Search Results (972)

Sepsis is a life-threatening syndrome characterized by severe immune dysregulation, frequently culminating in acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Current supportive therapies fail to reverse the underlying pathophysiological damage. However, mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic frontier due to their robust immunomodulatory, anti-inflammatory, and tissue-regenerative properties. Despite compelling preclinical evidence, translating these benefits into consistent clinical efficacy remains a major challenge. This review critically examines the biological and anatomical barriers limiting the efficacy of MSCs, particularly the pulmonary first-pass effect, which restricts the systemic delivery of viable cells to distant organs such as the kidneys. To overcome these physical limitations, we highlight the recent paradigm shift toward nanoscale, cell-free therapies, specifically MSC-derived extracellular vesicles (MSC-EVs). EVs effectively bypass pulmonary sequestration and thromboembolic risks, exerting their potent therapeutic effects through the horizontal transfer of bioactive cargo, notably microRNAs, to reprogram cellular fate and restore immune homeostasis. We also discuss the critical need for rigorous clinical trial designs, scalable good manufacturing practice protocols, and the integration of a precision medicine approach. Ultimately, incorporating validated biomarkers for targeted patient stratification will be the decisive step in unlocking the full therapeutic potential of MSCs and their derivatives in critical care. Full article

Background/Objectives: Hydrogen gas (H₂) inhalation has shown neuroprotective effects in neonatal hypoxic–ischemic models. However, its impact on pulmonary endothelial activation and respiratory function after hypoxic–ischemic insult remains unclear. This study investigated whether H₂ inhalation augments pulmonary endothelial activation or impairs pulmonary function during the acute phase after neonatal hypoxic–ischemic injury. Methods: Sixteen newborn Camborough^® piglets within 24 h of birth were subjected to hypoxic–ischemic insult and randomized to an untreated group (HI, n = 8) or an H₂-treated group (HI-H₂, n = 8). The HI-H₂ group received 2.1–2.7% H₂ for 6 h. Pulmonary ICAM-1 and inducible nitric oxide synthase (iNOS) expression were assessed by immunofluorescence, lung neutrophils were quantified histologically, and pulmonary function was evaluated using arterial blood gases, oxygen index, and alveolar–arterial oxygen difference. The relationship between lung neutrophil counts and right ventricular cardiac output was also examined. Results: H₂ inhalation did not increase pulmonary ICAM-1 expression or iNOS induction compared with untreated animals. Although lung neutrophil counts were significantly higher in the HI-H₂ group, pulmonary gas exchange remained preserved, with no significant differences in arterial blood gases, oxygen index, or alveolar–arterial oxygen difference. Lung neutrophil counts were positively correlated with right ventricular cardiac output, suggesting that enhanced pulmonary perfusion may contribute to neutrophil redistribution rather than inflammatory recruitment. Conclusions: H₂ inhalation preserved pulmonary endothelial homeostasis without impairing respiratory function during the acute phase after neonatal hypoxic–ischemic insult. The observed increase in lung neutrophils was not accompanied by evidence of endothelial activation or deterioration of gas exchange, supporting the acute pulmonary safety of H₂ inhalation while suggesting that neutrophil accumulation may, at least in part, reflect hemodynamic redistribution rather than injurious inflammatory infiltration. Full article

