Acute respiratory distress syndrome (ARDS) is a critical condition characterized by acute hypoxemia, non-cardiogenic pulmonary edema, and decreased lung compliance. The Berlin definition, updated in 2012, classifies ARDS severity based on the partial pressure of arterial oxygen/fractional inspired oxygen fraction ratio. Despite various treatment strategies, ARDS remains a significant public health concern with high mortality rates.

To evaluate the implications of driving pressure (DP) in ARDS management and its potential as a protective lung strategy.

We conducted a systematic review using databases including EbscoHost, MEDLINE, CINAHL, PubMed, and Google Scholar. The search was limited to articles published between January 2015 and September 2024. Twenty-three peer-reviewed articles were selected based on inclusion criteria focusing on adult ARDS patients undergoing mechanical ventilation and DP strategies. The literature review was conducted and reported according to PRISMA 2020 guidelines.

DP, the difference between plateau pressure and positive end-expiratory pressure, is crucial in ARDS management. Studies indicate that lower DP levels are significantly associated with improved survival rates in ARDS patients. DP is a better predictor of mortality than tidal volume or positive end-expiratory pressure alone. Adjusting DP by optimizing lung compliance and minimizing overdistension and collapse can reduce ventilator-induced lung injury.

DP is a valuable parameter in ARDS management, offering a more precise measure of lung stress and strain than traditional metrics. Implementing DP as a threshold for safety can enhance protective ventilation strategies, potentially reducing mortality in ARDS patients. Further research is needed to refine DP measurement techniques and validate its clinical application in diverse patient populations.

Sepsis-induced acute lung injury (ALI) is a critical condition characterized by excessive inflammation, with macrophage polarization playing a pivotal role in its pathogenesis. In this study, we constructed myeloid-specific Notch1 knockout mice, overexpressed the Notch intracellular domain (NICD), and inhibited β-catenin using XAV939 to investigate the impact and mechanisms of Notch1 regulation in macrophage polarization and inflammatory responses in cecal ligation and puncture (CLP)-induced septic mice. The results demonstrated that Notch1 knockout significantly reduced M1 macrophage polarization, alleviated systemic inflammation, mitigated lung injury, and improved survival in septic mice. In sepsis, Notch1 enhances β-catenin expression, which synergizes with the NF-κB pathway to promote M1 polarization and pro-inflammatory cytokine production. Specifically, NICD interacts with β-catenin in macrophages, amplifying NF-κB activation and its nuclear translocation. These results demonstrate that the Notch1 signaling pathway plays a pivotal role in regulating macrophage phenotypic switching, highlighting its potential as a therapeutic target for attenuating sepsis-associated ALI through immune homeostasis restoration.

Pulmonary endothelial barrier dysfunction is a hallmark of sepsis-induced acute lung injury (ALI). Ophiopogonin D (OP-D), isolated from the roots of Ophiopogon japonicus, is involved in regulating inflammation, apoptosis and intestinal permeability. However, the role of OP-D in ALI has not been reported and the related mechanisms remain unclear. In this study, cecal ligation and puncture (CLP) was used to establish a septic ALI model in mice. We found that OP-D effectively alleviated lung pathological damage. Moreover, OP-D decreased pulmonary microvascular permeability, restrained the inflammatory response and apoptosis in murine lung tissues and LPS-exposed PMVECs. Specifically, OP-D exerted the beneficial effects via mediating the inactivation of HIF-1α-VEGF pathway, which was partly abrogated by the overexpression of HIF-1α. Collectively, our findings showed that OP-D protected against sepsis-induced ALI through improving pulmonary microvascular endothelial barrier dysfunction via suppressing HIF-1α-VEGF pathway.

A challenge that limits our understanding of the underlying pathobiology of pediatric acute respiratory distress syndrome (PARDS) is the lack of a preclinical airway model that can be leveraged for the study of mechanisms and specific molecules for drug testing. We developed a physiologic model system of the small airways for mechanistic application in PARDS using a co-culture of primary human-derived small airway epithelial cells (SAECs) cultured at the air-liquid interface and umbilical vein endothelial cells in a transwell system. The model was validated by exposing the SAECs to a rhinovirus infection, to an inflammatory lung insult using a mixture of cytokines found in ARDS (cytomix), and to airway fluid samples from children with different severity strata of PARDS. We used a combination of transepithelial electrical resistance, immunofluorescence confocal microscopy of tight junctions, targeted gene expression, and cytokine responses to evaluate the model to the aforementioned insults. We then use the model in drug testing and show the reduction in IL-6 expression in conditioned media and STAT3 phosphorylation following co-treatment of SAECs with cytomix and the Janus kinase inhibitor (JAKi) baricitinib. This model enables mechanistic studies of airway pathobiology and may serve as a novel drug testing platform for PARDS.

This proof-of-concept study aimed to assess the optimal timing, dosing, and duration of vitamin C administration to increase survival and attenuate organ injuries in murine sepsis. Mice were randomized to receive ascorbic acid (AscA) at 1 or 6 h after cecal ligation and puncture (CLP). At each time point, mice randomly received AscA for 4 or 8 d. Mice were assigned to sham and CLP groups, as well as CLP + AscA groups that were treated with AscA at doses of 90, 180, or 360 mg/kg/d. The survival curves diverged significantly when AscA was injected at doses of 180 or 360 mg/kg/d for 8 d, although this was not observed when the treatment was limited to 4 d. AscA at doses of 180 or 360 mg/kg/d for 8 d preserved lung architecture while attenuating the abnormal expression of tight junction proteins. Kidney and liver injuries were evident in CLP mice, with elevated expression of biomarkers and inflammatory mediators; however, exposure to AscA at doses of 180 or 360 mg/kg/d for 8 d improved the histological changes and decreased biomarker expression levels. Very high-dose and prolonged vitamin C administration may potentially play a role in the management of sepsis-associated organ injuries.

