohorts. Age and CD8+ T cell counts (r=‒0.435, p<0.0001) were negatively correlated in COVID-19 patients. Moreover, SARS-CoV-2 infection age-dependently increased the plasma C-reactive protein concentrations (2.0, 5.0, 9.0, 11.6, and 36.1 mg/L in the five age-groups, respectively). These findings can be used to elucidate the role of CD8+ T cells in age-related pathogenesis and to help develop therapeutic strategies for COVID-19.
The WHO has upgraded the status of coronavirus disease 2019 (COVID-19) from epidemic to global pandemic. The psychometric properties aspects of COVID-19 patients without comorbidities in the short term after discharge have not been reported. In this study, the Short Form 36 (SF-36) was used to evaluate the psychometric properties and to find relevant risk factors.The study was conducted in seven hospitals from January 2020 to April 2020. The SF-36 questionnaire was administered one month after discharge. Univariate analysis and multivariate regression model were used to analyze the risk factors of psychometric properties impairment.In univariate analysis of independent risk factors, according to the comparison of whether the duration of positive nucleic acid was greater than 20 days, the positive nucleic acid duration was independently related to the decreased role-emotional value [100, IQR (66-100) vs 100, IQR (0, 100); p = 0.0156]. In addition, multivariable linear regression model showed that male sex and positive nucleic acid duration were related to decreased role-emotional value (p = 0.03< 0.05; p = 0.01< 0.05, respectively). Mental health was associated with age (p= 0.0435). Subsequently, we divided into three subgroups: less than seven days, 7 to 14 days and more than 14 days according to the positive nucleic acid duration. The results revealed that there were significant differences in the vitality value and mental health value of patients aged 46 to 69 in the subgroup where the positive nucleic acid duration longer than 14 days (p= 0.0472; p= 0.0311< 0.05, respectively). Similarly, there are also significant differences in role-emotional value in different genders (p= 0.0316).The study described the psychometric properties of COVID-19 patients without comorbidities shortly after discharge. Risk factors for psychometric properties damage included age, male sex, and nucleic acid duration.
To simultaneously determine clinical and immunological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old females and males, 681 coronavirus disease 2019 (COVID-19) patients and 369 normal controls (NCs) were analyzed based on age and sex classifications using multiple linear regression analysis. Compared to the age-matched NCs, both young and old male and female non-comorbid COVID-19 patients had lower lymphocyte counts and alanine aminotransferase (ALT) concentration, and only young male and female patients had lower neutrophil counts. Compared to young patients, both old males and females had significantly higher plasma ALT and AST concentrations. Compared to young and old females, age-matched males had higher plasma ALT and AST concentrations, but only young males had higher C-reactive protein (CRP) concentration. Compared to females, old males, but not young males, showed higher incidence of critical illness. Compared to young patients, old females had more leukocyte and neutrophil counts above the normal upper limit and B cell count below the normal lower limit (NLL), while old males had more lymphocyte and natural killer (NK) cell counts below the NLL. No sex or age associations with B cell and NK cell counts were observed. However, there were age-dependent decreases in CD8 + T-cell counts in both male and female COVID-19 patients. Age was negatively associated with CD8 + T cell counts but positively associated with neutrophil count, CRP, ALT, and AST concentrations, and sex (females) was negatively associated with neutrophil count, CRP, ALT, and AST concentrations. The present study suggests that SARS-CoV-2 infection mainly induced 1) beneficial sex (female)-related differences regarding reduced COVID-19 disease severity and negative associations with inflammatory responses and liver damage, and 2) harmful age-related differences relating to negative associations with CD8 + T cell count and positive associations with inflammatory responses and liver damage. Thus, sex and age are biological variables that should be considered in the prevention and treatment of COVID-19.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. An excessive inflammatory response results in the progression of ALI/ARDS, and the NLRP3 inflammasome is a key participant in inflammation. Erythropoietin (EPO), which is clinically used for anemia, reportedly exerts pleiotropic effects in ALI. However, whether EPO could protect against lipopolysaccharide (LPS)-induced ALI by regulating the NLRP3 inflammasome and its underlying mechanisms remain poorly elucidated. This study aimed to explore whether the therapeutic effects of EPO rely on the suppression of the NLRP3 inflammasome and the specific mechanisms in an LPS-induced ALI mouse model. ALI was induced in C57BL/6 mice by intraperitoneal injection of LPS (15 mg/kg). EPO was administered intraperitoneally at 5 U/g after LPS challenge. The mice were sacrificed 8 hours later. Our findings indicated that application of EPO markedly diminished LPS-induced lung injury by restoring histopathological changes, lessened lung wet/dry ratio, protein concentrations in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) levels. Meanwhile, EPO evidently decreased interleukin-1β (IL-1β) and IL-18 secretion, the expression of NLRP3 inflammasome components including pro-IL-1β, NLRP3 and Cleaved Caspase-1 as well as phosphorylation of NF-κB p65, which may be associated with activation of EPO receptor (EPOR), phosphorylation of JAK2 and STAT3. However, all the beneficial effects of EPO on ALI and modulation NLRP3 inflammasome were remarkably abrogated by the inhibition of EPOR/ JAK2/STAT3 pathway and knockout of NLRP3 gene. Taken together, this study indicates that EPO can effectively attenuate LPS-induced lung injury in mice by suppressing the NLRP3 inflammasome, which is dependent upon activation of EPOR/JAK2/STAT3 signaling and inhibition of the NF-κB pathway.
