Search Results (355)

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Its development and progression involve multiple interconnected mechanisms, including uncontrolled inflammation, immunosuppression, metabolic reprogramming, intestinal barrier disruption, and multi-organ injury. Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are important metabolites produced by the anaerobic fermentation of dietary fiber and indigestible carbohydrates by gut microbiota. During sepsis, antibiotic exposure, intestinal hypoperfusion, insufficient nutritional substrates, and microbial dysbiosis may deplete SCFA-producing bacteria and lower SCFA levels, thereby aggravating intestinal barrier dysfunction, endotoxin translocation, and systemic inflammatory responses. SCFAs can influence sepsis-associated intestinal, pulmonary, cardiac, hepatic, renal, and cerebral injury by activating receptors such as free fatty acid receptor 2 (FFAR2)/G protein-coupled receptor 43 (GPR43), free fatty acid receptor 3 (FFAR3)/G protein-coupled receptor 41 (GPR41), and G protein-coupled receptor 109A (GPR109A); inhibiting histone deacetylases; and regulating immune-cell metabolism, inflammasome activation, oxidative stress, mitochondrial function, and modes of cell death. In recent years, strategies such as direct SCFA supplementation, promotion of endogenous SCFA production, restoration of SCFA-producing microbial communities, and targeting of SCFA receptors and downstream signaling pathways have shown therapeutic potential. However, their clinical translation remains limited by uncertainties regarding dose, timing, route of administration, patient stratification, and safety. This review systematically summarizes the mechanisms of action and therapeutic advances of SCFAs in sepsis, aiming to provide a reference for microbiome-based interventions and metabolism-targeted therapies in sepsis. Full article

Cigarette smoke exposure is a major preventable risk factor for respiratory disease and drives oxidative and inflammatory lung injury, highlighting the urgent need for safe, multi-target interventions beyond conventional anti-inflammatory therapy. Formononetin (FMN), a naturally occurring isoflavone with antioxidant, anti-inflammatory, and microbiota-modulating potential, may offer a dietary-botanical strategy against smoke-related pulmonary damage. This study evaluated FMN against cigarette smoke extract (CSE)-induced lung injury and explored its associations with intestinal barrier integrity, gut microbiota, taurine metabolism, SLC6A6 expression, and NF-κB activation. In a CSE-challenged mouse model, oral FMN, particularly at 70 mg/kg, improved body weight gain, reduced the lung index, attenuated pulmonary histopathological injury, restored GSH/GSSG and SOD, decreased MDA, and suppressed TNF-α, IL-1β, and IL-6 expression. FMN also ameliorated colonic injury and restored ZO-1 and occludin expression. Exploratory 16S rRNA sequencing and fecal metabolomics indicated FMN-associated alterations in gut microbial composition and metabolic profiles, with taurine and hypotaurine metabolism identified as a candidate pathway for further investigation. FMN further restored lung taurine content and SLC6A6 expression while inhibiting NF-κB activation. These findings suggest that FMN alleviates CSE-induced lung injury and that this improvement is associated with coordinated changes in gut microbiota composition, taurine metabolism, SLC6A6 expression, and NF-κB activation. Full article

The 12-lead electrocardiogram (ECG) is inexpensive, noninvasive, and widely available, but conventional interpretation may not capture subtle signals related to cardiac structure, systemic physiology, and future risk. This review examines the use of deep learning–enabled ECG analysis beyond conventional arrhythmia detection and evaluates the maturity, clinical relevance, and implementation challenges of these applications. This narrative review synthesizes landmark studies, external validation cohorts, pragmatic implementation trials, and recent investigations of artificial intelligence–enabled ECG (AI-ECG) models for structural, metabolic, systemic, and prognostic assessment. Particular attention is given to model performance, validation, clinical actionability, and barriers to translation. AI-ECG models have demonstrated the ability to detect reduced left ventricular ejection fraction, hypertrophic cardiomyopathy, valvular disease, cardiac amyloidosis, pulmonary hypertension, hyperkalemia and other dyskalemias, hyperthyroidism, anemia, and sepsis, and to estimate biologic age and mortality risk. Evidence is most mature for screening for reduced left ventricular ejection fraction, supported by large derivation cohorts, external validation, prognostic follow-up, and the EAGLE pragmatic trial. Evidence for many other applications remains retrospective or exploratory, with limitations related to reference standards, generalizability, calibration, disease prevalence, interpretability, and the absence of clearly defined clinical pathways. AI-ECG has the potential to expand the ECG from a conventional diagnostic test into a screening and decision-support platform. Its near-term role is to identify patients who may benefit from confirmatory imaging, laboratory testing, rhythm monitoring, or specialist evaluation. Broader adoption will require prospective validation, workflow integration, subgroup assessment, post-deployment monitoring, regulatory oversight, and evidence that AI-guided care improves outcomes. Full article