Recent studies have focused on understand lung repair mechanisms, which are critical for treating respiratory diseases. In this study, we develop alveolar organoids to investigate the complex interactions between alveolar epithelial cells, niche fibroblasts and macrophages, which are essential for lung development, maintenance and repair, especially under physiological injury. Our results suggest that alveolar organoids may be a model for epithelial cell regeneration and the inflammatory response in lung tissue. Alveolar organoid studies can also serve as models for various lung injuries and demonstrate mechanisms in the injured human lung.

Systemic volume changes during acute lung injury (ALI) are closely related to lung injury severity, disease progression, and treatment methods. Twenty-one goats were divided into control, mild injury, and severe injury groups via oleic acid injection. Carotid ultrasound measured carotid diameter and corrected flow time (FTc), while cardiac ultrasound assessed aortic and pulmonary artery velocity-time integral (VTI). Post-euthanasia at 6 h, lung wet-to-dry (W/D) ratio and pathological scores were analyzed. Statistical trends, correlations between ultrasound parameters and lung injury markers, and diagnostic performance via ROC analysis were evaluated. The severe injury group had significantly higher lung W/D ratios and pathological scores than the mild injury group. Carotid ultrasound showed a progressive decrease in carotid diameter and FTc post-injury, with FTc significantly lower in the severe injury group at 6-h. FTc was negatively correlated with lung W/D ratio and pathological scores. Cardiac ultrasound indicated a decreasing trend in aortic and pulmonary artery VTI post-injury, with pulmonary artery VTI significantly lower in the severe injury group at all times and negatively correlated with lung W/D ratio and pathological scores. ROC analysis showed that pulmonary artery VTI had the highest area under the curve (AUC), with values greater than 0.8 at all time points. The combined use of pulmonary artery VTI and carotid FTc had AUC values greater than 0.85 at all time points, peaking at 6-h (AUC = 0.951). In conclusion, pulmonary artery VTI is an excellent indicator for evaluating ALI severity post-injury, and the combination of pulmonary artery VTI and carotid FTc shows strong diagnostic performance for assessing ALI severity.

The human respiratory system is vulnerable to viral infections. The influenza virus family alone accounts for one billion reported cases annually, some of which are severe and can be fatal. Among these, Influenza A viruses (IAVs) cause the most severe symptoms and course of disease. IAV has been a major health concern, especially since the emergence of the potentially pandemic avian H5N1 strain. However, despite the knowledge that IAVs recognize terminally attached sialic acids on the host cell surface for cell entry, the involvement of other glycans during early infection remains to be elucidated. In particular, the involvement of the alveolar epithelial glycocalyx as a last line of defense is often overlooked. Studying early infection of any virus in real time remains a challenge due to the currently available model systems and imaging techniques. Therefore, we extensively compare the use of different 3D cell systems and provide an overview of currently available scaffold-based and scaffold-free air-liquid interface (ALI) models. In addition, we discuss in detail the preferred use of a recently developed 3D organ tissue equivalent (OTE) model incorporating solubilized extracellular matrix components (sECM) to study viral interaction with glycosaminoglycans (GAGs) during the early stages of IAV infection. We further discuss and recommend the use of various synthetic virus models over IAV virions to reduce complexity by focusing only on surface protein interactions while simultaneously lowering the required biosafety levels, including, but not limited to virus-like particles (VLPs) or DNA origami. Finally, we delve into potential labeling strategies for IAV or IAV-like particles by reviewing internal and external labeling strategies with quantum dots (QDs) and potential GAG labeling, combined with a recommendation to combine high spatial resolution imaging techniques with high temporal resolution tracking, such as single virus tracking.

This study was to investigate the association between oral anticoagulant use and 28-day mortality and in-hospital mortality in patients with acute respiratory distress syndrome (ARDS).

A total of 1754 ARDS patients were identified in database from 2008 to 2022 in this cohort study. Univariable and multivariable cox regression models were applied to assess the associations of oral anticoagulant use with the risk of 28-day mortality and in-hospital mortality. Propensity score matching (PSM) was performed in ARDS patients according to whether they were taking oral anticoagulants or not to control potential bias. Subgroup analysis was performed according to severity of ARDS (mild, moderate, and severe), and comorbidities (atrial fibrillation, sepsis, and AKI). Hazards ratio (HR) and respective confidence interval (CI) were presented.

In total, 7758 patients not receiving oral anticoagulant and 905 patients receiving oral anticoagulant. The reduced risk of 28-day mortality in ARDS patients was identified in those undergoing oral anticoagulant use (HR = 0.32, 95%CI: 0.24-0.44). Oral anticoagulant use was associated with reduced risk of in-hospital mortality (HR = 0.27, 95%CI: 0.20-0.37). After adjusting for the respective confounding factors, the associations of Warfarin with decreased risk of 28-day and in-hospital mortality were not significant (P > 0.05).

Oral anticoagulant was related to decreased risk of 28-day/in-hospital mortality in patients with ARDS. Warfarin and novel oral anticoagulants showed no significant difference on 28-day/in-hospital mortality in patients with ARDS.

Lung ultrasound (LUS) has emerged as a valuable bedside decision-making tool, particularly since the COVID-19 pandemic, with applications in diagnosing pneumonia, managing fluid, and monitoring interstitial lung diseases (ILDs) and acute respiratory distress syndrome (ARDS), ultimately improving patient outcomes. Its repeatability, environmental safety, and reduced radiation exposure make it ideal for vulnerable populations and resource-limited settings. However, challenges such as inadequate documentation and a lack of standardized reporting formats limit its widespread adoption. The evolution of technology offers different possibilities, and improvements in software open up a range of possibilities, but this contrasts with the lack of postgraduate and undergraduate training and formal accreditation. This review addresses the impact of lung ultrasound through the course of air-liquid ratio impairment, crossing different clinical scenarios and exploring the challenges and opportunities for the implementation of lung ultrasound in the post-COVID era.

Cell-free hemoglobin (CFH) is released into the circulation during sepsis where it can redox cycle from the ferrous 2+ to ferric 3+ and disrupt endothelial function, but the mechanisms of CF-mediated endothelial dysfunction are unknown. We hypothesized that oxidized CFH induces mitochondrial dysfunction via the mitochondrial permeability transition pore (mPTP) in pulmonary endothelial cells, leading to the release of mitochondrial DNA (mtDNA).

