The role of macrophage-fibroblast interaction in lipopolysaccharide-induced pulmonary fibrosis: an acceleration in lung fibroblast aerobic glycolysis.

Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung fibroblasts is closely associated with the pathogenesis of septic pulmonary fibrosis. Nevertheless, the underlying mechanism remains poorly defined. In this study, we demonstrate that LPS promotes c-Jun N-terminal kinase (JNK) signaling pathway activation and endogenous tumor necrosis factor-α (TNF-α) secretion in pulmonary macrophages. This, in turn, could significantly promote aerobic glycolysis and increase lactate production in lung fibroblasts through 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) activation. Culturing human lung fibroblast MRC-5 cell line with TNF-α or endogenous TNF-α (cell supernatants of macrophages after LPS stimulation) both enhanced the aerobic glycolysis and increased lactate production. These effects could be prevented by treating macrophages with JNK pathway inhibitor, by administering TNF-α receptor 1 (TNFR1) siRNA, PFKFB3 inhibitor, or by silencing PFKFB3 with fibroblasts-specific shRNA. In addition, the inhibition of TNF-α secretion and PFKFB3 expression prevented LPS-induced pulmonary fibrosis in vivo. In conclusion, this study revealed that LPS-induced macrophage secretion of TNF-α could initiate fibroblast aerobic glycolysis and lactate production, implying that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in LPS-induced pulmonary fibrosis.

Using Postoperative Coagulation Parameters Within 24 h After Liver Transplantation to Predict Incidence of Stage 3 Acute Kidney Injury (AKI).

BACKGROUND This study aimed to investigate the relationship between coagulation function and the incidence of acute kidney injury (AKI) stage 3 within 24 h after liver transplantation (LT) and explore the predictive value of coagulation parameters for post-LT stage 3 AKI. MATERIAL AND METHODS A retrospective study was conducted on 241 patients who underwent LT at the Renji Hospital affiliated with Shanghai Jiao Tong University School of Medicine between February 2021 and February 2022. The coagulation parameters within 24 h after LT and the incidence of post-LT AKI within 7 days were recorded. The correlation between post-LT coagulation function and post-LT stage 3 AKI was determined using binary logistic regression analysis. RESULTS Post-LT AKI occurred in 99 cases (41.1%), 28 (28.3%) of which developed AKI stage 3. In univariate logistic regression analysis, multiple coagulation indexes of the AKI stage 3 group were worse than in the AKI stage 0-2 group. In multivariate logistic regression analysis, lower post-LT ADP-induced PLT aggregation rate (cut-off: 15.75%), higher D-dimer level (cut-off: 3.52 ug/ml), and prolonged R-value (cut-off: 7.5 min) within 24 h were independent risk factors for post-LT AKI stage 3. The AUROC value for predicting the incidence of post-LT AKI stage 3 combining the 3 indices was 0.835 (sensitivity: 83.3%, specificity: 76.9%). The decision curve showed that combining D-dimer, R-value, and ADP-induced PLT aggregation rate yielded the highest net benefit for predicting the incidence of stage 3 AKI. CONCLUSIONS Post-LT coagulation function within 24 h correlated with the incidence of post-LT AKI stage 3. Lower ADP-induced PLT aggregation rate, higher D-dimer level, and prolonged R-value from the TEG were independent risk factors for the incidence of post-LT AKI stage 3.

Effect of CRRT with oXiris filter on hemodynamic instability in surgical septic shock with AKI: A pilot randomized controlled trial.

BACKGROUND: Early identification and timely management of septic AKI continue to represent clinical challenges for intensive care. The aim was to evaluate the effect of renal replacement with oXiris filter on clinical outcomes in septic AKI. METHODS: This was a single-center randomized controlled trial that enrolled surgical septic shock with AKI patients admitted in the ICU, Renji Hospital, Shanghai Jiao Tong University, School of Medicine from Jan 1, 2021 to Sep 30, 2021, were screened. RESULTS: Sixteen subjects that met the inclusion and exclusion criteria were randomized into CRRT with AN69-oXiris group (n = 8) and AN69-ST group (n = 8). The PCT and IL-6 concentration decreased significantly after the first treatment compared to pre-CRRT levels in the oXiris group (PCT: 23.46 [4.18, 84.90] vs 52.79 [9.03, 100.00] µg/L, p = 0.046; IL-6: 3080.15 [527.62, 9806.61] vs 10,457.17 [8150.00, 15,528.87] pg/mL, p = 0.043). The levels of lactate decreased by 1.70 [1.03, 2.83] mmol/L after the first CRRT in the oXiris group (p = 0.028). The norepinephrine infusion rate was decreased by 0.06 [0, 0.09], 0.05 [0, 0.23] and 0.11 [0, 0.23] µg/kg/min at 4, 6, and 8 h in the oXiris group compared to the ST group (p = 0.005, 0.038, and 0.017). CONCLUSION: Using the oXiris filter may improve hemodynamic status during initial CRRT in severe surgical septic shock with AKI. Further large multicenter RCTs are needed to determine the effect of the oXiris filter on patient outcomes. (http://www.chictr.org.cn/index.aspx (ChiCTR2200055732)).