Background and Objectives: Patients with cirrhosis and acute kidney injury (AKI) frequently receive albumin, although plasma volume expansion may contribute to pulmonary or venous congestion. Point-of-care ultrasound (POCUS) may complement bedside assessment when formal echocardiography or advanced hemodynamic monitoring is not immediately available. This study evaluated baseline pulmonary and venous congestion using POCUS in patients with cirrhosis and AKI receiving albumin therapy. Materials and Methods: This exploratory prospective cohort included adults with cirrhosis, ascites, and ICA-AKI stage 1B or higher who were managed under an institutional protocol prescribing intravenous 20% or 25% albumin at 1 g/kg/day for two consecutive days, capped at 100 g/day. Before albumin administration, B-line-defined pulmonary congestion was assessed using a 28-site lung protocol, and IVC-defined venous congestion was assessed using inferior vena cava (IVC) diameter and collapsibility. Serum creatinine was recorded within 12 h before treatment and 48 h after initiation. Complete renal response was defined as serum creatinine within 0.3 mg/dL of the pre-AKI baseline; partial response was defined as regression by at least one ICA-AKI stage without complete response. Results: Twenty-two patients were included. B-line-defined pulmonary congestion was present in 18/22 (81.8%). IVC assessment was technically evaluable in 20 patients, of whom 6/20 (30.0%) met the criteria for IVC-defined venous congestion. The Hodges–Lehmann estimate of the median paired creatinine difference was +0.03 mg/dL (95% CI, −0.52 to 1.31) without pulmonary congestion and −0.33 mg/dL (95% CI, −0.67 to −0.20) with pulmonary congestion. Renal response occurred in 1/4 (25.0%) and 12/18 (66.7%), respectively (two-sided Fisher exact p = 0.264). Among patients with evaluable IVC examinations, renal response occurred in 8/14 (57.1%) without and 3/6 (50.0%) with IVC-defined venous congestion (p = 1.000). Conclusions: Baseline POCUS frequently identified ultrasound-defined congestion, but congestion status did not clearly distinguish short-term renal response. These exploratory findings support the feasibility of bedside POCUS phenotyping but do not establish that congestion modifies albumin response or clinical outcomes. Full article

Despite advances in the understanding of the pathophysiology of acute respiratory distress syndrome (ARDS), treatment options remain limited and are mainly supportive, while mortality remains high. Prone positioning (PP) has been shown to improve oxygenation and lung mechanics in ARDS by reducing the imbalance in ventilation distribution between ventral and dorsal lung regions, altering pulmonary blood flow distribution, modifying the density distribution of edematous lung tissue, and limiting areas with low ventilation–perfusion ratios. During the coronavirus disease 2019 (COVID-19) pandemic, the use of PP, referred to as awake prone positioning (APP), was extended to non-intubated patients with severe hypoxemic respiratory failure. However, several concerns remain, including worsening oxygenation following the transition from prone to supine position, the potential development of patient self-inflicted lung injury (P-SILI), and delays in endotracheal intubation and initiation of invasive mechanical ventilation. Evidence regarding the use of APP in non-COVID-19 ARDS is scarce and consists mainly of small case series and a limited number of prospective studies with small and heterogeneous populations. Therefore, in the present work, we aim to summarize the existing evidence on APP in non-COVID-19 ARDS and acute hypoxemic respiratory failure (AHRF), describe the underlying pathophysiological mechanisms, and highlight areas for future research. Full article

Objective: In a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model, the present study sought to assess the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and characterize their anti-inflammatory mechanistic basis. Methods: Forty mice were randomly divided into four groups: control, LPS model, LPS + DEX (positive control), and LPS + hUC-MSCs. Except for the control group, mice received intratracheal instillation of LPS to establish ALI. One hour after LPS administration, animals in the hUC-MSC group were intravenously infused with hUC-MSCs. The positive control group was given an intraperitoneal injection of DEX for 3 consecutive days, starting at 24 h after modeling. On day 4 after cell transplantation or at 24 h after the completion of DEX injection, lung function indicators were detected. Bronchoalveolar lavage fluid (BALF), serum, and lung tissues were subsequently obtained for evaluation of inflammatory cell infiltration, histopathological injury, lung wet-to-dry (W/D) ratio, and cytokine levels. Additionally, the localization of transplanted hUC-MSCs in lungs was examined, and the mRNA and protein expression levels of TLR4, MyD88, and NF-κB p65 were quantified. Results: LPS exposure markedly impaired pulmonary function and induced robust inflammatory responses, evidenced by elevated levels of pro-inflammatory cytokines, increased inflammatory cell counts in BALF and serum, and extensive histological lung damage. Moreover, hUC-MSC injection improved lung function, decreased inflammatory cytokine production and alleviated pulmonary edema, while inhibiting the TLR4/MyD88/NF-κB pathway at transcriptional and protein levels. Conclusions: Intravenous hUC-MSC administration alleviates LPS-induced ALI in mice, an effect associated with suppression of the TLR4/MyD88/NF-κB cascade. These results indicate that this signaling cascade partially mediates the observed anti-inflammatory effects. Full article