Human lung microvascular endothelial cells were treated with CFH2+/CFH3+. We measured mitochondrial mPTP activation (flow cytometry), network and mass (immunostaining), structure (electron microscopy), mtDNA release (PCR), and oxygen consumption rate (OCR; Seahorse). Plasma from critically ill patients and conditioned cell media were quantified for mtDNA and CFH.

CFH3+ disrupted the mitochondrial network, activated the mPTP (1434 (874-1642) vs. 2302 (1729-2654) mean fluorescent intensity, p = 0.02), increased the spare respiratory capacity (30.61 (29.36-37.78) vs. 7.83 (3.715-10.63) OCR, p = 0.004), and caused the release of mtDNA. CFH was associated with circulating mtDNA (R2 = 0.1912, p = 0.0077) in plasma from critically ill patients.

CFH3+, not CFH2+, is the primary driver of CFH-induced lung microvascular mitochondrial dysfunction. Activation of the mPTP and the release of mtDNA are a feature of CFH3+ mediated injury.

Drug-induced acute lung injury is a significant yet often underrecognized clinical challenge, associated with a wide range of therapeutic agents, including chemotherapy drugs, antibiotics, anti-inflammatory drugs, and immunotherapies. This comprehensive review examines the pathophysiology, clinical manifestations, and radiologic findings of drug-induced acute lung injury across different drug categories. Common imaging findings are highlighted to aid radiologists and clinicians in early recognition and diagnosis. The review emphasizes the importance of immediate cessation of the offending drug and supportive care, which may include corticosteroids. Understanding these patterns is crucial for prompt diagnosis and management, potentially improving patient outcomes.

The NAIP/NLRC4 inflammasome plays a pivotal role in the defense against bacterial infections, with its in vivo physiological function primarily recognized as driving inflammation in immune cells. Acute lung injury (ALI) is a leading cause of mortality in sepsis. In this study, we identify that the NAIP/NLRC4 inflammasome is highly expressed in both macrophages and pulmonary fibroblasts and that pyroptosis of these cells plays a critical role in lung injury. Mice challenged with gram-negative bacteria or flagellin developed lethal lung injury, characterized by reduced blood oxygen saturation, disrupted lung barrier function, and escalated inflammation. Flagellin-induced lung injury was protected in caspase-1 or GSDMD-deficient mice. These findings enhance our understanding of the NAIP/NLRC4 inflammasome's (patho)physiological function and highlight the significant role of inflammasome activation and pyroptosis in ALI during sepsis.

Acetaminophen (APAP) is widely used in the treatment of patients after surgery, but the prognosis of patients with coronary artery bypass grafting (CABG)-related acute respiratory distress syndrome (CABG-ARDS) is still unclear. This study aims to explore the role of APAP in the management of CABG related ARDS.

We collected clinical data on patients with CABG-ARDS from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The primary outcome was early mortality after ARDS, and the secondary outcomes were length of hospital stay and duration of mechanical ventilation (MV). Multivariate logistic regression and Cox regression models were used for statistical analysis, and inverse probability processing weighting (IPTW), overlap weighting (OW) and propensity score matching (PSM) were used to explore the robustness of the outcomes.

A total of 5459 patients were enrolled in the analysis. Multivariate logistic regression analysis revealed that the 14-day mortality in APAP group was significantly lower than that in non-APAP group (0.5% vs. 2.7%, OR = 0.301; 95% CI, 0.170-0.531; P < 0.001). The APAP group also showed a significant advantage in Cox regression analysis (0.5% vs. 2.7%, HR = 0.329; 95% CI, 0.187-0.577; P < 0.001). IPTW, OW, and PSM analyses were conducted between the two groups, and the differences remained significant. These results were consistent in 30-, 60-, and 90-day mortality analyses. Meanwhile, exposure to APAP was associated with a shorter length of hospital stay and a reduced duration of MV (P < 0.001).

The administration of APAP was associated with reduced early mortality in patients with CABG-ARDS, as well as shorter length of hospital stay and duration of MV.

Acute respiratory distress syndrome (ARDS) continues to pose significant difficulties due to the scarcity of successful preventative and therapeutic measures. Recent clinical trials and experimental research have confirmed the lung-protective and anti-inflammatory properties of dexmedetomidine. The objective of this study was to examine the relationship between the use of dexmedetomidine and mortality outcomes in ICU patients with ARDS.

This study retrospectively examined data from the Medical Information Mart for Intensive Care (MIMIC) IV, focusing on individuals diagnosed with ARDS. The primary endpoint was the occurrence of death within 28 days after entering the ICU. To ensure a balanced cohort, we applied propensity score matching at a 1:1 ratio. Additionally, multivariable analysis was performed to mitigate the effects of confounding factors.

In this study, a cohort comprising 612 patients diagnosed with ARDS was investigated. Analysis using both univariate and multivariate Cox regression indicated significantly reduced 28-day and 90-day mortality rates in patients administered dexmedetomidine compared to those who were not given this treatment. Following adjustments for potential confounders using propensity score matching, these results were confirmed to be robust.

The results indicate an association between the administration of dexmedetomidine and lower mortality rates among severely ill ARDS patients. However, this result should be interpreted with cause because of a lot of missing data of potential risk factors for clinical outcomes. Nonetheless, it is imperative to perform further randomized controlled trials to corroborate this finding.

To investigate the effect of Lipopolysaccharide (LPS)-induced acute lung injury (ALI) on the pulmonary pharmacokinetics (PK) of a systemically administered antibody in mice.

The PK of a non-target-binding antibody was evaluated in healthy mice and mice with intratracheal instillation of 5 mg/kg LPS. The plasma, bronchoalveolar lavage (BAL), trachea, bronchi, and lung homogenate PK of the antibody were measured following intravenous administration of 5 mg/kg antibody dose. Noncompartmental analysis was performed to determine AUC values. Antibody concentrations in all biological matrices were quantified using qualified ELISA. The effect of ALI on BAL albumin and total protein concentrations was also determined. BAL protein concentrations were corrected for dilution using plasma urea concentrations.

