Therapy For Acute Respiratory Distress Syndrome Research Articles

Abscisic acid for acute respiratory distress syndrome therapy by suppressing alveolar macrophage pyroptosis via upregulating acyloxyacyl hydrolase expression

ObjectiveAbscisic acid (ABA) is a phytohormone that inhibits airway inflammation in acute respiratory distress syndrome (ARDS) mouse models. However, the molecular mechanism underlying this phenomenon remains unclear. Methods: Serum ABA level in patients and mice was measured via liquid chromatography–tandem mass spectrometry (LC–MS/MS). In-depth molecular mechanism was investigated through transmission electron microscopy, RNA-sequencing, and molecular docking in ARDS mice and cultured primary alveolar macrophages (AMs). ResultsWe found that the serum ABA level was remarkably decreased in ARDS mice and patients. ABA inhibited lipopolysaccharide (LPS)-induced airway inflammation in mice; moreover, it downregulated genes associated with pyroptosis, as shown by RNA-sequencing and lung protein immunoblots. ABA inhibited the formation of membrane pores in AMs and suppressed the cleavage of gasdermin D (GSDMD) and the activation of caspase-11 and caspase-1 in vivo and in vitro; however, the overexpression of caspase-11 reversed the protective effect of ABA on LPS-induced pyroptosis of primary AMs. ABA inhibited intra-AM LPS accumulation while increasing the level of acyloxyacyl hydrolase (AOAH) in AMs, whereas AOAH deficiency abrogated the suppressive action of ABA on inflammation, pyroptosis, and intra-AM LPS accumulation in vivo and in vitro. Importantly, ABA promoted its intracellular receptor lanthionine C-like receptor 2 interacting with transcription factor peroxisome proliferator-activated receptor γ, which ultimately leading to increase AOAH expression to inactivate LPS and inhibit pyroptosis in AMs. ConclusionsABA protected against LPS-induced lung injury by inhibiting pyroptosis in AMs via proliferator-activated receptor γ-mediated AOAH expression.

Ethyl pyruvate ameliorates acute respiratory distress syndrome in mice

Acute respiratory distress syndrome (ARDS) became a focus of intensive research due to its death toll during the Covid-19 pandemic. An uncontrolled and excessive inflammatory response mediated by proinflammatory molecules such as high mobility group box protein 1 (HMGB1), IL-6, and TNF mounts as a response to infection. In this study, ethyl pyruvate (EP), a known inhibitor of HMGB1, was tested in the model of murine ARDS induced in C57BL/6 mice by intranasal administration of polyinosinic:polycytidylic acid (poly(I:C)). Intraperitoneal administration of EP ameliorated the ARDS-related histopathological changes in the lungs of poly(I:C)-induced ARDS and decreased numbers of immune cells in the lungs, broncho-alveolar lavage fluid and draining lymph nodes (DLN). Specifically, fewer CD8+ T cells and less activated CD4+ T cells were observed in DLN. Consequently, the lungs of EP-treated animals had fewer damage-inflicting CD8+ cells and macrophages. Additionally, the expression and production of proinflammatory cytokines, IL-17, IFN-γ and IL-6 were downregulated in the lungs. The expression of chemokine CCL5 which recruits immune cells into the lungs was also reduced. Finally, EP downregulated the expression of HMGB1 in the lungs. Our results imply that EP should be further evaluated as a potential candidate for ARDS therapy.

Stem Cell Extracellular Vesicles as Anti-SARS-CoV-2 Immunomodulatory Therapeutics: A Systematic Review of Clinical and Preclinical Studies.

COVID-19 rapidly escalated into a worldwide pandemic with elevated infectivity even from asymptomatic patients. Complications can lead to severe pneumonia and acute respiratory distress syndrome (ARDS), which are the main contributors to death. Because of their regenerative and immunomodulatory capacities, stem cells and their derived extracellular vesicles (EVs) are perceived as promising therapies against severe pulmonary conditions, including those associated with COVID-19. Herein, we evaluate the safety and efficacy of stem cell EVs in treating COVID-19 and complicating pneumonia, acute lung injury, and ARDS. We also cover relevant preclinical studies to recapitulate the current progress in stem cell EV-based therapy. Using PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science, we searched for all English-language published studies (2000-2023) that used stem cell EVs as a therapy for COVID-19, ARDS, or pneumonia. The risk of bias (ROB) was assessed for all studies. Forty-eight studies met our inclusion criteria. Various-sized EVs derived from different types of stem cells were reported as a potentially safe and effective therapy to attenuate the cytokine storm induced by COVID-19. EVs alleviated inflammation and regenerated the alveolar epithelium by decreasing apoptosis, proinflammatory cytokines, neutrophil infiltration, and M2 macrophage polarization. They also prevented fibrin production and promoted the production of anti-inflammatory cytokines and endothelial cell junction proteins. Similar to their parental cells, stem cell EVs mediate lung tissue regeneration by targeting multiple pathways and thus hold promise in promoting the recovery of COVID-19 patients and improving the survival rate of severely affected patients.