Pectolinarigenin (PEC), a naturally occurring flavonoid, exhibits anti-inflammatory and antioxidant activities in various experimental models. However, its protective effects against lipopolysaccharide (LPS)-induced lung inflammation and the underlying molecular mechanisms remain unclear. This study investigated the protective effects of PEC using LPS-treated MLE12 cells and RAW264.7 macrophages, as well as a prophylactic mouse model in which PEC was administered before LPS exposure. In LPS-treated MLE12 cells and RAW264.7 macrophages, PEC reduced inflammatory responses and cellular injury, accompanied by decreased reactive oxygen species production and modulation of the histone deacetylase 3 (HDAC3)/nuclear factor κB (NF-κB)/NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) signaling. Consistent with these findings, PEC pretreatment attenuated pulmonary edema, inflammatory cell infiltration, pro-inflammatory cytokine production, oxidative stress, pyroptosis-associated signaling, and histopathological lung injury in LPS-exposed mice. These protective effects were accompanied by reduced HDAC3 expression and nuclear localization, together with reduced NF-kB/NLRP3 signaling in lung tissues. Overall, PEC attenuated LPS-induced lung inflammation and injury, accompanied by reduced oxidative stress and modulation of HDAC3/NF-κB/NLRP3 signaling. These findings support the potential of PEC as a preventive agent against excessive pulmonary inflammation. Full article

Tamarix chinensis Lour. (T. chinensis) is a traditional herb with functions for releasing the exterior to promote the eruption of rashes, among other ailments. However, these function-related pharmacological effects, such as anti-complement, anti-oxidative, and anti-inflammatory, remain unclear. This study aims to reveal the aforementioned effects and the molecular mechanisms of the ethanol extract of T. chinensis (TCE). Our results demonstrated that TCE inhibited classical- and lectin-mediated complement activation, reduced intracellular ROS via NADPH oxidase inhibition, and directly scavenged DPPH radicals and superoxide anions. By using lipopolysaccharide (LPS)-stimulated macrophages, along with LPS-induced acute lung injury (ALI) and endotoxemia mice, the anti-inflammatory activity and the underlying molecular mechanisms of TCE were deeply investigated. In LPS-activated macrophages, it suppressed iNOS, CCL2, IL-6 and IL-1β transcriptionally and translationally. Mechanistically, TCE inhibited NF-κB signaling by blocking IκBα phosphorylation and p65 nuclear translocation, as well as suppresses AP-1 signaling by reducing ERK and JNK phosphorylation. In vivo, TCE lowered serum multiple pro-inflammatory cytokines of endotoxemic mice and alleviated lung injury of ALI mice. Collectively, our results demonstrated that TCE possesses anti-complement and anti-oxidative activities and exerts anti-inflammatory effects through inhibiting NF-κB and AP-1 signaling. These findings provide scientific evidence for supporting the traditional use of T. chinensis. Full article

The mammalian respiratory system stands as a frontline barrier, constantly exposed to environmental insults, balancing defensive immunity with gas exchange. Historically considered sterile, the lung harbors a dynamic, low-biomass microbiome that evolves continuously in response to pulmonary pathologies. Accumulating evidence underscores that respiratory health and structural recovery are not autonomous but are critically integrated with distal microbial systems, especially the intestinal tract, through the gut–lung axis (GLA). This review characterizes the GLA as a bidirectional communication highway fueled by immune pathways, microbial metabolites, and direct microbial translocations. During acute or chronic injuries, such as COVID-19, COPD, asthma, idiopathic pulmonary fibrosis (IPF) and lung cancer, the gut microbiota serves as a remote metabolic “rheostat”. It delivers pivotal signaling molecules, such as short-chain fatty acids (SCFAs) and tryptophan metabolites (indoles), that could shape the local microenvironment in which the respiratory epithelium undergoes functional repair or maladaptive, fibrotic remodeling. Mechanistically, gut-derived butyrate enhances mitochondrial activity in alveolar epithelial cells, while resident progenitors, such as Alveolar Type 2 (AT2) cells, depend on intact mitochondrial fatty acid oxidation for proper regenerative differentiation. Conversely, critical lung illness disrupts this homeostasis via a “pathological circuit,” where severe pulmonary inflammation drives gut permeability, fecal dysbiosis, and the subsequent translocation of pathogen-associated molecular patterns (PAMPs, such as LPS) or gut-associated bacteria back into the pulmonary circulation. This review highlights the systemic nature of lung regeneration, which likely depends heavily on intestinal health through the GLA. Ultimately, leveraging these remote microbial networks through precision postbiotic supplementation, dietary priming, or microbiota transplantation represents a crucial frontier in precision medicine to promote definitive alveolar repair. Full article

