Search Results (1,279)

Background and Objectives: Non-invasive mechanical ventilation is the first-line treatment for managing acute respiratory failure. However, patient variability and complex pulmonary mechanics complicate therapy adjustments, frequently leading to ventilator-induced lung injuries. This study aims to propose and define a simulation platform and decision support prototype, named VENTILA2, to optimize pressure-controlled ventilation strategies. Methods: The system integrates a bicompartmental series model of the respiratory system incorporating severity-stratified physiological profiles of chronic obstructive pulmonary disease and acute respiratory distress syndrome, and it is coupled with a Mamdani fuzzy inference system. This architecture maps inspiratory time adjustments based on pressure errors and their derivatives across predefined clinical profiles within a scenario-based feedforward parameter-mapping framework. Results: Evaluated through quantitative operational verification across all profiles and proof-of-concept case studies, the platform successfully recreates complex clinical scenarios, accurately simulating phenomena such as accelerated lung emptying in severe acute respiratory distress syndrome and air trapping in moderate chronic obstructive pulmonary disease. Conclusions: VENTILA2 provides a controlled simulation environment for evaluating pathology-specific ventilatory configurations across simulated profiles prior to clinical implementation, though it remains an early-stage prototype whose clinical effectiveness, safety, and robustness remain to be rigorously evaluated. Full article

Despite decades of clinical experience, the physiological rationale for extracorporeal life support (ECLS) in acute respiratory distress syndrome (ARDS) remains incompletely defined. Existing trials have primarily evaluated ECLS as a rescue intervention, with limited attention to the physiological adaptations required to sustain extracorporeal gas exchange. We propose that the maternal–fetal circulation, the only naturally occurring example of prolonged extracorporeal gas exchange, provides a hypothesis-generating physiological analogy. In this paradigm, gas exchange is externalized through a low-resistance, high-flow circuit while systemic physiology reorganizes to unload the native lung. Translating this concept to severe ARDS suggests that ECLS should be viewed not simply as an adjunct to conventional support, but as a transition to an alternative physiological state centered on extracorporeal gas exchange. This perspective may inform physiology-based patient selection, management strategies, and the design of future clinical trials. Full article

Background: Seasonal influenza is typically a self-limiting illness in healthy young adults, but severe and potentially life-threatening complications can occur. Influenza A infection may predispose patients to secondary bacterial infections, including Staphylococcus aureus pneumonia and bacteremia, which can rapidly progress to necrotizing pneumonia, acute respiratory distress syndrome (ARDS), and cardiovascular dysfunction. Case Presentation: We report the case of a young adult with influenza A(H3) infection complicated by Staphylococcus aureus bacteremia, necrotizing pneumonia, ARDS, and biventricular dysfunction. The patient experienced rapid cardiopulmonary deterioration requiring advanced critical care support, including extracorporeal membrane oxygenation (ECMO) and left ventricular unloading. Serial point-of-care ultrasound (POCUS) was central to clinical management, enabling early recognition of worsening respiratory and cardiac function and guiding timely escalation of supportive strategies. Conclusions: This case highlights the potential severity of influenza-associated complications even in young and previously healthy individuals. Repeated POCUS assessment can play a pivotal role in detecting rapid cardiopulmonary deterioration and guiding advanced interventions. Efficient hub-and-spoke organization may further support timely referral and management of critically ill patients requiring ECMO and specialized care. 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

Acute respiratory distress syndrome (ARDS) represents a major cause of morbidity and mortality in critically ill patients and is most frequently triggered by severe respiratory infections, including nosocomial pneumonia. Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are highly prevalent in intensive care units and share overlapping pathophysiological mechanisms with ARDS. Despite this close interrelationship, the proportion of patients with nosocomial pneumonia who subsequently develop ARDS remains poorly defined, underscoring the need to identify potential predisposing factors and improve early recognition of patients at risk. While the development of pneumonia in patients with an established diagnosis of ARDS has been extensively investigated, limited data are available on patients who develop ARDS as a complication of HAP/VAP. This narrative review summarizes the limited direct evidence on this topic and discusses potential clinical characteristics, risk factors, and predictive tools, while considering indirect evidence from CAP and broader ARDS populations. Full article

