Although several chemokines play key roles in the pathogenesis of acute lung injury (ALI), the roles of chemokine (C‐X‐C motif) ligand 16 (CXCL16) and its receptor C‐X‐C chemokine receptor type 6 ...(CXCR6) in ALI pathogenesis remain to be elucidated. The mRNA and protein expression of CXCL16 and CXCR6 was detected after lipopolysaccharide (LPS) stimulation with or without treatment with the nuclear factor‐κB (NF‐κB) inhibitor pyrrolidine dithiocarbamate (PDTC). Lung injury induced by LPS was evaluated in CXCR6 knockout mice. CXCL16 level was elevated in the serum of ALI patients (n = 20) compared with healthy controls (n = 30). CXCL16 treatment (50, 100, and 200 ng/mL) in 16HBE cells significantly decreased the epithelial barrier integrity and E‐cadherin expression, and increased CXCR6 expression, reactive oxygen species (ROS) production, and p38 phosphorylation. Knockdown of CXCR6 or treatment with the p38 inhibitor SB203580 abolished the effects of CXCL16. Moreover, treatment of 16HBE cells with LPS (5, 10, 20 and 50 μg/mL) significantly increased CXCL16 release as well as the mRNA and protein levels of CXCL16 and CXCR6. The effects of LPS treatment (20 μg/mL) were abolished by treatment with PDTC. The results of the luciferase assay further demonstrated that PDTC treatment markedly inhibited the activity of the CXCL16 promoter. In conclusion, CXCL16, whose transcription was enhanced by LPS, may be involved in ROS production, epithelial barrier dysfunction and E‐cadherin down‐regulation via p38 signalling, thus contributing to the pathogenesis of ALI. Importantly, CXCR6 knockout or inhibition of p38 signalling may protect mice from LPS‐induced lung injury by decreasing E‐cadherin expression.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory lung diseases. Methylprednisolone (MP) is a common drug against inflammation in clinic. In this study, ...we aim to investigate the protective effect of MP on ALI and potential mechanisms.
Male BABL/c mice were injected through tail vein using lipopolysaccharide (LPS, 5 mg/kg) with or without 5 mg/kg MP. Lung mechanics, tissue injury and inflammation were examined. Macrophage subsets in the lung were identified by flow cytometry. Macrophages were cultured from bone marrow of mice with or without MP. Then, we analyzed and isolated the subsets of macrophages. These isolated macrophages were then co-cultured with CD4
T cells, and the percentage of regulatory T cells (Tregs) was examined. The expression of IL-10 and TGF-β in the supernatant was measured. The Tregs immunosuppression function was examined by T cell proliferation assay. To disclose the mechanism of the induction of Tregs by M2c, we blocked IL-10 or/and TGF-β using neutralizing antibody.
Respiratory physiologic function was significantly improved by MP treatment. Tissue injury and inflammation were ameliorated in the MP-treated group. After MP treatment, the number of M1 decreased and M2 increased in the lung. In in vitro experiment, MP promoted M2 polarization rather than M1. We then induced M1, M2a and M2c from bone marrow cells. M1 induced more Th17 while M2 induced more CD4
CD25
Fxop3
Tregs. Compared with M2a, M2c induced more Tregs, and this effect could be blocked by anti-IL-10 and anti-TGF-β antibodies. However, M2a and M2c have no impact on Tregs immunosuppression function.
In conclusion, MP ameliorated ALI by promoting M2 polarization. M2, especially M2c, induced Tregs without any influence on Tregs immunosuppression function.
Sepsis is an abnormal immune response after infection, wherein the lung is the most susceptible organ to fail, leading to acute lung injury. To overcome the limitations of current therapeutic ...strategies and develop more specific treatment, the inflammatory process, in which T cell-derived extracellular vesicles (EVs) play a central role, should be explored deeply.
Liquid chromatography-tandem mass spectrometry was performed for serum EV protein profiling. The serum diacylglycerol kinase kappa (DGKK) and endotoxin contents of patients with sepsis-induced lung injury were measured. Apoptosis, oxidative stress, and inflammation in A549 cells, bronchoalveolar lavage fluid, and lung tissues of mice were measured by flow cytometry, biochemical analysis, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot.