Background: Polymorphonuclear (PMN) leukocyte recruitment to activated pulmonary endothelium is a central mechanism in acute respiratory distress syndrome (ARDS). This process is mediated by selectins and their counter-ligand, P-selectin glycoprotein ligand-1 (PSGL-1), encoded by SELPLG. Genetic variation in SELPLG has been associated with ARDS susceptibility, while disruption of PSGL-1/P-selectin interactions attenuates lung injury in preclinical models. Because inflammatory stimuli increase both SELPLG expression and circulating PSGL-1 levels, PSGL-1 represents a promising biomarker and therapeutic target. We sought to define the genetic determinants of plasma PSGL-1 levels and evaluate their causal relationships with key inflammatory and endothelial biomarkers. Methods: Genome-wide association study (GWAS) summary statistics for plasma PSGL-1 levels were obtained from the UK Biobank Pharma Proteomics Project (n = 35,571) and the SCALLOP consortium (n = 21,758 across 13 cohorts). Associated variants underwent functional annotation and in silico analyses to identify potential effects on protein structure and gene regulation. Bidirectional Mendelian randomization (MR) was performed using GWAS summary statistics for C-reactive protein (CRP), E-selectin, GlycA, and soluble intercellular adhesion molecule-1 (sICAM-1) to assess potential causal relationships with PSGL-1 levels. Results: Multiple cis- and trans-acting loci were significantly associated with plasma PSGL-1 concentrations. Three coding SELPLG variants (rs201689859, rs74792300, and rs139943851) were predicted to alter PSGL-1 protein structure and were associated with lower circulating PSGL-1 levels. Four promoter variants (rs1420663, rs1833245, rs1420664, and rs8179110) were linked to altered transcriptional activity, including a potential effect of rs1420664 on hypoxia-inducible factor binding. Bidirectional MR demonstrated that genetically predicted CRP, E-selectin, GlycA, and sICAM-1 levels were associated with increased plasma PSGL-1 concentrations. Additional loci implicated pathways related to immune signaling, cell adhesion, and protein stability. Conclusions: Large-scale GWAS and Mendelian randomization analyses identified genetic variants that regulate plasma PSGL-1 levels and demonstrated causal links between inflammatory and endothelial biomarkers and PSGL-1 expression. These findings provide new insights into the genetic regulation of leukocyte trafficking pathways and support a role for PSGL-1 in inflammatory diseases, including ARDS, sepsis, and cardiovascular disorders. Full article

Adipose tissue has emerged as a pivotal endocrine organ, secreting bioactive proteins termed adipokines that regulate metabolic and immune processes across multiple organ systems. In the context of sepsis and critical illness, conditions defined by a dysregulated host response to infection with life-threatening organ dysfunction, the role of novel adipokines has attracted considerable research interest. This review focuses on three novel adipokines: chemerin, vaspin (SERPINA12), and omentin-1 (intelectin-1). We will discuss current in vitro, in vivo experimental animal models, and clinical evidence, emphasizing their biology, mechanisms of action, and potential as diagnostic and prognostic biomarkers in critically ill patients. All three adipokines are elevated in sepsis compared with healthy controls and correlate with established severity scores, including APACHE II and SOFA. Chemerin and omentin-1 have both been independently associated with 28-day mortality in prospective cohort studies. Vaspin exhibits robust cardioprotective effects in murine sepsis models via inhibition of kallikrein 7 (KLK7) and attenuates lipopolysaccharide (LPS)-induced acute lung injury (ALI) both in vitro and in vivo. Omentin-1 suppresses LPS-induced macrophage activation through TLR4/MyD88/NF-κB inhibition in vitro and protects against LPS-induced ALI in murine models. Despite these promising findings, substantial methodological heterogeneity and limited large-scale clinical data currently preclude clinical implementation. Future research that standardizes assays, expands to multicenter cohorts, and investigates therapeutic modulation of these pathways is urgently needed. Full article