The respiratory tract is a dynamic biological interface where microbiome, environmental exposure, epithelial integrity, and host metabolic regulation converge to maintain pulmonary homeostasis. Once considered sterile, the lung is now recognized as a low-biomass yet structured microbial ecosystem that contributes to immune calibration, colonization resistance, epithelial barrier function, and tissue resilience. Disruption of this equilibrium, known as pulmonary dysbiosis, has been increasingly associated with acute and chronic lung diseases, including cystic fibrosis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, asthma, bronchiectasis, and lung cancer. In parallel, mitochondria have emerged as central regulators of pulmonary cell function, extending beyond ATP production to control redox signaling, apoptosis, innate immunity, epithelial repair, and inflammatory responses. This review examines the bidirectional crosstalk between the respiratory microbiome and mitochondria as an integrated pathogenic axis in lung disease. Dysbiotic microbial communities and respiratory pathogens can induce mitochondrial stress through toxins, virulence factors, microbial metabolites, and pattern-recognition receptor activation, leading to mitochondrial alteration and the release of mitochondrial damage-associated molecular patterns. Conversely, dysfunctional mitochondria reshape the pulmonary microenvironment by altering oxygen consumption, nutrient availability, cytokine production, redox balance, and barrier repair, thereby favoring pathogen persistence and chronic inflammation. Understanding mitochondria–microbiome interactions may support precision medicine strategies that integrate microbial, metabolic, inflammatory, and bioenergetic biomarkers to improve the diagnosis, prognosis, and treatment of inflammatory-related lung diseases. Full article

Backgorund/Objectives: Respiratory diseases represent a substantial global health burden and require effective localised pulmonary delivery strategies, particularly for poorly water-soluble therapeutic molecules. Nanoparticle-based drug delivery systems, especially those manufactured using microfluidics, have emerged as promising approaches to overcome pulmonary barriers, enhance local drug retention, and reduce systemic side effects. Among these nanocarriers, solid lipid nanoparticles (SLNs) and solid hybrid nanoparticles (SHNs) combine biocompatibility with controlled release and improved formulation stability. Methods: In this study, SLNs and lipid–chitosan SHNs were developed using microfluidic technology as candidate platforms for pulmonary drug delivery, with Cyclosporine A (CyA) used as a model hydrophobic cyclic peptide. Nanocarriers were produced using 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol as lipids, with low-molecular-weight chitosan incorporated to obtain hybrid systems. Physicochemical properties were evaluated using dynamic light scattering (DLS) and ζ potential measurements, while morphology and structural organisation were investigated using transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Results: The microfluidic approach enabled the production of nanoparticles with controlled sizes below 200 nm, narrow size distributions, and good reproducibility. In addition, the SHNs exhibited a positive surface charge, high encapsulation efficiency (~80%), and good colloidal and thermal stability. In vitro release studies showed an initial burst release followed by sustained CyA release, reaching approximately 94% cumulative release within 6 h. The Korsmeyer–Peppas model was used as the standard kinetic model. No blank nanoparticles were used as controls in the EE and release assay. Conclusions: Overall, these findings support further investigation of microfluidic-produced lipid and hybrid nanoparticles as candidate platforms for pulmonary drug delivery. Full article

