BACKGROUND: Volume-targeted noninvasive ventilation (VT-NIV), a hybrid mode that delivers a preset target tidal volume (V _T ) through the automated adjustment of pressure support, could guarantee a relatively constant target V _T over pressure-limited noninvasive ventilation (PL-NIV) with fixed-level pressure support. Whether VT-NIV is more effective in improving ventilatory status in subjects with acute hypercapnic respiratory failure (AHRF) remains unclear. Our aim was to verify whether, in comparison with PL-NIV, VT-NIV would be more effective in correcting hypercapnia, hence reducing the need for intubation and improving survival in subjects with AHRF. METHODS: We performed a prospective randomized controlled trial in the general respiratory wards of 8 university-affiliated hospitals in China over a 12-month period. Subjects with AHRF, defined as arterial pH <7.35 and ≥7.25 and P aCO ₂ >45 mm Hg, were randomly assigned to undergo PL-NIV or VT-NIV. The primary end point was the decrement of P aCO ₂ from baseline to 6 h after randomization. Secondary end points included the decrement of P aCO ₂ from baseline to 2 h after randomization as well as outcomes of subjects (eg, need for intubation, in-hospital mortality). RESULTS: A total of 58 subjects were assigned to PL-NIV (29 subjects) or VT-NIV (29 subjects) and included in the analyses. The decrement of P aCO ₂ from baseline to 6 h after randomization was not statistically different between the PL-NIV group and the VT-NIV group (9.3 ± 12.6 mm Hg vs 11.7 ± 12.9 mm Hg, P = .48). There were no differences between the PL-NIV group and the VT-NIV group in the decrement of P aCO ₂ from baseline to 2 h after randomization (6.4 ± 12.7 mm Hg vs 5.0 ± 15.8 mm Hg, P = .71) as well as in the need for intubation (17.2% vs 10.3%, P = .70), and in-hospital mortality (10.3% vs 6.9%, P > .99). CONCLUSIONS: Regardless of whether a VT- or PL-NIV strategy is employed, it is possible to provide similar support to subjects with AHRF. (ClinicalTrials.gov registration NCT02538263.)

Background: Idiopathic pulmonary fibrosis (IPF) bears high mortality due to unclear pathogenesis and limited therapeutic options. Therefore, identifying novel regulators is required to develop alternative therapeutic strategies. Methods: The lung fibroblasts from IPF patients and Reticulocalbin 3 (RCN3) fibroblast-selective knockdown mouse model were used to determine the importance of Rcn3 in IPF; the epigenetic analysis and protein interaction assays, including BioID, were used for mechanistic studies. Results: Reticulocalbin 3 (RCN3) upregulation is associated with the fibrotic activation of lung fibroblasts from IPF patients and Rcn3 overexpression blunts the antifibrotic effects of pirfenidone and nintedanib. Moreover, repressing Rcn3 expression in mouse fibroblasts ameliorates bleomycin-induced lung fibrosis and pulmonary dysfunction in vivo. Mechanistically, RCN3 promotes fibroblast activation by maintaining persistent activation of TGFβ1 signalling via the TGFβ1-RCN3-TGFBR1 positive feedback loop, in which RCN3 upregulated by TGFβ1 exposure detains EZH2 (an epigenetic methyltransferase) in the cytoplasm through RCN3-EZH2 interaction, leading to the release of the EZH2-H3K27me3 epigenetic repression of TGFBR1 and the persistent expression of TGFBR1. Conclusions: These findings introduce a novel regulating mechanism of TGFβ1 signalling in fibroblasts and uncover a critical role of the RCN3-mediated loop in lung fibrosis. RCN3 upregulation may cause resistance to IPF treatment and targeting RCN3 could be a novel approach to ameliorate pulmonary fibrosis. Graphical

Background: Septic-acute respiratory distress syndrome (ARDS), characterized by the acute lung injury (ALI) secondary to aberrant systemic inflammatory response, has high morbidity and mortality. Despite increased understanding of ALI pathogenesis, the therapies to prevent lung dysfunction underlying systemic inflammatory disorder remain elusive. The high density lipoprotein (HDL) has critical protective effects in sepsis and its dysfunction has a manifested contribution to septic organ failure. However, the adverse changes in HDL composition and function in septic-ARDS patients are large unknown.Methods: To investigate HDL remodeling in septic-ARDS, we analyzed the changes of HDL composition from 40 patients with septic-ARDS (A-HDL) and 40 matched normal controls (N-HDL). To determine the deleterious functional remodeling of HDL, A-HDL or N-HDL was administrated to C57BL/6 and apoA-I knock-out (KO) mice after cecal ligation and puncture (CLP) procedure. Mouse lung microvascular endothelial cells (MLECs) were further treated by these HDLs to investigate whether the adverse effects of A-HDL were associated with endothelial dysfunction.Results: Septic-ARDS patients showed significant changes of HDL composition, accompanied with significantly decreased HDL-C. We further indicated that A-HDL treatment aggravated CLP induced ALI. Intriguingly, these deleterious effects of A-HDL were associated with pulmonary endothelial dysfunction, rather than the increased plasma lipopolysaccharide (LPS). Further in vitro results demonstrated the direct effects of A-HDL on MLECs, including increased endothelial permeability, enhanced expressions of adhesion proteins and pro-inflammatory cytokines via activating NF-κB signaling and decreased junction protein expression.Conclusions: Our results depicted the remodeling of HDL composition in sepsis, which predisposes lung to ARDS via inducing ECs dysfunction. These results also demonstrated the importance of circulating HDL in regulating alveolar homeostasis.

Since the outbreak of coronavirus disease 2019 (COVID-19), studies have found correlations between blood cell count-derived inflammatory markers (BCDIMs) and disease severity and prognosis in COVID-19 patients. However, there is currently a lack of systematic comparisons between procalcitonin (PCT), C-reactive protein (CRP), C-reactive protein-to-albumin ratio (CAR) and BCDIMs for assessing the severity and prognosis of COVID-19 patients. A total of 1040 COVID-19 patients were included in the study. Demographics, comorbidities and laboratory results were analysed. BCDIMs refer to the following ratios: neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-C-reactive protein ratio (LCR), systemic inflammation response index (SIRI) and systemic inflammation index (SII). Disease severity and 28-day mortality are clinical outcomes of this study. Area under the curve (AUC) of receiver operating characteristic (ROC) curve was calculated for these markers, and DeLong’s test compared their statistical differences. Cox regression analysis assessed their predictive value for the 28-day mortality rate. Among the 1040 patients, 35.3% were severe/critical, 49.6% were moderate and 15.1% were mild cases. Within 28 days, 15.1% died. The NLR had the highest predictive value for disease severity (AUC: 0.790, 95% CI: 0.762–0.818). NLR differed significantly from other markers, except LCR. LCR best predicted 28-day mortality (AUC: 0.798, 95% CI: 0.766–0.829). Some markers showed significant differences in AUC with LCR. Multivariable Cox regression identified BCDIMs, PCT, CRP and CAR as significant risk factors for 28-day mortality. PCT, CRP, CAR and BCDIMs, easily obtained in clinical settings, are valuable predictors of disease severity and the 28-day mortality in COVID-19 patients. The NLR is particularly effective for disease severity, while the LCR is highly predictive of 28-day mortality. These markers provide guidance for stratified management of COVID-19 patients.