Intratracheal instillation of LPS and the resultant ALI led to ~2-4-fold higher concentrations of albumin and proteins in the BAL. LPS-induced ALI also notably altered the pulmonary PK of the antibody. The effect of ALI on the antibody PK was time and tissue dependent. The trachea and bronchi showed ~1.7-fold and ~1.4-fold lower antibody exposure compared with the control group, but the BAL fluid exhibited ~4-fold increase in antibody exposure following LPS treatment. Most noticeable changes in antibody PK occurred 24 h after LPS administration, and the effect was temporary for the bronchi and trachea. However, the changes in lung homogenate and, more notably, in BAL persisted until the end of the experiment. Thus, our investigation suggests that due to the acute nature of ALI-induced pathophysiology and the changing severity of the disease, the dose and timing of antibody administration following ALI may need to be optimized based on the target site of action (e.g., bronchi, trachea, BAL, lung parenchyma, etc.) to maximize the therapeutic effect of the antibody.

ALI may significantly affect pulmonary PK of systemically administered antibodies. Changes caused by ALI are time and tissue dependent, and hence, the timing and dose of antibody following ALI may need to be optimized to maximize the therapeutic effect of the antibody at the site of action.

The air-blood barrier protects the lung from blood/serum entering the air spaces, i.e., from "drowning in your own fluids". Failure leads to pulmonary edema, a regularly fatal complication during the Covid-19 pandemic which claimed 7 million lives worldwide. Finding no mathematical models for the underlying fluid mechanics, we created the first. Governing flow equations for alveolar capillary, interstitium, and alveolus are coupled by crossflows at the capillary and epithelial membranes and end-exit flows to the lymphatics. Case examples include normal/recovery, cardiogenic pulmonary edema, acute respiratory distress syndrome, effects of positive end expiratory pressure, and a wide range of parameter values for permeability of the membranes and interstitial matrix. Previously unknown membrane fluid shear stresses calculate to values that affect cell function in many systems. We add active epithelial reabsorption which has two effects: shifting streamlines to favor alveolar-lymphatic clearance and adding to the direct alveolar-capillary clearance. Simple algebraic equations are derived for the interstitial fluid pressure, pi, membrane crossflow velocities and the critical capillary pressure, pcrit, above which edema occurs. For validation, the pcrit predictions fit clinical definitions and flow calculations of lymphatic vs capillary clearance match animal experimental data. For decades the value of pi has been imposed as an input, whereas we calculate the value as an output. They don't agree. Since the space is too small for measurements, the ability to calculate pi and pcrit offers new insights, questions long-held beliefs, and opens applications from physiological studies to personalized clinical care.

Impaired alveolar fluid clearance (AFC) is an important cause of alveolar edema fluid accumulation in patients with acute respiratory distress syndrome (ARDS). Alveolar edema leads to insufficient gas exchange and worse clinical outcomes. Thus, it is important to understand the pathophysiology of impaired AFC in order to develop new therapies for ARDS. Over the last few decades, multiple experimental studies have been done to understand the molecular, cellular, and physiological mechanisms that regulate AFC in the normal and the injured lung. This review provides a review of AFC in the normal lung, focuses on the mechanisms of impaired AFC, and then outlines the regulation of AFC. Finally, we summarize ongoing challenges and possible future research that may offer promising therapies for ARDS.

Acute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Here, we use a combination of gnotobiotic mice, cell culture experiments, and re-analyses of a large metabolomics dataset from ARDS patients to reveal that gut bacteria impact lung cellular respiration by releasing metabolites that alter mitochondrial activity in lung epithelium. Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species, Bifidobacterium adolescentis, was sufficient to replicate this effect, leading to a significant increase in mitochondrial membrane potential in lung epithelial cells. We then used genome sequencing and mass spectrometry to confirm that B. adolescentis produces L -lactate, which was sufficient to increase mitochondrial activity in lung epithelial cells. Finally, we found that serum lactate was significantly associated with disease severity in patients with ARDS from the Early Assessment of Renal and Lung Injury (EARLI) cohort. Together, these results emphasize the importance of more broadly characterizing the microbial etiology of ARDS and other lung diseases given the ability of gut bacterial metabolites to remotely control lung cellular respiration. Our discovery of a single bacteria-metabolite pair provides a proof-of-concept for systematically testing other microbial metabolites and a mechanistic biomarker that could be pursued in future clinical studies. Furthermore, our work adds to the growing literature linking the microbiome to mitochondrial function, raising intriguing questions as to the bidirectional communication between our endo- and ecto-symbionts.

N-acetylcysteine (NAC) can take part in the treatment of chronic respiratory diseases because of the potent mucolytic, antioxidant, and anti-inflammatory effects of NAC. However, less is known about its use in the treatment of acute lung injury. Nowadays, an increasing number of studies indicates that early administration of NAC may reduce markers of oxidative stress and alleviate inflammation in animal models of acute lung injury (ALI) and in patients suffering from distinct forms of acute respiratory distress syndrome (ARDS) or pulmonary infections including community-acquired pneumonia or Coronavirus Disease (COVID)-19. Besides low costs, easy accessibility, low toxicity, and rare side effects, NAC can also be combined with other drugs. This article provides a review of knowledge on the mechanisms of inflammation and oxidative stress in various forms of ALI/ARDS and critically discusses experience with the use of NAC in these disorders. For preparing the review, articles published in the English language from the PubMed database were used.