Cryptococcosis often begins in the lungs and may later reach the central nervous system, where it can lead to severe or fatal disease. The course of infection is shaped by changing interactions between host cells, fungal adaptive states, and local tissue environments. Many virulence factors and immune responses have been studied in detail, but the evidence remains divided across organs, cell types, and experimental systems. As a result, pulmonary infection is better understood than later stages, including dissemination, crossing of the blood–brain barrier, CNS involvement, and long-term persistence. In this review, we use a stage-resolved phenomic framework to connect host cell states, fungal adaptive phenotypes, and tissue niches throughout the course of infection. Evidence from multi-omics studies, spatial analyses, cellular experiments, animal models, and clinical cohorts is brought together to show how phenotypic features differ between stages and how uneven the current evidence base remains. The strongest evidence remains concentrated in pulmonary infection, whereas dissemination, crossing of the blood–brain barrier, and CNS disease are supported by more model-dependent data. Evidence for persistence and reactivation is the most limited. By organizing these findings into a disease-course map, this review outlines testable questions for biomarker discovery, host-directed therapy, and risk stratification in cryptococcal infection. Full article

Repair programs are pervasive in idiopathic pulmonary fibrosis (IPF), yet they fail to reach completion. While single-cell and spatial omics have identified cellular states associated with injury-repair programs, a central paradox remains: why do these programs persist without reconstituting functional lung architecture? This review integrates evidence from multiscale omics, spatial analyses, and translational studies to propose a lesion-centered “non-resolving repair” framework that explains IPF progression. We argue that disease progression is driven by the persistence of cellular repair programs after the pathways required for maturation, state exit, and microenvironmental reset have become compromised. These compartment-specific failures converge within spatially organized lesion units, where aberrant cellular activity and matrix distortion reinforce one another, embedding failed repair within tissue architecture. This perspective shifts the focus from cataloging disease-associated cell states toward evaluating failed biological transitions and regional resolution capacity. Clinically, it reframes antifibrotic therapy around overcoming spatial barriers to repair and highlights the need for translational endpoints that distinguish marker suppression from structural stabilization and functional tissue reconstruction. Delineating which lesional niches retain resolution capacity will be essential for identifying where repair-oriented interventions may still re-engage organized tissue repair in IPF. Full article

Congenital diaphragmatic hernia (CDH) is increasingly recognized as a dynamic cardiopulmonary disease in which pulmonary hypoplasia, pulmonary hypertension, and cardiac dysfunction interact to shape clinical instability, therapeutic response, and outcomes. Hemodynamic phenotyping has emerged as a strategy to move beyond binary classification of pulmonary hypertension and toward physiology-directed care. Early single-center experiences suggest potential clinical utility of echocardiography-guided, phenotype-directed management; however, external validation remains limited. Further important challenges remain, including technical and institutional barriers to timely echocardiography, limitations of static single-time-point assessments, uncertainty regarding what exactly defines each phenotype, and incomplete understanding of the impact of time and therapies on phenotype presentations. In this perspective, we summarize the evolution of heart-focused care in CDH, describe current hemodynamic phenotyping approaches, examine unresolved questions in phenotype classification and implementation, and outline future research priorities needed to advance dynamic, mechanism-based precision cardiopulmonary care for infants with CDH. Full article

Background: Airborne microplastics (AMPs) are an emerging air pollutant and there are growing concerns about their potential effects on respiratory health due to their persistence, inhalability and ability to carry other toxic pollutants. Methods: Relevant peer-reviewed studies released from 2015 to 2025 were located by searches on PubMed, Scopus, and Web of Science. Data from experimental, epidemiological, and review research were amalgamated to investigate sources of airborne microplastics, routes of exposure, analytical methodologies, respiratory toxicological processes, and regulatory viewpoints. Results: Modern studies suggest inhaled antimicrobic peptides can reach the lower respiratory tract and cause chronic pulmonary inflammation via induction of oxidative stress, mitochondrial dysfunction, epithelial barrier damage, inflammasome activation, immune system imbalance and extracellular matrix remodeling. These pathways have been associated with chronic respiratory diseases, such as chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, and lung carcinoma. Toxicity can be increased by the accumulation of heavy metals, persistent organic pollutants and microbiological impurities. However, the lack of standardised protocols for exposure assessment, inconsistency of sampling and analytical methods and limited human epidemiological data hamper health risk assessment. Conclusions: Airborne microplastics are an emerging environmental health concern with potentially significant effects on respiratory health. Harmonised surveillance strategies, standardised analytical methods, improved inhalation exposure models and prolonged epidemiological studies are urgently needed to improve risk assessment and enable evidence-based air quality policy for the protection of respiratory health. Full article