Background/Objectives: Mechanical power (MP) quantifies the energy delivered to the respiratory system during ventilation and serves as a promising marker for ventilator-induced lung injury (VILI). According to its original definition by Gattinoni, MP reflects the energy transferred from the ventilator to the respiratory system under conditions of deep sedation, passive breathing, neuromuscular blockade, and volume-controlled ventilation. Its role in coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome (ARDS) remains under investigation. This systematic review aimed to synthesize the available evidence on the association between MP and VILI, complications related to mechanical ventilation (MV), and mortality in adult patients with COVID-19 undergoing invasive mechanical ventilation (IMV). Methods: A systematic review was conducted using PubMed-MEDLINE (Medical Literature Analysis and Retrieval System Online) for studies published in recent years, focusing on adult COVID-19 patients undergoing IMV. Inclusion criteria centered on studies reporting MP and its association with VILI, complications, or mortality. Ten studies met eligibility criteria after screening 356 retrieved articles. Results: Most included studies were retrospective and observational, encompassing critically ill COVID-19 patients. Elevated MP was correlated with more severe outcomes, including increased 28-day mortality, prolonged MV, and weaning failure. Franck et al. demonstrated strong correlations between MP and driving pressure, elastance, and positive end-expiratory pressure, emphasizing the importance of calculation methods. González-Castro et al. identified a threshold of 17 J/min, above which mortality risk increased. Stalla et al. highlighted that dynamic MP reductions during prone positioning were associated with survival. Registry-based analyses confirmed that both magnitude and cumulative exposure above 18 J/min increased intensive care unit mortality. Novel indices combining MP with oxygenation parameters improved prognostic accuracy. While absolute MP at initiation provided limited predictive value, temporal trends and individual components were strongly linked to VILI. Conclusions: Higher MP has been associated with adverse clinical outcomes in patients with COVID-19 receiving invasive mechanical ventilation, supporting its potential role as a prognostic indicator. Its dynamic assessment, thresholds, and integration with ventilatory strategies such as prone positioning enhance risk stratification and may guide individualized, lung-protective ventilation. Continuous monitoring and standardized calculation are recommended to optimize clinical decision-making. Full article

Background: Acute respiratory distress syndrome (ARDS) occurs in 20–40% of patients following esophagectomy and is associated with substantial postoperative morbidity and mortality. A major contributor to postoperative ARDS is pulmonary ischemia–reperfusion injury (IRI); however, the role of IRI in ARDS following esophagectomy is not adequately addressed in current experimental models. In this study, we established a large animal model of pulmonary IRI that reproduces key physiological, inflammatory, and histopathological features of pulmonary ischemia–reperfusion-induced acute lung injury relevant to postoperative ARDS after esophagectomy. Methods: Sequential pulmonary ischemia–reperfusion injury was induced in ten anesthetized Landrace pigs using unilateral hilar inflow occlusion. Right lung ischemia was achieved by clamping the hilar inflow for three hours, followed by reperfusion. Subsequently, the left lung underwent two hours of ischemia. Hemodynamic, respiratory, and inflammatory parameters were continuously monitored throughout the experiment. Blood samples were collected to assess leukocyte counts and circulating inflammatory cytokines, including tumor necrosis factor-α and interleukin-6. Lung tissue samples were obtained for histopathological evaluation. Results: ARDS-like lung injury was successfully induced in all animals, with PaO₂/FiO₂ ratios falling below 200 mmHg during the predefined reperfusion observation period. Lung compliance decreased by approximately 50% after ischemia and further declined following reperfusion. Progressive leukocyte elevation and elevated tumor necrosis factor-α and interleukin-6 levels were observed, indicating a systemic inflammatory response. Hallmark features of ARDS were histologically confirmed, including intra-alveolar hemorrhage, interstitial and perivascular edema, and neutrophil infiltration. Conclusions: This porcine model reproduces key physiological, inflammatory, and histopathological features consistent with pulmonary ischemia–reperfusion-induced ARDS-like lung injury. Although it does not reproduce the complete clinical syndrome of post-esophagectomy ARDS, it provides a clinically relevant translational platform for investigating pulmonary ischemia–reperfusion injury and evaluating potential preventive and therapeutic strategies. Full article