Objectives: There is a scarcity of pharmacological treatments that efficiently address lung injury in individuals experiencing acute respiratory distress syndrome (ARDS). Early inhaled corticosteroids and ipratropium may reduce pulmonary inflammation and injury of the lungs, minimizing the risk of ARDS. Method: This is a double-blinded randomized control trial conducted on patients at risk of ARDS. Patients were randomly allocated into two groups; the intervention group (63 patients) were administered aerosolized budesonide and ipratropium bromide, and the control group (56) were administered a placebo every eight hours for five days. Alteration in oxygen saturation divided by inspired oxygen (Fio2) (S/F) after five days was the primary outcome. Secondary outcomes included ARDS occurrence, mechanical ventilation (MV) requirement, hospital stay duration, and mortality rates. Results: Of the 604 screened, only 119 patients were included. The intervention group (63 patients) S/F ratio recovered versus the fall of the control group. Both groups had similar organ dysfunction and 28-day mortality. The intervention group had significantly (p < 0.001) fewer cases developing ARDS (9.5%) and MV (9.5%) than the control group (46.4% and 35.7%, respectively). Conclusions: The administration of inhaled budesonide and ipratropium bromide improved oxygenation, as assessed by the S/F ratio, and significantly reduced the rate of ARDS development and the requirement of MV versus the control group. Larger multi-center trials including diverse patient populations are needed to validate these results.

In recent years, the incidence of acute respiratory distress syndrome (ARDS) has been gradually increasing. Despite advances in supportive care, ARDS remains a significant cause of morbidity and mortality in critically ill patients. ARDS is characterized by acute hypoxaemic respiratory failure with diffuse pulmonary inflammation and bilateral edema due to excessive alveolocapillary permeability in patients with non-cardiogenic pulmonary diseases. Over the past seven decades, our understanding of the pathology and clinical characteristics of ARDS has evolved significantly, yet it remains an area of active research and discovery. ARDS is highly heterogeneous, including diverse pathological causes, clinical presentations, and treatment responses, presenting a significant challenge for clinicians and researchers. In this review, we comprehensively discuss the latest advancements in ARDS research, focusing on its heterogeneity, pathophysiological mechanisms, and emerging therapeutic approaches, such as cellular therapy, immunotherapy, and targeted therapy. Moreover, we also examine the pathological characteristics of COVID-19-related ARDS and discuss the corresponding therapeutic approaches. In the face of challenges posed by ARDS heterogeneity, recent advancements offer hope for improved patient outcomes. Further research is essential to translate these findings into effective clinical interventions and personalized treatment approaches for ARDS, ultimately leading to better outcomes for patients suffering from ARDS.

Acute lung injury (ALI) is a critical condition characterized by severe inflammation and oxidative stress, leading to high morbidity and mortality. Despite advances in understanding ALI pathophysiology, effective treatment options remain limited. The increasing global burden of ALI, driven by factors such as infections, trauma, and environmental pollutants, emphasizes the urgent need for new therapeutic strategies. This study investigates the role of ubiquitin-specific protease 11 (USP11) in modulating Forkhead box protein O1 (FOXO1) to promote autophagy and alleviate oxidative stress in lung epithelial cells, which could provide novel insights into ALI therapeutic strategies.

Bioinformatics were utilized to analyze the expression pattern of USP11 and FOXO1 in ALI, and their functions were detected based on gain- and loss-of function studies in vitro and in vivo. Besides, the effects of USP11 on FOXO1 stability and autophagy were examined through Western blot, immunofluorescence, and co-immunoprecipitation assays.

USP11 was found to be significantly downregulated in ALI, and its over-expression stabilized FOXO1, enhancing autophagy in lung epithelial cells. USP11 over-expression reduced oxidative stress and inflammatory cytokine production in vitro and in vivo. These results highlight the protective role of the USP11-FOXO1 axis in mitigating ALI pathophysiology.

This study identifies USP11 as a key regulator of FOXO1 and autophagy in ALI. The stabilization of FOXO1 through USP11 represents a promising therapeutic strategy for reducing oxidative stress and inflammation in ALI, warranting further clinical investigation.

Immunometabolism has emerged as a key area of focus in immunology and has the potential to lead to new treatments for immune-related diseases. It is well-established that glycolytic metabolism is essential for adaptation to hypoxia and for macrophage inflammatory function. Macrophages have been shown to upregulate their glycolytic metabolism in response to pathogens and pathogen-associated molecular patterns such as LPS. As a direct link to the external environment, the lungs' distinctive nutrient composition and multiple macrophage subtypes provide a unique opportunity to study macrophage metabolism. This review aims to highlight how the steady-state airway and severely inflamed airway offer divergent environments for macrophage glycolytic metabolism. We describe the differences in glycolytic metabolism between tissue-resident alveolar macrophages, and other lung macrophages at steady-state and during inflammation/injury. We also provide an overview of experimental guidelines on how to assess metabolism at the cellular level using Seahorse-based bioenergetic analysis including a review of pharmacologic agents used to inhibit or activate glycolysis.

Acute respiratory distress syndrome (ARDS) is the leading cause of mortality in pathogen-mediated lung inflammation. Viral-induced cytokine release syndrome (CRS) has emerged as a global pandemic, characterized by a hyperactive immune response and excessive cytokine production causing irreversible lung injury. This study aimed to evaluate FDA-approved drugs for their potential to target hyperactive immune response and SARS-CoV-2 viral replication simultaneously. Six potential 3-CLpro inhibitors were identified by molecular docking using MOE software, including ebastine (1), orlistat (2), atracurium besylate (3), piperaquine phosphate (4), valsartan (5), and acarbose (6), among which 1-3 binds strongly to the target protein with binding affinity of - 8.22, - 9.12, and - 7.81, kcal/mol, respectively. Additionally, all identified inhibitors except 4 revealed significant anti-viral potential, with a 50-100% reduction in SARS-CoV-2 plaques. Significant attenuation of phagocyte oxidative burst and inflammatory cytokines (IFN-γ, GM-CSF, IL-6, IL-2, IL-1β, TNF-α) demonstrated the immunomodulatory potential of these drugs. This study demonstrates the potential of pre-existing drugs to ameliorate the cytokine storm and oxidative damage with simultaneous anti-viral effects. The data provide pre-clinical support to develop these drugs as potential therapeutic agent against ARDS.