Cell-based Therapies for Acute Respiratory Distress Syndrome: Where Are We Now?

There is considerable interest in the potential for cell-based therapies, particularly mesenchymal stromal cells (MSCs) and their products, as a therapy for acute respiratory distress syndrome (ARDS). MSCs exert effects via diverse mechanisms including reducing excessive inflammation by modulating neutrophil, macrophage and T-cell function, decreasing pulmonary permeability and lung edema, and promoting tissue repair. Clinical studies indicate that MSCs are safe and well tolerated, with promising therapeutic benefits in specific clinical settings, leading to regulatory approvals of MSCs for specific indications in some countries.This perspective reassesses the therapeutic potential of MSC-based therapies for ARDS given insights from recent cell therapy trials in both COVID-19 and in 'classic' ARDS, and discusses studies in graft-vs.-host disease, one of the few licensed indications for MSC therapies. We identify important unknowns in the current literature, address challenges to clinical translation, and propose an approach to facilitate assessment of the therapeutic promise of MSC-based therapies for ARDS.

A comprehensive systematic review of the phenotypes and their role in improving medications and clinical results in the acute respiratory distress syndrome: exploring the potential of personalized therapy

The Acute Respiratory Distress Syndrome (ARDS) is a disorder that can be severe and it is characterized by severe breathing difficulties, such as the various clinical risk factors, lung injury mechanisms, microbiological aspects and biological factors. The current systematic review intends to investigate the phenotypic diversity in ARDS and the possibility of individualized treatment in improving clinical outcomes. In the field of molecular phenotyping, biomarker panels show promise as useful tools for identifying patients who are at risk of developing ARDS, diagnosing the disease, assisting in risk assessment and allowing for ongoing observation. The hyper-inflammatory subphenotype is associated with diseases including metabolic acidosis, shock and worse clinical outcomes. Biologic phenotypes are taken into consideration, such as gene expression, common causal microbiologic infections and plasma protein biomarkers. This review underlines the variations in etiology, clinical manifestations and treatment responses for the diverse phenotypes, including subtypes of direct and indirect lung damage. We will talk about the significance of customizing research trials to the exact stage of lung damage that patients are experiencing, as well as premature treatment and preventive intervention and developed ARDS therapy. Customized therapy can become a reality as a result of improved clinical trial design and execution brought by a deeper comprehension of the interactions between various factors in ARDS.

Mesenchymal stem cell therapy modulates macrophage dynamics in ARDS-associated liver injury in rats

Acute Respiratory Distress Syndrome (ARDS) is a life-threatening pulmonary condition characterized by severe hypoxemia and respiratory failure. Beyond its devastating impact on the lungs, ARDS often triggers systemic responses affecting vital organs throughout the body. One such organ commonly affected is the liver, which experiences various degrees of injury during the course of ARDS. Pathophysiological changes in liver during ARDS, particularly polarization of Kupffer cells during the disease and its treatment, have drawn increasing attention. Purpose. To explore the macrophage transformation in liver injury associated with ARDS and investigate the potential of mesenchymal stem cell (MSC) therapy as a means to modulate macrophage responses and mitigate liver injury. Materials and methods. 72 mature male Wistar rats were randomly allocated to nine experimental groups as follows: the control group, groups assessed at 3 days, 7 days, and 28 days following intranasal LPS administration, groups that received 24 hours of LPS followed by 2 days of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), groups exposed to 4 days of LPS and 3 days of hUC-MSCs, groups subjected to 14 days of LPS and 14 days of hUC-MSCs, groups treated with LPS 21 days and 7 days with hUC-MSCs injection, and a control group assessed 3 days after hUC-MSCs injection. For the administration of hUC-MSCs, intraperitoneal injections were performed at a dose of 1∙106 cells/kg body weight. Immunohistochemistry was employed to analyze macrophage subpopulations in liver tissues. Animal experiments adhered to ethical guidelines. Results. Early ARDS stages showed increased M1 macrophages, indicating pro-inflammatory responses, while later stages showed M2 macrophage activation, suggestive of anti-inflammatory and tissue repair roles. MSC administration facilitated the transition from M1 to M2 macrophages, promoting an anti-inflammatory milieu. Conclusions. MSCs demonstrate the potential to modulate macrophage polarization into M2 anti-inflammatory phenotype. Such findings reflect one of the mechanisms of MSC action which holds practical significance for future ARDS therapies, aiming to mitigate excessive inflammation and enhance tissue repair.