DGKK, the key regulator of the diacylglycerol (DAG)/protein kinase C (PKC) pathway, exhibited elevated expression in serum EVs of patients with sepsis-induced lung injury and showed strong correlation with sepsis severity and disease progression. DGKK was expressed in CD4
T cells under regulation of the NF-κB pathway and delivered by EVs to target cells, including alveolar epithelial cells. EVs produced by CD4
T lymphocytes exerted toxic effects on A549 cells to induce apoptotic cell death, oxidative cell damage, and inflammation. In mice with sepsis induced by cecal ligation and puncture, EVs derived from CD4
T cells also promoted tissue damage, oxidative stress, and inflammation in the lungs. These toxic effects of T cell-derived EVs were attenuated by the inhibition of PKC and NOX4, the downstream effectors of DGKK and DAG.
This approach established the mechanism that T-cell-derived EVs carrying DGKK triggered alveolar epithelial cell apoptosis, oxidative stress, inflammation, and tissue damage in sepsis-induced lung injury through the DAG/PKC/NOX4 pathway. Thus, T-cell-derived EVs and the elevated distribution of DGKK should be further investigated to develop therapeutic strategies for sepsis-induced lung injury.
Skin mottling is a common manifestation of peripheral tissue hypoperfusion, and its severity can be described using the skin mottling score (SMS). This study aims to evaluate the value of the SMS in ...detecting peripheral tissue hypoperfusion in critically ill patients following cardiac surgery.
Critically ill patients following cardiac surgery with risk factors for tissue hypoperfusion were enrolled (n = 373). Among these overall patients, we further defined a hypotension population (n = 178) and a shock population (n = 51). Hemodynamic and perfusion parameters were recorded. The primary outcome was peripheral hypoperfusion, defined as significant prolonged capillary refill time (CRT, > 3.0 s). The characteristics and hospital mortality of patients with and without skin mottling were compared. The area under receiver operating characteristic curves (AUROC) were used to assess the accuracy of SMS in detecting peripheral hypoperfusion. Besides, the relationships between SMS and conventional hemodynamic and perfusion parameters were investigated, and the factors most associated with the presence of skin mottling were identified.
Of the 373-case overall population, 13 (3.5%) patients exhibited skin mottling, with SMS ranging from 1 to 5 (5, 1, 2, 2, and 3 cases, respectively). Patients with mottling had lower mean arterial pressure, higher vasopressor dose, less urine output (UO), higher CRT, lactate levels and hospital mortality (84.6% vs. 12.2%, p < 0.001). The occurrences of skin mottling were higher in hypotension population and shock population, reaching 5.6% and 15.7%, respectively. The AUROC for SMS to identify peripheral hypoperfusion was 0.64, 0.68, and 0.81 in the overall, hypotension, and shock populations, respectively. The optimal SMS threshold was 1, which corresponded to specificities of 98, 97 and 91 and sensitivities of 29, 38 and 67 in the three populations (overall, hypotension and shock). The correlation of UO, lactate, CRT and vasopressor dose with SMS was significant, among them, UO and CRT were identified as two major factors associated with the presence of skin mottling.
In critically ill patients following cardiac surgery, SMS is a very specific yet less sensitive parameter for detecting peripheral tissue hypoperfusion.
Background
Evaluation of fluid responsiveness during veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support is crucial. The aim of this study was to investigate whether changes in left ...ventricular outflow tract velocity–time integral (ΔVTI), induced by a Trendelenburg maneuver, could predict fluid responsiveness during VA-ECMO.
Methods
This prospective study was conducted in patients with VA-ECMO support. The protocol included four sequential steps: (1) baseline-1, a supine position with a 15° upward bed angulation; (2) Trendelenburg maneuver, 15° downward bed angulation; (3) baseline-2, the same position as baseline-1, and (4) fluid challenge, administration of 500 mL gelatin over 15 min without postural change. Hemodynamic parameters were recorded at each step. Fluid responsiveness was defined as ΔVTI of 15% or more, after volume expansion.
Results
From June 2018 to December 2019, 22 patients with VA-ECMO were included, and a total of 39 measurements were performed. Of these, 22 measurements (56%) met fluid responsiveness. The
R
2
of the linear regression was 0.76, between ΔVTIs induced by Trendelenburg maneuver and the fluid challenge. The area under the receiver operating characteristic curve of ΔVTI induced by Trendelenburg maneuver to predict fluid responsiveness was 0.93 95% confidence interval (CI) 0.81–0.98, with a sensitivity of 82% (95% CI 60–95%), and specificity of 88% (95% CI 64–99%), at a best threshold of 10% (95% CI 6–12%).
Conclusions
Changes in VTI induced by the Trendelenburg maneuver could effectively predict fluid responsiveness in VA-ECMO patients.