Despite international guidelines for lung protective ventilation in neonatal or pediatric acute respiratory distress syndrome (nARDS/ pARDS), prospective data on bedside monitoring tools for regional ventilation distribution and lung mechanics are still rare. As a bedside and radiation-free procedure, electrical impedance tomography (EIT) offers a practical and safe approach for analyzing regional ventilation distributions. Recent trials in adults have shown the efficacy of an individualized EIT guided strategy for the improvement of ventilator induced lung injury (VILI).

We performed a single-center prospective feasibility study from November/2021 to December/2023 in the department of neonatal and pediatric intensive care medicine at the University Children´s Hospital in Bonn. All patients with diagnosis of nARDS (or history of perinatal lung disease-PLD)/ pARDS were screened for study inclusion. In all patients a decremental PEEP (positive end-expiratory pressure) trial was performed with a continuous EIT monitoring for an individual analysis of the EIT guided pixel compliance (CEIT) and PEEP finding (EIT-PEEP). In the offline analysis, further EIT derived indices, such as global inhomogeneity index (GI), and center of ventilation (CoV), were calculated.

Overall, 40 EIT measurements were performed in 26 neonatal and pediatric patients (nARDS/PLD, n = 6; and pARDS, n = 20) within a predefined decremental PEEP trial. Thirteen patients were classified as having severe nARDS (PLD)/ pARDS with an Oxygen Saturation Index (OSI) > 12 or Oxygenation Index (OI) > 16. In-hospital mortality rate was 27% in the overall cohort. The median EIT-PEEP (11mbar) was calculated as lowest, as compared to the clinically set PEEP (11.5mbar, p < 0.001), and the ARDSnetwork PEEP table recommendation (ARDSnet-PEEP, 14mbar, p = 0.018). In patients with nARDS/PLD, the EIT-PEEP was calculated 3mbar below the clinically set PEEP (p = 0.058) and 11 mbar below the ARDSnet-PEEP (p = 0.01). In the linear regression analysis, EIT-PEEP and the dynamic compliance (CDYN) at -2mbar presented a significant correlation with a Cohen´s R2 of 0.265 (β: 0.886, p = 0.005).

EIT is feasible and can be performed safely in patients with diagnosis of nARDS/PLD and pARDS, even during ongoing extracorporeal membrane oxygenation (ECMO) support. An individualized PEEP finding strategy according to the EIT compliance might optimize regional ventilation distribution in these patients and can potentially decrease VILI.

The study was registered at the German Clinical Trials Register (GCT; trial number: DRKS 00034905, Registration Date 15.08.2024). The registration was performed retrospectively after inclusion of the last patient.

Endothelial injury destroys endothelial barrier integrity, triggering organ dysfunction and ultimately resulting in sepsis-related death. Considerable attention has been focused on identifying effective targets for inhibiting damage to endothelial cells to treat endotoxemia-induced septic shock. Global gasdermin D (Gsdmd) deletion reportedly prevents death caused by endotoxemia. However, the role of endothelial GSDMD in endothelial injury and lethality in lipopolysaccharide-induced (LPS-induced) endotoxemia and the underlying regulatory mechanisms are unknown. Here, we show that LPS increases endothelial GSDMD level in aortas and lung microvessels. We demonstrated that endothelial Gsdmd deficiency, but not myeloid cell Gsdmd deletion, protects against endothelial injury and death in mice with endotoxemia or sepsis. In vivo experiments suggested that hepatocyte GSDMD mediated the release of high-mobility group box 1, which subsequently binds to the receptor for advanced glycation end products in endothelial cells to cause systemic vascular injury, ultimately resulting in acute lung injury and lethality in shock driven by endotoxemia or sepsis. Additionally, inhibiting endothelial GSDMD activation via a polypeptide inhibitor alleviated endothelial damage and improved survival in a mouse model of endotoxemia or sepsis. These data suggest that endothelial GSDMD is a viable pharmaceutical target for treating endotoxemia and endotoxemia-induced sepsis.

Rapid progression of symptoms and development of Acute Respiratory Distress Syndrome (ARDS) frequently occurred during COVID-19 pandemic, while CT-Scan was useful to assess severity of lung damage, with classic patterns like early Ground Glass Opacity and/or late consolidation. Likewise, lung injury has been related to activation of the coagulation-fibrinolysis systems and pro-inflammatory mediators; where D-Dimer acquires prognostic relevance. The present study aimed to evaluate whether the extent of lung involvement and pattern of lung injury, as determined by chest CT-scan, are related with D-Dimer; and further impact clinical prognosis in patients with ARDS due to COVID-19.

Longitudinal, prospective, observational, multi-center study. Patients diagnosed with ARDS due to COVID-19, without previous lung damage, clotting disorder and/or anticoagulants use, who were attended at the Intensive Care Unit and Internal Medicine Department from March to June 2020. Tomographic extent of lung involvement was analyzed by image software, as well as damage patterns, assessed by experienced radiologists. Endpoints included relation of lung injury with coagulopathy markers like D-Dimer, and prognostic outcome including mortality, mechanical ventilation and hospitalization time.

One-hundred and four patients mean aged 55 years old, 66% males, main comorbidities obesity, hypertension and diabetes mellitus. Larger lung damage was associated with older age, male gender and higher pro-inflammatory mediators like leukocytes and ferritin; whilst consolidation pattern was related to higher Body Mass Index. Higher values of D-Dimer were related either to a larger extent of lung involvement or late consolidation pattern. In addition, the extent of lung involvement was related with longer hospital stay, higher requirement of mechanical ventilation (HR 0.12, p < 0.01) and mortality rate (HR 0.13, p < 0.01); whereas late consolidation was mainly associated with requirement of mechanical ventilation (HR 0.23, p < 0.01).

Tomographic extent of lung involvement and the pattern of lung injury are related with coagulopathy severity markers like D-Dimer, and own prognostic clinical ability in ARDS.

