Daily Ards Research Analysis

Pulmonary endothelial cell (EC) activation is a key factor in acute respiratory distress syndrome (ARDS). In sepsis, increased glycolysis leads to lactate buildup, which induces lysine lactylation (Kla) on histones and other proteins. However, the role of protein lactylation in EC dysfunction during sepsis-induced ARDS remains unclear. Integrative lactylome and proteome analyses were performed to identify the global lactylome profile in the lung tissues of septic mice. Cut&Tag analysis was used to identify the transcriptional targets of histone H3 lysine 14 lactylation (H3K14la) in ECs. Septic mice presented elevated levels of lactate and H3K14la in lung tissues, particularly in pulmonary ECs. Suppressing glycolysis reduced both H3K14la and EC activation, suggesting a link between glycolysis and lactylation. Moreover, H3K14la was enriched at promoter regions of ferroptosis-related genes such as transferrin receptor (TFRC) and solute carrier family 40 member 1 (SLC40A1), which contributed to EC activation and lung injury under septic conditions. For the first time, we reported the role of lactate-dependent H3K14 lactylation in regulating EC ferroptosis to promote vascular dysfunction during sepsis-induced lung injury. Our findings suggest that manipulation of the glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for sepsis-associated ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is causatively associated with excessive alveolar inflammation involving deregulated pro-inflammatory macrophage polarization. High-density lipoprotein (HDL) showed critical anti-inflammatory roles by modulating macrophage function, and its adverse transition to pro-inflammation has an important role in the pathogenesis of ARDS. However, the relationship between HDL protein constituents and functional remodeling is unknown in ARDS. METHODS: Proteomic techniques were applied to examine the protein profile changes in HDL from septic-ARDS patients versus HDL from healthy controls across two distinct cohorts: a discovery cohort (8 patients and 8 healthy controls) and a validation cohort (22 patients and 10 healthy controls). The changed components significantly associated with prognosis were identified. Luminex assessed the levels of 38 plasma cytokines and chemokines. The in vitro constructed pro-SFTPB enriched HDL was applied to confirm the effect on M1 polarization of THP1-derived macrophage. RESULTS: 18 proteins were validated from 102 changed HDL proteins identified in the discovery cohort, including HDL particle components, such as apolipoproteins, pro-inflammatory substances known as serum amyloid As (SAAs), and anti-oxidative proteins like paraoxonases (PONs). Among these proteins, only the increase of pro-SFTPB in HDL was significantly associated with poor prognosis of ARDS patients. Notably, HDL-pro-SFTPB level was correlated with plasma pro-inflammatory cytokines and chemokines levels. The correlation assay of pro-SFTPB with other HDL components showed that it was positively and negatively correlated with SAA2 and PON3, respectively. Furthermore, the in vitro studies confirmed that the pro-SFTPB enriched HDL significantly promoted M1 polarization of monocyte-derived macrophages. CONCLUSIONS: The increase of HDL-pro-SFTPB promotes HDL pro-inflammatory transition during septic ARDS, leading to exacerbated progression of ARDS through enhancing M1 macrophage polarization. HDL-pro-SFTPB could be a useful prognostic biomarker for septic ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) associated with coronavirus infectious disease (COVID)-19 has been a challenge in intensive care medicine for the past three years. Dysregulation of the renin-angiotensin system (RAS) is linked to COVID-19, but also to non-COVID-19 ARDS. It is still unclear whether changes in the RAS are associated with prognosis of severe COVID-19. METHODS: In this prospective exploratory study, blood samples of 94 patients with COVID-19 were taken within 48 h of admission to a medical ward or an ICU. In ICU patients, another blood sample was taken seven days later. Angiotensin (Ang) I-IV, Ang 1-7, Ang 1-5 and aldosterone concentrations were measured with liquid chromatography tandem mass spectrometry (LC-MS/MS) followed by calculation of markers for activities of renin (PRA-S) and ACE (ACE-S), alternative RAS activation (ALT-S) as well as the ratio of aldosterone to Ang II (AA2R). Angiotensin-converting enzyme (ACE) and ACE2 concentrations were measured by LC-MS/MS-based assays. All RAS parameters were evaluated as predictors of 28-day and 60-day survival using receiver operating characteristic and multivariate logistic regression analysis. RESULTS: AA2R at inclusion was a predictor of 60-day survival for ICU patients with an AUROC of 0.73. Ang II and active ACE2 were inversely associated with survival (OR 0.07; 95%CI 0.01, 0.39 and OR 0.10; 95%CI 0.01, 0.63) while higher Ang 1-7 predicted favorable outcome (OR 6.8; 95%CI 1.5, 39.9). ICU patients showed higher concentrations of all measured angiotensin metabolites, PRA-S, ALT-S and active ACE2, and lower ACE-S and AA2R than patients in the medical ward at inclusion. After seven days in the ICU, Ang I, Ang II, Ang III and Ang IV concentrations decreased, while ACE and ACE2 levels increased. Ang I, PRA-S, Ang 1-7 and Ang 1-5 concentrations correlated with the SOFA score both at the time of inclusion and after seven days, and driving pressure after seven days. CONCLUSIONS: AA2R at inclusion predicted 60-day survival with moderate sensitivity, revealing a dissociation between unchanged aldosterone and increased Ang II levels in the most severely ill COVID-19 patients. After adjustment for confounders, Ang 1-7 as the final metabolite of alternative RAS was predictive for survival.