Case Report: Expanding the Digenic Variants Involved in Thyroid Hormone Synthesis-10 New Cases of Congenital Hypothyroidism and a Literature Review.

Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. Although it has been understood to be a monogenic disease, some CH patients are reported to carry two or more variants at different genes. Here, ten permanent congenital hypothyroidism (PCH) patients were retrospectively reviewed, with elevated levels of serum thyroid-stimulating hormone and levothyroxine dependence during follow-up between 2015 and 2019. Each affected individual carried digenic variants, which were heterozygous at two of pathogenic genes. In total, five pathogenic genes, TSHR, TG, TPO, DUOX2 and DUOXA2, were simultaneously identified in subjects that were involved in the same metabolic pathway: thyroid hormone biosynthesis. There were digenic variants at TSHR and DUOX2 combined in three patients, DUOX2 and TG combined in two patients, DUOX2 and DUOXA2 combined in two patients, TG and DUOXA2 combined in two patients, and TG and TPO combined in one patient. Additionally, seven novel variants, TSHR c.679G>A, DUOX2 c.127A>T, c.608-619del, c.959T>C, TG c.2307G>A, and c.6759_6765del, and DUOXA2 c.93T>G, were identified in these PCH patients. Along with a literature review on digenic variants in patients with CH, our findings illustrated the complexity of genetic etiology in CH.

Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8.

BACKGROUND: Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive metabolic disorder resulting from variants in ACAD8, and is poorly understood, as only dozens of cases have been reported previously. Based on a newborn screening program, we evaluated the incidence, phenotype and genotype of IBDD as well as the prognosis. Moreover, we reviewed the variant spectrum in ACAD8 associated with IBDD. METHODS: Forty unrelated patients with IBDD were retrospectively screened for newborns between Jan 2012 and Dec 2020. Tandem mass spectrometry (MS/MS) was used to determine the concentrations of C4-acylcarnitine, C4/C2 (acetylcarnitine), and C4/C3 (propionylcarnitine). All suspected cases were genetically tested by metabolic genes panel. RESULTS: The incidence of IBDD here was 1: 62,599. All patients presented continuously elevated C4-acylcarnitine levels with higher ratios of C4/C2 and C4/C3. Isobutyrylglycine occurred in only 8 patients. During follow-up, four patients had a transient motor delay, and two patients had growth delay. Notably, one case harbored both ACAD8 compound heterozygous variants and a KMT2A de novo variant (c.2739del, p.E914Rfs*35), with IBDD and Wiedemann-Steiner syndrome together, had exact severe global developmental delay. All patients were regularly monitored once they were diagnosed, and each patient gradually had a normal diet after 6 months of age. After 3-108 months of follow-up, most individuals were healthy except the case harboring the KMT2A variant. A total of 16 novel variants in ACAD8, c.4_5delCT, c.109C > T, c.110-2A > T, c.236G > A, c.259G > A, c.381-14G > A, c.413delA, c.473A > G, c.500delG, c.758 T > G, c.842-1G > A, c.911A > T, c.989G > A, c.1150G > C, c.1157A > G and c.1165C > T, were identified. Along with a literature review on 51 ACAD8 variants in 81 IBDD patients, we found that the most common variant was c.286G > A (27.2%), which has been observed solely in the Chinese population to date, followed by c.1000C > T (8.6%), c.1176G > T (3.7%) and c.455 T > C (3.1%). CONCLUSION: The concentration of C4-acylcarnitine in NBS plus subsequent genetic testing is necessary for IBDD diagnosis. Both the genotypes and ACAD8 variants in IBDD are highly heterogeneous, and no significant correlations between genotype and phenotype are present here in patients with IBDD. Our IBDD cohort with detaied clinical characteristics, genotypes and long-term prognosis will be helpful for the diagnosis and management of patients with IBDD in the future.