Hemoadsorption as Adjuvant Therapy in Acute Respiratory Distress Syndrome (ARDS): A Systematic Review and Meta-Analysis.

Acute respiratory distress syndrome (ARDS) is often a consequence of a dysregulated immune response; therefore, immunomodulation by extracorporeal cytokine removal has been increasingly used as an adjuvant therapy, but convincing data are still missing. The aim of this study was to investigate the effects of adjunctive hemoadsorption (HA) on clinical and laboratory outcomes in patients with ARDS. We performed a systematic literature search in PubMed, Embase, CENTRAL, Scopus, and Web of Science (PROSPERO: CRD42022292176). The population was patients receiving HA therapy for ARDS. The primary outcome was the change in PaO2/FiO2 before and after HA therapy. Secondary outcomes included the before and after values for C-reactive protein (CRP), lactate, interleukin-6 (IL-6), and norepinephrine (NE) doses. We included 26 publications, with 243 patients (198 undergoing HA therapy and 45 controls). There was a significant improvement in PaO2/FiO2 ratio following HA therapy (MD = 68.93 [95%-CI: 28.79 to 109.06] mmHg, p = 0.005) and a reduction in CRP levels (MD = -45.02 [95%-CI: -82.64; -7.39] mg/dL, p = 0.026) and NE dose (MD = -0.24 [95%-CI: -0.44 to -0.04] μg/kg/min, p = 0.028). Based on our findings, HA resulted in a significant improvement in oxygenation and a reduction in NE dose and CRP levels in patients treated with ARDS. Properly designed RCTs are still needed.

Acute respiratory distress syndrome heterogeneity and the septic ARDS subgroup.

Acute respiratory distress syndrome (ARDS) is an acute diffuse inflammatory lung injury characterized by the damage of alveolar epithelial cells and pulmonary capillary endothelial cells. It is mainly manifested by non-cardiogenic pulmonary edema, resulting from intrapulmonary and extrapulmonary risk factors. ARDS is often accompanied by immune system disturbance, both locally in the lungs and systemically. As a common heterogeneous disease in critical care medicine, researchers are often faced with the failure of clinical trials. Latent class analysis had been used to compensate for poor outcomes and found that targeted treatment after subgrouping contribute to ARDS therapy. The subphenotype of ARDS caused by sepsis has garnered attention due to its refractory nature and detrimental consequences. Sepsis stands as the most predominant extrapulmonary cause of ARDS, accounting for approximately 32% of ARDS cases. Studies indicate that sepsis-induced ARDS tends to be more severe than ARDS caused by other factors, leading to poorer prognosis and higher mortality rate. This comprehensive review delves into the immunological mechanisms of sepsis-ARDS, the heterogeneity of ARDS and existing research on targeted treatments, aiming to providing mechanism understanding and exploring ideas for accurate treatment of ARDS or sepsis-ARDS.

Abstract 17260: Endothelium-Targeted Nanoparticle Delivery of FOXM1 Reactivates Aging-Impaired Endothelial Regeneration for Vascular Repair and Inflammatory Lung Injury Resolution: Precision Gene Therapy of Acute Respiratory Distress Syndrome

