Vascular endothelial growth factor (VEGF) plays a central role in the pathogenesis of acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), yet targeted therapies for these conditions remain elusive. This study identified the VEGF-A splice variant VEGF165b as a crucial endogenous protector against ALI/ARDS. In patients, the circulating ratio of VEGF165b to total VEGF-A was significantly reduced and correlated inversely with disease severity. In murine models of LPS-induced ALI, administration of exogenous VEGF165b alleviated pulmonary edema, inflammation, and injury, whereas its neutralization exacerbated damage. Mechanistically, VEGF165b functioned as a competitive antagonist, selectively inhibiting VEGF165a-induced phosphorylation of VEGFR2 at tyrosine 1175. This blockade suppressed the downstream PI3K/AKT/eNOS permeability pathway, reducing SRC-mediated VE-cadherin phosphorylation and thereby enhancing endothelial barrier integrity. Additionally, VEGF165b downregulated the chemokine CCL2, limiting monocyte-endothelial adhesion through a distinct anti-inflammatory mechanism. Our findings established VEGF165b as a key endogenous stabilizer of the vascular barrier, acting via dual pathways-direct junctional reinforcement and anti-inflammatory activity-and highlighted its potential as both a biomarker and a therapeutic agent for ALI/ARDS. This work revealed the critical balance of VEGF splicing variants in vascular homeostasis and offers a novel strategy for treating vascular barrier dysfunction in critical lung diseases.

Fat embolism is a rare but feared complication of liposuction combined with autologous fat grafting (lipofilling). It carries a high mortality rate, predominantly affecting young patients with few or no comorbidities. To date, few guidelines exist, and management remains largely supportive. We report the case of a 40-year-old woman admitted to our center following cardiac arrest during breast lipofilling surgery. Given persistent hemodynamic instability and echocardiographic evidence of acute right ventricular overload with an intracardiac mass, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated immediately upon return of spontaneous circulation. The patient subsequently developed massive disseminated intravascular coagulation (DIC), requiring 52 units of blood products within 24 hours. The clinical course was further complicated by acute respiratory distress syndrome (ARDS), recurrent DIC with stroke, and cardiogenic shock due to acute right heart failure, ultimately leading to withdrawal of care. Autopsy revealed pulmonary fat emboli and adipose material entrapped within the tricuspid valve chordae, corresponding to the intracardiac mass identified on echocardiography. This case highlights the echocardiographic identification of a fat embolus entrapped within the tricuspid subvalvular apparatus following cosmetic fat grafting surgery. Its early recognition may reflect a substantial embolic burden and could provide additional prognostic information when interpreted alongside established clinical, hemodynamic, and echocardiographic parameters. The case also illustrates severe DIC as a potentially important systemic complication of fat embolism in this setting.

The endothelial glycocalyx depends on Exostosin-1 (Ext1)-mediated heparan sulfate synthesis; however, its endothelial cell-autonomous role in acute inflammation remains unclear. Therefore, we examined the role of Ext1 during acute inflammation. In this study, endothelial-specific Ext1-deficient mice (Ext1[flox/flox] and VE-cadherin-Cre) were generated, and their response to endotoxin challenge was investigated using transcriptomics and imaging. Transcriptomic profiling revealed downregulation of heparan sulfate- and glycocalyx-related genes, with upregulation of genes associated with immune activation. Fluorescence imaging demonstrated lectin- and heparan sulfate-defined glycocalyx depletion; dextran extravasation confirmed impaired barrier integrity. Ultrastructural analyses demonstrated a near-complete absence of the luminal glycocalyx at baseline in Ext1-deficient lungs. Following lipopolysaccharide administration, Ext1-deficient mice exhibited altered cytokine kinetics, delayed clearance of neutrophils and CD11b[+] myeloid cells, increased late-phase macrophage accumulation, and prolonged pulmonary edema, indicating impaired resolution of inflammation. Gene set enrichment analysis revealed upregulated leukocyte transendothelial migration, chemokine signaling, and vascular endothelial growth factor pathways, consistent with a persistently activated endothelial phenotype. Endothelial Ext1 is indispensable for heparan sulfate biosynthesis, endothelial glycocalyx integrity, and timely inflammation resolution. Loss of Ext1 leads to an intrinsically pro-inflammatory endothelial state characterized by impaired heparan sulfate-dependent signaling and dysregulated leukocyte-endothelial interactions, heightened vascular permeability, and prolonged tissue injury. Our findings support glycocalyx-targeted therapy in sepsis, acute respiratory distress syndrome, diabetes-associated inflammation, and other conditions of endothelial vulnerability.