Trial registration
ClinicalTrials.gov, NCT 03553459 (the TEMPLE study). Registered on May 30, 2018
Septic myocardial depression has been associated with increased morbidity and mortality. miR-885-5p has been shown to regulate cell growth, senescence, and/or apoptosis. Published studies ...demonstrated that Homeobox-containing protein 1 (HMBOX1) inhibits inflammatory response, regulates cell autophagy, and apoptosis. However, the role of miR-885-5p/HMBOX1 in sepsis and septic myocardial depression and the underlying mechanism is not fully understood.
Exosomes (exos) derived from sepsis patients (sepsis-exos) were isolated using ultracentrifugation. Rats were subjected to cecal ligation and puncture surgery and treated with sepsis-exos. HMBOX1 was knocked down or overexpressed in AC16 cells using lentiviral plasmids carrying short interfering RNAs targeting human HMBOX1 or carrying HMBOX1 cDNA. Cell pyroptosis was measured by flow cytometry. The secretion of IL-1β and IL-18 was examined by ELISA kits. Quantitative polymerase chain reaction (PCR) or western blot was used for gene expression.
Sepsis-exos increased the level of miR-885-5p, decreased HMBOX1, elevated IL-1β and IL-18, and promoted pyroptosis in AC16 cells. Septic rats treated with sepsis-exos increased the serum inflammatory cytokines is associated with increased pyroptosis-related proteins of hearts. MiR-885-5p bound to the three prime untranslated regions of HMBOX1 to negatively regulate its expression. Overexpressing HMBOX1 reversed miR-885-5p-induced elevation of inflammatory cytokines and upregulation of NLRP3, caspase-1, and GSDMD-N in AC16 cells. The mechanistic study indicated that the effect of HMBOX1 was NF-κB dependent.
Sepsis-exos promoted the pyroptosis of AC16 cells through miR-885-5p
HMBOX1. The results show the significance of the miR-885-5p/HMBOX1 axis in myocardial cell pyroptosis and provide new directions for the treatment of septic myocardial depression.
Aims
Recombinant human brain natriuretic peptide (rh‐BNP) is commonly used as a decongestive therapy. This study aimed to investigate the instant effects of rh‐BNP on cardiac output and venous return ...function in post‐cardiotomy patients with congestive heart failure (CHF).
Methods and results
Twenty‐four post‐cardiotomy heart failure patients were enrolled and received a standard loading dose of rh‐BNP. Haemodynamic monitoring was performed via a pulmonary artery catheter before and after the administration of rh‐BNP. The cardiac output and venous return functions were estimated by depicting Frank‐Starling and Guyton curves. After rh‐BNP infusion, variables reflecting cardiac congestion and venous return function, such as pulmonary artery wedge pressure, mean systemic filling pressure (Pmsf) and venous return resistance index (VRRI), reduced from 15 ± 3 to 13 ± 3 mmHg, from 32 ± 7 to 28 ± 7 mmHg and from 6.7 ± 2.6 to 5.7 ± 1.8 mmHg min m2/L, respectively. Meanwhile, cardiac index, stroke volume index, and the cardiac output function curve remained unchanged per se. The decline in Pmsf −13% (−22% to −8%) and VRRI −12% (−25% to −5%) was much greater than that in the systemic vascular resistance index −7% (−14% to 0%). In the subgroup analysis of reduced ejection fraction (<40%) patients, the aforementioned changes were more significant.
Conclusions
rh‐BNP might ameliorate venous return rather than cardiac output function in post‐cardiotomy CHF patients.
Background
The present study aimed at comparing the success rate and safety of proximal versus distal approach for ultrasound (US)-guided axillary vein catheterization (AVC) in cardiac surgery ...patients susceptible to bleeding.
Methods
In this single-center randomized controlled trial, cardiac surgery patients susceptible to bleeding and requiring AVC were randomized to either the proximal or distal approach group for US-guided AVC. Patients susceptible to bleeding were defined as those who received oral antiplatelet drugs or anticoagulants for at least 3 days. Success rate, catheterization time, number of attempts, and mechanical complications within 24 h were recorded for each procedure.