Background: Legionella pneumophila is a rare but severe cause of community-acquired pneumonia and can lead to acute respiratory distress syndrome (ARDS). Awake prone positioning (APP) has been recognized as an effective adjunct for non-intubated patients with hypoxemic respiratory failure, primarily studied in coronavirus disease 2019 (COVID-19) and other ARDS etiologies. Its application in Legionella-associated ARDS remains poorly documented. Therefore, in this work, we present a case of Legionella-associated ARDS successfully managed with APP, high-flow nasal cannula (HFNC), non-invasive ventilation (NIV), levofloxacin, and corticosteroids. Case presentation: A 62-year-old male with multiple comorbidities, including type 2 diabetes mellitus (T2DM) and a history of coronary artery bypass surgery, presented with a 3-day history of productive cough, exertional dyspnea, and general malaise. Oxygen saturation on admission was 90%, with fever and tachycardia. Inflammatory markers were markedly elevated. Chest computed tomography (CT) revealed extensive bilateral pulmonary infiltrates. Despite a negative urinary Legionella antigen test, sputum polymerase chain reaction (PCR) confirmed Legionella pneumophila on day 2. A Horowitz index of 147 mmHg on day 2 established moderate ARDS. The patient was treated with HFNC oxygen therapy, NIV, and APP for up to 12 h daily. Antibiotic therapy was initiated with amoxicillin/clavulanic acid and clarithromycin, subsequently streamlined to levofloxacin upon microbiological confirmation. Methylprednisolone 40 mg/day was administered for 8 days as adjunctive ARDS therapy. The patient demonstrated gradual clinical and respiratory improvement without requiring endotracheal intubation. Follow-up chest CT on day 7 showed regression of bilateral consolidations and ground-glass opacities (GGOs). The patient was transferred to pulmonary rehabilitation on day 11 and completed antibiotic therapy as an outpatient. Conclusions: This case illustrates the successful use of APP combined with HFNC and NIV alongside standard medical therapies, including appropriate antibiotics and corticosteroids, to avoid intubation in moderate ARDS secondary to Legionella pneumonia. Early initiation of APP may be a valuable strategy in Legionella-associated ARDS in carefully selected patients. Full article

Early detection of acute lung injury (ALI) remains challenging, as conventional diagnostics rarely capture initial molecular changes. We therefore examined whether extracellular vesicles (EVs) in bronchoalveolar lavage fluid (BALF) can detect early regional injury and distinguish initial stress mechanisms in a porcine ALI model. Unilateral ALI was induced using Triton X-100, followed by six hours of mechanical ventilation with either fixed positive end-expiratory pressure (PEEP) at 5 cmH₂O or transpulmonary-pressure (TPP)-guided PEEP. Spatially separated BALF sampling allowed direct comparison between injured and contralateral mechanically stressed lungs. EV concentration and size distribution were quantified by nano-flow cytometry, while vesicular identity was confirmed by transmission electron microscopy and tetraspanin dot blot analyses. Furthermore, EV metrics were related to corresponding histologic injury scores. Across both PEEP strategies, EV concentration was markedly higher in both directly injured and contralateral mechanically stressed lungs compared with sham controls, indicating alveolar stress beyond the primary injury site. Median EV size differed significantly by injury type and correlated inversely with histologic injury, particularly with alveolar neutrophil infiltration. BALF-derived EV concentration and size may therefore provide complementary, spatially resolved molecular readouts of early ALI. 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