Acute lung injury (ALI) is a devastating clinical syndrome without effective therapy. Celastrol, as a natural anti-inflammatory compound, has showed therapeutic potential against inflammatory diseases. In this study, we have investigated the potential effect of Celastrol on lipopolysaccharide (LPS)-induced ALI. C57BL/6J mice, Nrf1-knockout mice and A549 (human alveolar epithelial cell line) cells were used to investigate the protective role of Celastrol in LPS-induced ALI. Our data showed that administration of Celastrol significantly alleviated lung pathologic injury and increased the survival rate, which was associated with the improvement of mitochondrial function in the injured lung. Moreover, Celastrol enhanced phosphorylation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear translocation of nuclear respiratory factor 1 (Nrf1) and subsequent up-regulation of its downstream mitochondria electron transport chain complex I (NDUF) gene expression, which induced an increase in mitochondrial complex Ⅰ activity. The beneficial effects of Celastrol on regulation of Nrf1 were abolished by inhibition of AMPK and PGC-1α. Finally, in Nrf1 deficient mice, the protective effects of Celastrol on LPS-induced ALI were largely vanished. Our data indicated that Celastrol can prevent LPS-induced ALI by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism, suggesting that Celastrol may represent a novel therapeutic potential for LPS-induced ALI.

Acute respiratory distress syndrome (ARDS) is a severe organ dysfunction associated with significant mortality and morbidity among critically ill patients admitted to the Intensive Care Unit (ICU). The etiology related to ARDS can be highly heterogeneous, with infection or trauma as the most common associations. The Berlin criteria, the current gold standard for ARDS diagnosis, often necessitates manual adjudication of chest radiographs, limiting automation tools. ARDS diagnosis relies on the presence of bilateral infiltrates on radiographs, which is often not available in Electronic Medical Records (EMRs). Automated identification of radiological evidence would facilitate a comprehensive study of the syndrome, eliminating the need for costly individual image inspections by physicians. Radiological reports enable Natural Language Processing (NLP) to assess lung status and evaluate imaging criteria. We developed a NLP pipeline to analyze radiology notes of 362 patients satisfying sepsis-3 criteria from the EMR for possible ARDS diagnosis using BERT model for classification. These classification models showed F1-score of 74.5% and 64.22% for Emory and Grady dataset respectively.

Nephroblastoma overexpressed protein (NOV, also named CCN3), a member of the CCN (Cy61, CTGF, and NOV) family, is a critical biological marker of the severity of acute respiratory distress syndrome (ARDS). However, no evidence has been presented that CCN3 directly affects acute lung injury (ALI) or ARDS. Intratracheal infusion of LPS is an established method to simulate sepsis and induce ALI. To examine the effect of CCN3 on ALI, we developed in vivo and in vitro models of this disease on mice and type II alveolar epithelial A549 cells, respectively. To further clarify the role of CCN3 in ALI, we constructed a CCN3 overexpression model based on plasmid transfection. The results showed that CCN3 expression was up-regulated in LPS-induced ALI both in vivo and in vitro; this effect was time- and dose-dependent. ELISA revealed that overexpression of CCN3 increased the levels of proinflammatory cytokines IL-1β and TNFα. Flow cytometry and Western blotting showed that overexpression of CCN3 increased the expression of proapoptotic protein Bax and decreased the expression of anti-apoptotic protein Bcl-2, thereby promoting apoptosis of A549 cells. The results suggest that CCN3 antagonists can inhibit progression of inflammation and the development of apoptosis in lung epithelial cells, thereby exerting a possible therapeutic effect in ALI.

To investigate the effects of lycopene supplementation on inflammation, lung histopathology and systemic DNA damage in an experimentally induced lung injury model, ventilated by conventional mechanical ventilation and high-frequency oscillatory ventilation, compared with a control group.

Fifty-five rabbits sampled by convenience were supplemented with 10mg/kg lycopene for 21 days prior to the experiment. Lung injury was induced by tracheal infusion of warm saline. The rabbits were randomly assigned to the control group and subjected to protective conventional mechanical ventilation (n = 5) without supplementation or the experimental group that was subjected to acute lung injury and provided conventional mechanical ventilation and high-frequency oscillatory ventilation with and without lycopene supplementation (n = 10 rabbits in each group). Lung oxidative stress and the inflammatory response were assessed based on the number of polymorphonuclear leukocytes in bronchoalveolar lavage fluid, DNA damage and pulmonary histological damage.

A significant worsening of oxygenation and a decrease in static lung compliance was noted in all groups after pulmonary injury induction (partial pressure of oxygen before 451.86 ± 68.54 and after 71 ± 19.27, p < 0.05). After 4 hours, the high-frequency oscillatory ventilation groups with and without lycopene supplementation as well as the group receiving protective conventional mechanical ventilation with lycopene supplementation showed significant oxygenation improvement compared with the protective conventional mechanical ventilation group without supplementation (partial pressure of oxygen of the group with mechanical ventilation without lycopene of 102 ± 42, of the group that received conventional protective mechanical ventilation with lycopene supplementation of 362 ± 38, of the high-frequency group without lycopene supplementation of 420 ± 28 and of the high-frequency group with lycopene supplementation of 422 ± 25; p < 0.05). Compared with rabbits not receiving supplementation, those in the groups that received protective conventional mechanical ventilation with lycopene supplementation and high-frequency oscillatory ventilation with lycopene supplementation had significantly less inflammation as well as less histological injury (p < 0.05). Compared with rabbits subjected to protective conventional mechanical ventilation, significantly lower DNA damage was observed in rabbits supplemented with lycopene (p < 0.05).

Lycopene supplementation reduces inflammatory and histopathological lung injuries, regardless of the associated ventilatory mode. In addition, lycopene improved oxygenation and reduced DNA damage when protective conventional mechanical ventilation was used.

Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.

Acute respiratory distress syndrome (ARDS) is a pulmonary inflammatory process primarily caused by sepsis. The resolution of inflammation is an active process involving the endogenous biosynthesis of specialized pro-resolving mediators, including resolvin D1 (RvD1). Resident alveolar macrophages (RAMs) maintain pulmonary homeostasis and play a key role in the resolution phase. However, the role of RAMs in promoting the resolution of inflammation by RvD1 is unclear.