Background: The alveolar epithelial glycocalyx is a layer of glycosaminoglycans (GAGs) and proteoglycans (e.g., syndecan-1) that is located between the apical alveolar epithelium and the surfactant layer. It is degraded in murine models of lung injury and in patients with ARDS. Targeted degradation of the epithelial glycocalyx impairs surfactant function in mice. We sought to determine the relationship between epithelial glycocalyx degradation, pulmonary physiology, and clinical outcomes in patients with ARDS. Methods: We first analyzed the relationship between the concentration of syndecan-1 (a marker of glycocalyx shedding) in directly aspirated pulmonary edema fluid and both lung injury severity and patient outcomes in a retrospective cohort of patients with ARDS or hydrostatic pulmonary edema. Subsequently, we prospectively collected heat-moisture-exchange (HME) filter fluid, a noninvasive approach to distal airspace sampling, at two additional centers and determined the relationships between syndecan-1, respiratory mechanics, patient outcomes, and other established ARDS biomarkers. Results: Airspace fluid syndecan-1 was associated with impaired lung mechanics (static respiratory system compliance and driving pressure), more severe hypoxemia, prolonged mechanical ventilation, and increased mortality. Other airspace biomarkers of lung injury were not associated with lung mechanics. These findings were observed similarly across multiple cohorts, using either directly aspirated pulmonary edema fluid or noninvasively collected HME fluid. Conclusions: Airspace fluid syndecan-1 is associated with the severity of hypoxemia, impaired lung mechanics, and worse clinical outcomes in ARDS patients. These results support further research into therapeutics to restore the integrity of the epithelial glycocalyx in ARDS.

A recent study associated early proliferative or fibrotic diffuse alveolar damage with mortality in acute respiratory distress syndrome. We highlight four interpretive concerns: phenotype status was assigned at biopsy after follow-up began, creating potential immortal-time bias; a single biopsy cannot measure pathological velocity; sparse and imbalanced phase-by-timing cells limit component-specific inference; and concurrent physiological measurements complicate causal interpretation. Until delayed-entry survival and phase-specific sensitivity analyses are reported, the phenotype is better viewed as early advanced-phase histology than evidence of accelerated pathology.

Management of sepsis-associated acute lung injury (S-ALI) remains challenging due to complex inflammatory cascades, oxidative stress amplification, and limited therapeutic delivery to injured pulmonary tissues. Here, we developed a biomimetic "dual-lock-inspired" nanoplatform (M@ORNP) that integrates a neutrophil-mimetic membrane interface with an OR-based encapsulated prodrug core to enable inflammation-associated pulmonary targeting and coordinated therapeutic regulation. The platform consists of a self-assembled ester-linked prodrug composed of 4-octyl-itaconate and retinol, encapsulated within a membrane derived from differentiated HL-60 cells. The neutrophil-mimetic membrane endows M@ORNPs with enhanced interaction with inflammatory endothelial cells and promotes preferential accumulation within injured lung tissues. Following cellular internalization, M@ORNPs exhibited progressive dissociation from lysosomal compartments, consistent with altered endo-lysosomal trafficking behavior and potential intracellular release of therapeutic components. In vitro and in vivo studies demonstrated that M@ORNPs coordinated the suppression of reactive oxygen species (ROS) accumulation and inflammatory signaling pathways, including NF-κB, STAT1, and the NLRP3 inflammasome, in macrophage-associated inflammatory models. In murine S-ALI models, M@ORNP treatment reduced inflammatory responses, alleviated pulmonary injury, and improved survival outcomes under lethal challenge conditions. Collectively, this study presents a biomimetic nanotherapeutic strategy that combines inflammatory-site accumulation with complementary anti-inflammatory and antioxidant activities, providing a platform for the treatment of severe inflammatory disorders.