Enolase-1 (ENO-1) is classically known as a highly conserved glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate in the final steps of glycolysis. This enzyme, however, is being increasingly implicated as a multifunctional moonlighting protein with compartment-specific roles in inflammation. Within the cytosol, ENO-1 regulates macrophage inflammation during sepsis; on the cell surface, it functions as a plasminogen receptor, and extracellularly, it can participate in innate immune signaling. Across innate and adaptive immunity, ENO-1 has been implicated in macrophage activation, neutrophil recruitment, endothelial cell dysfunction, fibroblast remodeling, and autoantigenicity. These functions have been linked to sepsis, acute respiratory distress syndrome, acute organ injury, hemorrhagic shock, rheumatoid arthritis, and cancer-associated inflammation in the tumor microenvironment. Therapeutic targeting of ENO-1 includes small-molecule inhibitors and monoclonal antibodies. ENO-1, with its compartment-specific functions in disease pathogenesis, serves as a significant therapeutic target for inflammatory diseases. In this review, we discuss the novel compartment-specific roles of ENO-1 in inflammatory diseases, defining its functions beyond its role in glycolysis. We conclude that both the metabolic and moonlighting functions of ENO-1 contribute to inflammation, and future studies should delineate its compartment-specific roles in inflammatory pathophysiology, as compartment-specific targeting may represent the future of ENO-1-directed therapy. Full article

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

Efforts to liberate patients from invasive mechanical ventilation (MV) begin when the underlying cause of acute hypoxemic respiratory failure (AHRF) or adult respiratory distress syndrome (ARDS) that led to use of invasive ventilation has resolved or improved and patients can initiate spontaneous breaths. In preparation for liberation, clinicians transition patients to spontaneous modes of ventilation as soon as possible while ensuring that patients’ respiratory effort is not insufficient or excessive during weaning attempts. Concurrently, clinicians aim to minimize the effects of sedative and analgesic agents, screen daily to identify patients who are ready to undergo a spontaneous breathing trial (SBT), and conduct SBTs to help assess patients’ readiness for extubation. Extubation failure is rarely the consequence of a single physiological abnormality. Rather, it reflects the interaction of multiple mechanisms that often coexist, including an imbalance between respiratory system load and capacity, ineffective cough, and secretion burden among others. For these reasons, single weaning parameters and SBTs may fail to identify some patients who are at risk for extubation failure. Conversely, indices and scores that combine two or more parameters and newer techniques may provide mechanistic insights into the pathways that lead to extubation failure, help to characterize ‘at-risk’ phenotypes, and identify patients who may benefit from closer monitoring, targeted therapeutic strategies, and/or early application of noninvasive respiratory support strategies such as high-flow nasal cannula (HFNC) and bilevel noninvasive positive pressure ventilation (NIV). Full article

Respiratory diseases impose a substantial global burden; however, early diagnosis, disease-activity monitoring, and the clinical translation of nucleic acid therapeutics are constrained by the lack of robust biomarkers and efficient delivery systems. This narrative review focuses on four classes of RNA—messenger RNA (mRNA), circular RNA (circRNA), small interfering RNA (siRNA), and microRNA (miRNA)—using exosomes as a representative subtype of extracellular vesicles (EVs) to discuss EV biogenesis, transport, uptake, and engineered cargo loading. We summarize the diagnostic and therapeutic applications of EV-associated nucleic acids in chronic or non-severe respiratory diseases, including asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cystic fibrosis, as well as in severe acute conditions such as acute respiratory distress syndrome and severe pneumonia. Biofluid-derived EV-associated RNAs can reflect inflammation, immune dysregulation, epithelial injury, infection, and fibrosis, supporting their potential use in disease classification, monitoring, and prognostic assessment. Natural EVs may modulate inflammation and tissue repair through their endogenous cargo, while engineered EVs can deliver therapeutic nucleic acids to exert anti-inflammatory, anti-infective, antifibrotic, and barrier-restorative effects. However, clinical translation is limited by non-standardized isolation and characterization methods, product heterogeneity, variable cargo loading, and insufficient stability and quality-control frameworks. Continued advances in EV isolation, characterization, nucleic acid loading, potency assessment, and manufacturing control are required to realize the diagnostic and therapeutic potential of EV-associated nucleic acids in respiratory diseases. 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