Here, we investigated the mechanisms of RvD1 on regulating RAMs to promote the resolution of ARDS.

Mice were administered lipopolysaccharide and/or Escherichia coli via aerosol inhalation to establish a self-limited ARDS model. Then, RvD1 was administered at the peak inflammatory response. RAMs self-renewal was measured by flow cytometry, RAM phagocytosis was measured by two-photon fluorescence imaging. In addition, plasma was collected from intensive care unit patients on days 0-2, 3-5, and 6-9 to measure RvD1 and S100A8/A9 levels using triple quadrupole/linear ion trap mass spectrometry.

RAMs were found to play a pivotal role in resolving inflammation during ARDS, and RvD1 enhanced RAM proliferation and phagocytosis, which was abrogated by a lipoxin A4 receptor (ALX, RvD1 receptor) inhibitor. Both primary RAMs transfected with rS100A8/A9 and/or S100A8/A9 siRNA and S100A9-/- mice (also deficient in S100A8 function) showed higher turnover and phagocytic function, indicating that RvD1 exerted its effects on RAMs by inhibiting S100A8/A9 production in the resolution phase. RvD1 reduced S100A8/A9 and its upstream MAPK14 levels in vivo and in vitro. Finally, in the patients, RvD1 levels were lower, but S100A8/A9 levels were higher.

We propose that RvD1 improved RAM self-renewal and phagocytosis via the ALX/MAPK14/S100A8/A9 signaling pathway. Plasma RvD1 and S100A8/A9 levels were negatively correlated, and associated with the outcome of sepsis-induced ARDS.

This editorial explores the clinical implications of organizing pneumonia (OP) secondary to pulmonary tuberculosis, as presented in a recent case report. OP is a rare condition characterized by inflammation in the alveoli, which spreads to alveolar ducts and terminal bronchioles, usually after lung injuries caused by infections or other factors. OP is classified into cryptogenic (idiopathic) and secondary forms, the latter arising after infections, connective tissue diseases, tumors, or treatments like drugs and radiotherapy. Secondary OP may be triggered by infections caused by bacteria, viruses, fungi, mycobacteria, or parasites. Key diagnostic features include subacute onset of nonspecific respiratory symptoms such as dry cough, chest pain, and exertional dyspnea. Imaging with computed tomography scans typically reveals three patterns: (1) Bilateral subpleural consolidation; (2) Nodular consolidation; and (3) A reticular pattern. Bronchoscopy with bronchoalveolar lavage helps exclude other causes. Standard treatment consists of corticosteroid therapy tapered over 6 months to 12 months. This editorial highlights clinical and diagnostic strategies to ensure timely and effective patient care.

The functional and structural integrity of the endothelium is essential for vascular homeostasis. Loss of barrier function in quiescent and migratory capacity in proliferative endothelium causes exuberant vascular permeability, a cardinal feature of many inflammatory diseases including acute lung injury (ALI). However, the signals governing these fundamental endothelial cell (EC) functions are poorly understood. Here, we identify mechanistic target of rapamycin (MTOR) as an important link in preserving the barrier integrity and migratory/angiogenic responses in EC and preventing lung vascular injury and mortality in mice. Knockdown of MTOR in EC altered cell morphology, impaired proliferation and migration, and increased endocytosis of cell surface vascular endothelial (VE)-cadherin leading to disrupted barrier function. MTOR-depleted EC also exhibited reduced VE-cadherin and vascular endothelial growth factor receptor-2 (VEGFR2) levels mediated in part by autophagy. Similarly, lungs from mice with EC-specific MTOR deficiency displayed spontaneous vascular leakage marked by decreased VE-cadherin and VEGFR2 levels, indicating that MTOR deficiency in EC is sufficient to disrupt lung vascular integrity and may be a key pathogenic mechanism of ALI. Indeed, MTOR as well as VEGFR2 and VE-cadherin levels were markedly reduced in injured mouse lungs or EC. Importantly, EC-targeted gene transfer of MTOR complementary DNA, either prophylactically or therapeutically, mitigated inflammatory lung injury, and improved lung function and survival in mouse models of ALI. These findings reveal an essential role of MTOR in maintaining EC function, identify loss of endothelial MTOR as a key mechanism of lung vascular injury, and show the therapeutic potential of EC-targeted MTOR expression in combating ALI and mortality in mice.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the leading causes of acute respiratory failure in many critical diseases and are among the main respiratory diseases with high clinical mortality. The global outbreak of coronavirus disease 2019 (COVID-19) can cause severe ARDS, resulting in a steep rise in the number of patient deaths. Therefore, it is important to explore the pathogenesis of ALI and find effective therapeutic agents. In recent years, thanks to modern biomedical tools, some progress has been made in the application of traditional Chinese medicine (TCM) treatment principles based on syndromic differentiation and holistic concepts in clinical and experimental studies of ALI. More and more TCM effective components and formulae have been verified to have significant curative effects, which have a certain guiding significance for clinical practice.

It is hoped to provide reference for the clinical research of ALI/ARDS and provide theoretical basis and technical support for the scientific application of TCM in respiratory related diseases.

We performed a literature survey using traditional books of Chinese medicine and online scientific databases including PubMed, Web of Science, Google Scholar, ScienceDirect, China National Knowledge Infrastructure (CNKI), and others up to January 2023.

In recent years, thanks to modern biomedical tools, some progress has been made in the application of TCM treatment principles based on syndromic differentiation and holistic concepts in clinical and experimental studies of ALI. This paper mainly reviews the research progress of ALI/ARDS mechanism, the understanding of its etiology and pathogenesis by TCM, and the therapeutic effects of TCM formulae and active ingredients of Chinese medicine. A large number of studies have shown that the effective components and formulae of TCM can prevent or treat ALI/ARDS in vivo and in vitro experiments.

TCM effective components and formulae play an important role in the prevention and treatment of ALI/ARDS through multiple approaches and multiple targets, and provide necessary theoretical support for the further development and utilization of TCM resources.