Results
A total of 198 patients underwent randomization: 99 patients each to the proximal and distal groups. The proximal group had the higher first puncture success rate (75.8% vs. 51.5%,
p
< 0.001) and site success rate (93.9% vs. 83.8%,
p
= 0.04) than the distal group. However, the overall success rates between the two groups were similar (99.0% vs. 99.0%;
p
= 1.00). Moreover, the proximal group had fewer average number of attempts (
p
< 0.01), less access time (
p
< 0.001), and less successful cannulation time (
p
< 0.001). There was no significant difference in complications between the two groups, such as major bleeding, minor bleeding, arterial puncture, pneumothorax, nerve injuries, and catheter misplacements.
Conclusions
For cardiac surgery patients susceptible to bleeding, both proximal and distal approaches for US-guided AVC can be considered as feasible and safe methods of central venous cannulation. In terms of the first puncture success rate and cannulation time, the proximal approach is superior to the distal approach.
Trial registration
Clinicaltrials.gov, NCT03395691. Registered January 10, 2018,
https://clinicaltrials.gov/ct2/show/NCT03395691?cond=NCT03395691&draw=1&rank=1
.
Background： In cardiac surgery, elevation of procalcitonin （PCT） could be observed postoperatively in the absence of any evidence of infection and also seems to be a prognostic marker. PCT levels ...measured in patients undergoing Type A aortic dissection （TAAD） were used to determine prognostic values for complications and surgical outcomes. Methods： Measurements of PCT, C-reactive protein （CRP）, and leukocyte count were observed in TAAD surgery patients （n = 251 ; average age： 49.02 ± 12.83 years; 78.5% male） at presurgery （TO） and 24 h （T1）, 48 h （T2）, and 7 days （T3） postsurgery. PCT clearance （PCTc） oll days 2 and 7 was calculated： （PCTd - PCTd,±,, d,,v）/PCTdx 100%. Endotracheal intubation duration, length of stay （LOS） in the Intensive Care Unit （1CU）/hospital, and complications were recorded± Results： PCT peaked 24 h postsurgery （median 2.73 ng/ml） before decreasing, Correlation existed between PCT levels at T1 and duration of cardiopulmonary bypass （P = 0.001, r = 0.278）. Serum PCT concentrations were significantly higher in nonsurvivor and multiple organ dysfunction syndrome groups on all postoperative days. PCT levels at T1 correlated with length of time of ventilation support and ICU/hospital LOS. Comparing PCT values of survivors versus nonsurvivors, a PCT cutoff level of 5.86 ng/ml at T2 had high sensitivity （70.6%） and specificity （74.3%） in predicting in-hospital death. PCTc-day 2 and 7 were significantly higher in survivor compared with nonsurvivor patients （38% vs. 8%, P = 0.012, 83% vs. -39%, P 〈 0.001）. A PCTc-day 7 cutoff point of 48.7% predicted survival with high sensitivity （77.8%） and specificity （81.8%）. Conclusions： PCT level and PCTc after TAAD surgery might serve as early prognostic markers to predict postoperative outcome. PCT measurement may help identify high-risk patients.
To investigate the impact of timing the initiation of renal replacement therapy (RRT) on clinical outcomes in critically ill patients with acute kidney injury (AKI), focusing on the randomized ...controlled trials (RCTs) in this field.
The PubMed, EMBASE and Cochrane databases were searched between January 1, 1985, and June 30, 2016, to identify randomized trials that assessed the timing of initiation of RRT in patients with AKI.
Nine RCTs, with a total of 1636 patients, were enrolled in this meta-analysis. A pooled analysis of the studies indicated no mortality benefit with "early" RRT, with an RR of 0.98 (95% CI 0.78 to 1.23, P = 0.84). There was no significant difference in intensive care unit (ICU) length of stay (LOS) or hospital LOS between the early and late RRT groups for survivors or nonsurvivors. Pooled analysis also demonstrated no significant change in renal function recovery (RR 1.02, 95% CI 0.88 to 1.19, I2 = 59%), RRT dependence (RR 0.76, 95% CI 0.42 to 1.37, I2 = 0%), duration of RRT (Mean difference 1.43, 95% CI -1.75 to 4.61, I2 = 78%), renal recovery time (Mean difference 0.73, 95% CI -2.09 to 3.56, I2 = 70%) or mechanical ventilation time (Mean difference - 0.95, 95% CI -3.54 to 1.64, I2 = 64%) between the early and late RRT groups. We found no significant differences in complications between the groups.
Our meta-analysis revealed that the "early" initiation of RRT in critically ill patients did not result in reduced mortality. Pooled analysis of secondary outcomes also showed no significant difference between the early and late RRT groups. More well-designed and large-scale trials are expected to confirm the result of this meta-analysis.
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