The respiratory tract microbiota has been recognized as a niche with complex and diverse microbial communities, the composition and function of which in the state of health and disease have become increasingly clear. Relevant literature on respiratory tract microbiota and immune and respiratory disease published in PubMed, SpringerLink and Web of Science up to June 2026 was narratively reviewed. This review aims to elucidate the interactions between the commensal microbiota of the respiratory tract and the host immune system and reveal how these interactions evolve from homeostasis to disease pathogenesis. We also analyze how dysbiosis can promote chronic airway inflammation by changing microbial metabolites, destroying the integrity of epithelial barrier, and activating abnormal immune and inflammatory pathways, thus playing a key driving role in chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF), bronchiectasis and other diseases. Additionally, the potential and challenges of current treatment strategies based on microbiota regulation, such as herbal medicines and probiotics, in the prevention and treatment of respiratory diseases are discussed. This review provides a new perspective for revealing the etiology of respiratory diseases and lays a solid theoretical foundation for the development of microbial intervention therapy. Full article

Automated pulmonary auscultation demands rapid and reliable anomaly detection. Contemporary deep learning frameworks frequently face deployment barriers due to their reliance on memory-intensive Transformer mechanisms and high-cost processing hardware. Addressing this limitation, the present study introduces the Neuro Scatter Mamba Kolmogorov–Arnold Neural Network (NSMK-Net), a lightweight, Transformer-free architecture. The model integrates 1D Wavelet Scattering, bi-directional Selective State Space Models (Mamba), and Kolmogorov–Arnold Networks (KAN). By substituting quadratic self-attention with continuous-time differential discretization, the framework achieves very good computational efficiency under severe hardware constraints. Model optimization followed an eco-friendly “Green-AI” methodology, successfully converging on a standard 4 GB VRAM graphics unit. Regarding real-world deployment, the finalized architecture can be considered as a possible candidate for future “Edge-AI” applications, because it requires only 0.34 MB of parameter storage (89,342 parameters) and executes inference in approximately 48 milliseconds per respiratory cycle. Evaluated on the SPRSound dataset, the proposed model achieved a cycle-level accuracy of 84.67% (Macro-F1: 0.48). When tested under the strict official 60/40 partition of the ICBHI 2017 dataset, the network delivered a global accuracy of 41.56% (Macro-F1: 0.31) alongside an official reported ICBHI Score of 49.38%. These metrics indicate a stable detection capability when processing highly imbalanced clinical data. By replacing fixed activation nodes with learnable edge non-linearities and utilizing linear sequence memory, this new structural approach reduces the dependency on high-end hardware for medical acoustic processing. Full article

Sepsis-associated acute lung injury (SALI) is characterized by disruption of the alveolar–capillary barrier, uncontrolled inflammation, oxidative stress, and impaired tissue repair. Ferroptosis and cellular senescence have emerged as potentially interacting stress-response programs that may jointly shape the progression of septic lung injury. Ferroptosis promotes epithelial and endothelial damage through iron-dependent lipid peroxidation, glutathione depletion, and impaired GPX4-mediated lipid repair. In parallel, senescence-associated remodeling may contribute to persistent cell-cycle arrest, senescence-associated secretory phenotype (SASP) production, endothelial dysfunction, and defective regenerative capacity. This review summarizes current evidence on the molecular and cellular crosstalk between ferroptosis and cellular senescence in SALI. Candidate regulatory intersections include context-dependent mitochondrial dysfunction, reactive oxygen species accumulation, iron dyshomeostasis, metabolic reprogramming, lysosomal dysfunction, DNA-damage responses, and stress-responsive pathways involving p53, NRF2, ATF4, STAT3, and FOXO1. Direct SALI evidence is currently strongest for ferroptosis-induced senescence-associated remodeling in pulmonary endothelial cells, whereas senescence-associated ferroptosis resistance is supported mainly by non-pulmonary models. Likewise, SASP-mediated paracrine ferroptosis in neighboring pulmonary cells remains insufficiently validated. We therefore propose an evidence-informed, temporally and cell-type-dependent ferroptosis–senescence framework in SALI, in which acute senescence-associated responses may coexist with ferroptotic injury, whereas persistent senescence-associated remodeling may contribute to defective repair and microenvironmental injury amplification. Targeting this axis through ferroptosis inhibition, restoration of endogenous antioxidant defenses, senotherapeutic modulation, and regenerative strategies may offer stage-informed therapeutic opportunities. Further time-resolved and cell-specific studies are required to define causal relationships and clinically actionable therapeutic windows. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is closely associated with fibroblast proliferation, macrophage polarization, and the accumulation of extracellular matrix (ECM). Targeting CSF-1R can rebalance macrophages, reduce ECM deposition, and block pro-fibrotic signaling. Methods: A Fab fragment targeting CSF-1R was screened via phage display. After sequence optimization, it was constructed into an IgG1 antibody (BC006). In vitro activity, domain binding, and signaling blockade were investigated, and in vitro safety indicators were evaluated. Efficacy was assessed using an induced IPF organoid-on-a-chip and bleomycin-induced mouse model. In vivo safety evaluation was conducted in cynomolgus monkeys. Results: BC006 showed an EC₅₀ value of 226 ± 57 nM and a KD of 30 ± 2 nM. It specifically bound to the Ig4-5 domain of CSF-1R by inhibiting receptor dimerization without blocking ligand binding. It could dose-dependently inhibit the differentiation of monocytes into M2 macrophages and exert anti-IPF effects. In the induced IPF organoid-on-a-chip model, BC006 maintained lung barrier function and decreased α-SMA and Collagen I. It also improved lung function and attenuated the degree of fibrosis in the mouse model. Moreover, BC006 had no ADCC, CDC, cytokine release, or hemagglutination, and demonstrated favorable safety profiles in cynomolgus monkeys. Conclusions: BC006 is a novel anti-fibrosis antibody specifically targeting the CSF-1R Ig4-5 domain and offers a new therapeutic strategy for IPF. Full article