Background. Acute kidney injury (AKI) is a common clinical syndrome carrying high morbidity and mortality. Body mass index (BMI) is a common health indicator, and a high BMI value-obesity has been shown to be associated with the outcomes of several diseases. However, the relationship between different BMI categories and mortality in all critically ill patients with AKI is unclear and needs further investigation. Therefore, we evaluated the ability of BMI to predict the severity and all-cause mortality of AKI in critically ill patients. Methods. We extracted clinical data from the MIMIC-III v1.4 database. All adult patients with AKI were initially screened. The baseline data extracted within 24 hours after ICU admission were presented according to WHO BMI categories. Logistic regression models and the Cox proportional hazards models were, respectively, constructed to assess the relationship between BMI and the severity and all-cause mortality of AKI. The generalized additive model (GAM) was used to identify nonlinear relationships as BMI was a continuous variable. The subgroup analyses were performed to further analyze the stability of the association between BMI category and 365-day all-cause mortality of AKI. Result. A total of 15,174 patients were extracted and were divided into four groups according to BMI. Obese patients were more likely to be young and male. In the fully adjusted logistic regression model, we found that overweight and obesity were significant predictors of AKI stage III (OR, 95 CI: 1.17, 1.05–1.30; 1.32, 1.18–1.47). In the fully adjusted Cox proportional hazards model, overweight and obesity were associated with significantly lower 30-day, 90-day, and 365-day all-cause mortality. The corresponding adjusted HRs (95 CIs) for overweight patients were 0.87 (0.77, 0.99), 0.84 (0.76, 0.93), and 0.80 (0.74, 0.88), and for obese patients, they were 0.87 (0.77, 0.98), 0.79 (0.71, 0.88), and 0.73 (0.66, 0.80), respectively. The subgroup analyses further presented a stable relationship between BMI category and 365-day all-cause mortality. Conclusions. BMI was independently associated with the severity and all-cause mortality of AKI in critical illness. Overweight and obesity were associated with increased risk of AKI stage III; however, they were predictive of a relatively lower mortality risk in these patients.
Acute respiratory distress syndrome is a life-threatening critical syndrome resulting largely from the accumulation of and the inability to clear pulmonary edema. Protectin DX, an endogenously produced lipid mediator, is believed to exert anti-inflammatory and pro-resolution effects. Protectin DX (5 µg/kg) was injected i.v. 8 h after LPS (14 mg/kg) administration, and alveolar fluid clearance was measured in live rats (n = 8). In primary rat ATII epithelial cells, protectin DX (3.605 × 10−3 mg/l) was added to the culture medium with LPS for 6 h. Protectin DX improved alveolar fluid clearance (9.65 ± 1.60 vs. 15.85 ± 1.49, p < 0.0001) and decreased pulmonary edema and lung injury in LPS-induced lung injury in rats. Protectin DX markedly regulated alveolar fluid clearance by upregulating sodium channel and Na, K-ATPase protein expression levels in vivo and in vitro. Protectin DX also increased the activity of Na, K-ATPase and upregulated P-Akt via inhibiting Nedd4–2 in vivo. In addition, protectin DX enhanced the subcellular distribution of sodium channels and Na, K-ATPase, which were specifically localized to the apical and basal membranes of primary rat ATII cells. Furthermore, BOC-2, Rp-cAMP, and LY294002 blocked the increased alveolar fluid clearance in response to protectin DX. Protectin DX stimulates alveolar fluid clearance through a mechanism partly dependent on alveolar epithelial sodium channel and Na, K-ATPase activation via the ALX/PI3K/Nedd4–2 signaling pathway. Treatment that involves boosting levels of a signaling molecule could help reduce fluid on the lungs in acute respiratory distress syndrome (ARDS). This condition usually affects critically ill patients with illnesses such as pneumonia or sepsis, and leads to severe inflammation and flooding of the lungs with fluid. This prevents microscopic air sacs called aveoli from processing oxygen and carbon dioxide effectively. At present there is no effective management for the condition. Now, Sheng-Wei Jin at Wenzhou Medical University, China, and co-workers have shown that boosting levels of a signaling molecule called protectin DX can help with aveolar fluid clearance in rats. They found that protectin DX activates sodium channels within the aveoli, helping clear fluid, and also acts as an anti-inflammatory and pro-resolving mediator to protect lung tissues from further injury.
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