Background/Objectives: This study is the first to investigate the potential mechanism of star anise extract (SAE) in protecting against cold stress-aggravated acute lung injury (CSALI) in rats. Methods: A rat CSALI model was induced via combined lipopolysaccharide challenge and cold stress exposure. The preventive effects of SAE were evaluated using cytotoxicity assays, quantification of biochemical indices and inflammatory factors, and histopathological examination. Ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC–HRMS)-based serum metabolomics was employed to systematically profile CSALI-associated metabolic alterations and decipher the potential mechanism underlying the preventive effects of SAE. Results: SAE alleviated pathological progression of CSALI, suppressed inflammatory cell migration, markedly reduced pulmonary inflammatory cell infiltration, and ameliorated lung tissue injury in CSALI rats. SAE also improved abnormal liver function indicators and lowered the levels of pro-inflammatory factors in both serum and bronchoalveolar lavage fluid (BALF). Serum metabolomics analysis identified and annotated 24 disease-altered differential metabolites and evaluated the protective effects of SAE on them. These metabolites were significantly enriched in two key metabolic pathways related to the pathogenesis of CSALI, including arachidonic acid metabolism and glycerophospholipid metabolism. Furthermore, based on metabolite changes, phospholipase A2 was hypothesized as a potential key regulatory factor that may cooperate with arachidonic metabolism to suppress the inflammatory cascade. Conclusions: These findings demonstrated that SAE exerted prominent anti-inflammatory activity and effectively protected against lung injury in CSALI rats. Full article

Exposure to high altitudes for hours or days is defined as acute hypobaric hypoxia (AHH) condition, which rapidly engages adjustments such as signaling pathways involving inflammation, immune modulation and oxidative stress, whose dysregulation has been described as contributing to the pathophysiology of high-altitude illnesses, due to insufficient acclimatization, such as developing acute mountain sickness (AMS). Given its traditional high-altitude use and bioactive properties, Senecio nutans (S. nutans) extract, or chachacoma (CH), has emerged as a potential therapeutic strategy to mitigate high-altitude related pathobiology. The aim of this study was to evaluate the effects of S. nutans on acclimatization, regarding the status of oxidative stress, inflammation, immune and symptoms associated with AMS in an animal model exposed to AHH. Twenty-eight female Wistar rats (≈3 months old) were randomly allocated into four experimental groups (n = 7 each): normobaric normoxia (NX), normobaric normoxia plus S. nutans administration (NX+CH), acute hypobaric hypoxia (AHH; 48 h exposure), and acute hypobaric hypoxia plus S. nutans administration (AHH+CH). S. nutans was administered subcutaneously at a dose of 80 mg/kg, one hour prior to hypoxic exposure. Outcomes included body weight, food intake, hematological parameters, lung histopathology, pulmonary mRNA expression of HIF-1α, NF-κB, TNF-α, IL-1β, IL-6, and VEGF, and lipid peroxidation in lung tissue assessed by malondialdehyde (MDA) levels. After 48 h of AHH, animals exhibited a decrease in body weight and food intake, increase in hematocrit level and total leukocytes, as well as lung injury characterized by thickening of alveolar walls and inflammatory infiltrates. In addition, AHH induced an increase in pulmonary IL-6 and IL-1β mRNA expression. In contrast, S. nutans administration partially attenuated hypoxia-induced body weight loss, mitigated the rise in hematocrit levels, and reduced lung damage, while returning total leukocyte counts to control levels. Notably, S. nutans also decreased the hypoxia-induced overexpression of IL-6 and IL-1β. Regarding lipid peroxidation, no significant differences were observed among groups. These findings suggest that S. nutans exerts a protective effect against acute hypobaric hypoxia by attenuating inflammatory responses and preserving pulmonary structure, thereby supporting its potential as a preventive strategy to mitigate early pathophysiological alterations associated with high-altitude exposure. Full article