Mannheimia haemolytica (Mh) is a major bovine respiratory pathogen that can trigger marked inflammatory and barrier injuries. This study evaluated the protective effect of oral curcumin pretreatment in a proof-of-concept mouse model of early Mh-induced acute pulmonary injury. Mice received curcumin at 50 or 150 mg/kg/day for seven days before an intranasal Mh challenge and were evaluated 12 h after infection. Curcumin pretreatment was associated with lower lung wet-to-dry ratios, bronchoalveolar lavage fluid protein concentrations, histological injury scores, and serum pro-inflammatory cytokine levels. It was also associated with reduced abundance or phosphorylation of NF-κB/NLRP3-related proteins, increased expression of Nrf2-associated antioxidant proteins, reduced apoptosis, and preservation of the tight-junction protein ZO-1. In addition, curcumin pretreatment was associated with changes in fecal microbial composition and intestinal short-chain fatty acid profiles, including partial recovery of propionic acid. Because this study did not include a curcumin-only group, post-infection treatment, bacterial-burden measurements, pathway-perturbation experiments, or microbiota-causality experiments, the findings support prophylactic host-protective associations in an early mouse model rather than antibacterial activity, therapeutic efficacy after established infection, or causal gut–lung mechanisms. Validation in bovine models is required before veterinary application. Full article

Mucosal microbiota contribute broadly to host defense and immune homeostasis, while the lung and gut microbiota form a particularly important bidirectional ecological and immunological network that shapes pulmonary host defense, inflammatory injury, and tissue repair. In pneumonia, loss of colonization resistance and altered microbial metabolite production may weaken innate and adaptive immunity; respiratory infection, antibiotics, and critical-care exposures can, in turn, remodel both microbial communities. In acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), intestinal barrier failure, circulating microbial products, immune cell trafficking and, in selected settings, lymphatic or hematogenous dissemination of gut-derived organisms may aggravate alveolar–capillary injury. Alveolar macrophages integrate these signals through pattern-recognition, metabolic, and epigenetic pathways, linking microbial ecology to pathogen clearance and inflammatory resolution. The evidence, however, remains uneven. Mechanistic causality rests largely on animal studies, most human data are associative, and trials of microbiota-directed interventions are heterogeneous and strain-specific. This Review examines bacterial and viral pneumonia, sepsis-associated ALI and ventilator-associated injury; separates mechanistic, observational, and interventional evidence; and evaluates probiotics, live biotherapeutic products, microbial metabolites, and dietary approaches. Translation will depend on longitudinal sampling, source-resolved microbial tracking, metabolite-informed patient stratification, and adequately powered trials with clinically relevant endpoints. Full article