Daily Sepsis Research Analysis

Sepsis-associated acute lung injury (S-ALI), in which pulmonary microvascular endothelial cells act as key drivers of disease progression by increasing vascular permeability and ultimately exacerbating lung injury, is associated with a high mortality rate. Here, we report that PEAR1 expression and vascular permeability are increased in the lung tissues of septic mice. Pear1 knockdown markedly reduces pulmonary vascular permeability and consequently attenuates lung injury in septic mice. Mechanistically, PEAR1 promotes the AARS1-mediated lactylation of HIF-1α, primarily at lysine 172 (K172). This lactylation event, in turn, increases the affinity of HIF-1α for importin α, thereby facilitating HIF-1α nuclear translocation. Importantly, HIF-1α K172 lactylation promotes glycolysis, and glycolysis-derived lactate further drives H3K18 lactylation. In addition, this lactate-dependent histone modification is enriched at the Pear1 promoter, resulting in further increases in glycolysis and pulmonary vascular permeability. In vivo, both Pear1 knockout and the targeted delivery of Pear1 siRNA to inflammatory vascular endothelial cells using E-selectin-binding peptide-modified liposomes ameliorate ALI, and improve survival in mice with polymicrobial sepsis. Our study identifies K172 as a previously unreported lactylation site on HIF-1α and shows that PEAR1 promotes AARS1-mediated HIF-1α lactylation, enhances glycolysis, and increases H3K18la enrichment at the Pear1 promoter, thereby forming a positive feedback loop.

Acute lung injury (ALI) is a respiratory insufficiency syndrome precipitated by factors such as infection, sepsis, or systemic trauma. Excessive polymorphonuclear neutrophil (PMN) infiltration and activation represent the hallmark cellular features of early-stage ALI. However, it remains poorly understood how the pulmonary biomechanical microenvironment, remodeled by ALI-induced diffuse edema, decreased lung compliance, and mechanical ventilation, modulates PMN hyperactivation. Using a sequential model of LPS-induced lung injury and differential mechanical ventilation combined with an in vitro cell compression system, we demonstrate that PMN Piezo1 senses pathological physical strain and orchestrates pro-inflammatory responses. Single-cell RNA sequencing identified a mechanosensitive "mitochondrial-stress" PMN cluster that expands during ALI, defined by profound mitochondrial damage and elevated ROS production. Mechanistically, Piezo1 transduces mechanical stimuli into cytosolic Ca

BACKGROUND: To enhance biological understanding of acute respiratory distress syndrome (ARDS), pneumonia, and sepsis and accelerate therapeutic development in these areas, the National Institutes of Health developed the ARDS, Pneumonia, and Sepsis (APS) Consortium. RESEARCH QUESTION: Is the APS Consortium study rapidly generating data and biospecimens from a large cohort of critically ill adults with ARDS, pneumonia, and sepsis that will facilitate phenotyping of these syndromes? STUDY DESIGN AND METHODS: The APS Consortium Phenotyping Study is a multicenter longitudinal prospective observational cohort study aimed at enrolling 4,000 critically ill adults with ARDS, pneumonia, and/or sepsis over 4 years. Data and biospecimens are collected to characterize many aspects of each participant's chronic health, acute illness, and long-term recovery to facilitate phenotyping-that is, subclassifying ARDS, pneumonia, and sepsis into precise biologically-based subsets with shared pathophysiology. Feasibility of the study was assessed by evaluating the first 1,000 participants in terms of recruitment pace, participant characteristics, biospecimen collection, and proportion with confirmed ARDS, pneumonia, and sepsis based on expert adjudication. RESULTS: The first 1,000 participants were recruited ahead of schedule in less than 13 months. Median age was 64 years, 75% received vasopressors, 50% received invasive mechanical ventilation, and 25% died in the hospital within 4 weeks of enrollment. Biospecimen collection rates were high, with 99% of participants with blood, 98% with upper respiratory swabs, 37% with lower respiratory samples, 80% with urine, and 65% with gastrointestinal samples. Expert adjudication resulted in 40% classified with ARDS, 52% with pneumonia, and 89% with sepsis. INTERPRETATION: The APS Consortium Phenotyping Study is producing a cohort of critically ill adults with ARDS, pneumonia, and sepsis with high severity of disease and a rich set of data and biospecimens. The study will continue to full enrollment of 4,000 participants. REGISTRATION: Clinicaltrials.gov NCT06521502.