Experimental acute lung injury (ALI) models are widely used to investigate pulmonary inflammation and evaluate therapeutic strategies for acute respiratory distress syndrome (ARDS). Kaempferia marginata is a traditional medicinal plant used to treat fever and has been reported to possess anti-inflammatory properties in lipopolysaccharide (LPS)-activated macrophages. 6β-Acetoxysandaracopimaradien-1α,9α-diol (ASPD), a major isopimarane-type diterpenoid isolated from this plant, has not previously been investigated for its effects on ALI. This study employed an integrated network pharmacology, molecular docking, and experimental validation strategy to investigate the protective effects and potential mechanisms of ASPD against LPS-induced ALI. Network pharmacology analysis identified several inflammation-related hub targets associated with Src, MAPK, and PI3K/Akt signalling. In LPS-stimulated MLE-12 cells, ASPD reduced inflammatory cytokine production and inhibited the phosphorylation of JNK1/2, ERK1/2, p38 MAPK, Akt, and GSK-3β. In mice with LPS-induced ALI, ASPD alleviated histopathological lung injury, pulmonary oedema, and inflammatory cell infiltration while reducing IL-6, TNF-α, and myeloperoxidase activity without apparent toxicity. Immunohistochemical analysis demonstrated reduced Src and ERK1/2 expression in lung tissue. Molecular docking analysis predicted favourable binding affinities between ASPD and selected Src- and MAPK-related signalling proteins. These findings suggest that ASPD attenuates LPS-induced ALI and is associated with alterations in Src-, MAPK-, and Akt/GSK-3β-related signalling. Full article

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted in response to food intake that acts biologically by binding to GLP-1 receptors. The primary function of GLP-1 is to stimulate insulin secretion and inhibit glucagon secretion, which helps limit after-meal spikes in blood glucose. GLP-1 reduces intestinal contractility, slows down gastrointestinal motility and emptying, and also acts directly on the hypothalamus, thereby regulating appetite and food intake. Due to its metabolic effects, GLP-1 forms the basis of medications currently used to treat type 2 diabetes (T2DM) and obesity. However, it has also been observed that the use of GLP-1 agonists in the treatment of obesity or diabetes has a beneficial effect on comorbid respiratory conditions. This narrative review analyzes the scientific literature and describes the most recent information on the impact of GLP-1 receptor agonist (GLP-1 RA) therapies on the most common respiratory disorders—both the beneficial and undesirable effects. We discuss evidence that acute lung injury, COVID-19, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea can benefit from therapies with various GLP-1 RAs. They can complement existing lung-targeted treatments, but as research progresses, they are likely to play an ever more important role in the treatment of respiratory diseases. Full article

Congestion is a major driver of symptoms, hospitalization, and adverse outcomes in heart failure (HF), yet its clinical assessment remains challenging. Traditional approaches based on physical examination, biomarkers, and isolated imaging surrogates often fail to capture the complexity of systemic venous congestion and its impact on organ function. In HF, congestion should be interpreted as a multifactorial process resulting from the interaction between intravascular volume burden, venous compliance, cardiac filling pressures, neurohormonal activation, blood volume redistribution, and organ-specific susceptibility. In this context, point-of-care ultrasound has emerged as a promising adjunctive tool for bedside congestion assessment. The Venous Excess Ultrasound (VExUS) score integrates inferior vena cava assessment with Doppler analysis of hepatic, portal, and intrarenal veins, allowing for the evaluation of venous pressure transmission and organ-level congestion. Observational studies suggest that VExUS and related venous Doppler abnormalities correlate with invasive hemodynamic parameters and are associated with acute kidney injury, diuretic response, heart failure hospitalization, and mortality. Serial changes in venous congestion may provide additional information regarding treatment response and clinical trajectory. However, the available evidence remains heterogeneous across acute HF, ambulatory HF, cardiorenal syndrome, and critical care populations, and randomized trials evaluating VExUS-guided management are lacking. Therefore, VExUS should be interpreted as a complementary tool within a multimodal assessment that includes echocardiography, lung ultrasound, biomarkers, renal function, urine output, physical examination, and response to therapy. By integrating fluid burden with venous pressure transmission and organ perfusion, multimodal ultrasound may support more individualized congestion assessment and risk stratification in HF. Full article