Introduction: Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS). However, the underlying molecular mechanisms remain elusive and there is no effective therapy for ARDS. Hypothesis: Impaired endothelial regeneration and vascular repair in aged lungs causes persistent lung injury leading to high incidence of ARDS and high mortality in elderly patients following sepsis challenge. Methods: Genetic lineage tracing was employed to determine the cell origin of endothelial regeneration. Aged Foxm1Tg mice was used for assessing the role of FoxM1 in activating endothelial regeneration. Endothelium-targeted nanoparticles were employed to deliver FOXM1 gene selectively to endothelial cells (ECs) in aged mice. Methylation analysis was employed to determine how aging impairs FoxM1 expression. Results: Genetic lineage tracing study showed that endothelial regeneration was mediated by lung endothelial proliferation in adult mice whereas this intrinsic regenerative program was impaired in aged mice. Expression of FoxM1, an important mediator of endothelial regeneration in young adult mice, was not induced in lungs of aged mice due to aging-induced hypermethylation of the Foxm1 promoter. Transgenic FOXM1 expression or in vivo endothelium-targeted nanoparticle delivery of FOXM1 gene reactivated endothelial regeneration, normalized vascular repair and promoted survival of aged mice following sepsis. Furthermore, nanoparticle delivery of FoxM1 gene selectively in lung ECs also reactivated endothelial regeneration in aged mice, supporting the novel concept of precision gene therapy. In COVID-19 lung autopsy samples, FOXM1 expression was not induced in vascular ECs of elderly patients in contrast to mid-age patients, validating the clinical relevance of our findings. Conclusions: We have demonstrate that persistent lung injury and high mortality in aged mice following sepsis challenge is ascribed to impaired endothelial regeneration and vascular repair. Therapeutic reactivation of FoxM1-dependent endothelial regeneration and vascular repair represents a potential effective therapy for elderly ARDS patients by endothelium-targeted nanoparticle delivery of FOXM1 gene.

Evaluating service needs for veno-venous extracorporeal membrane oxygenation in patients with severe acute respiratory distress syndrome in Saskatchewan

To determine the number of patients with acute respiratory distress syndrome (ARDS) who would be eligible to receive veno-venous extracorporeal membrane oxygenation (VV-ECMO). We conducted a retrospective observational study of ARDS patients admitted to Regina General Hospital Intensive Care Unit (ICU). VV-ECMO eligibility was assessed using selection criteria from the Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Syndrome trial (EOLIA), the Extracorporeal Life Support Organization (ELSO), New South Wales (NSW), Critical Care Services Ontario (CCSO) and a Regina-restrictive criteria. Of 415 patients admitted between October 16, 2018, and January 21, 2021, 103 (25%) had mild, 175 (42%) had moderate, and 64 (15%) had severe ARDS. Of the cohort, 144 (35%) had bacterial pneumonia, 86 (21%) had viral pneumonia (including COVID-19), and 72 (17%) had aspiration pneumonia. Using the EOLIA, ELSO, NSW, CCSO and Regina-restrictive criteria, 7/415 (1.7%), 6/415 (1.5%), 19/415 (4.6%), 26/415 (6.3%) and 12/415 (2.9%) were eligible for VV-ECMO, respectively. Of all ECMO-eligible patients, only one (2.4%) actually received VV-ECMO, 20/42 (48%) received prone positioning and 21/42 (50%) received neuromuscular blockade. There is potential for service expansion of VV-ECMO in Regina; however, there is still a need to improve the delivery of evidence-based ARDS therapies.

High-dose methylprednisolone pulse therapy during refractory COVID-19 acute respiratory distress syndrome: a retrospective observational study

BackgroundCurrent COVID-19 guidelines recommend the early use of systemic corticoids for COVID-19 acute respiratory distress syndrome (ARDS). It remains unknown if high-dose methylprednisolone pulse therapy (MPT) ameliorates refractory COVID-19 ARDS after many days of mechanical ventilation or rapid deterioration with or without extracorporeal membrane oxygenation (ECMO).MethodsThis is a retrospective observational study. Consecutive patients with COVID-19 ARDS treated with a parenteral high-dose methylprednisolone pulse therapy at the intensive care units (ICU) of two University Hospitals between January 1st 2021 and November 30st 2022 were included. Clinical data collection was at ICU admission, start of MPT, 3-, 10- and 14-days post MPT.ResultsThirty-seven patients (mean age 55 ± 12 years) were included in the study. MPT started at a mean of 17 ± 12 days after mechanical ventilation. Nineteen patients (54%) received ECMO support when commencing MPT. Mean paO2/FiO2 significantly improved 3- (p = 0.034) and 10 days (p = 0.0313) post MPT. The same applied to the necessary FiO2 10 days after MPT (p = 0.0240). There were no serious infectious complications. Twenty-four patients (65%) survived to ICU discharge, including 13 out of 20 (65%) needing ECMO support.ConclusionsLate administration of high-dose MPT in a critical subset of refractory COVID-19 ARDS patients improved respiratory function and was associated with a higher-than-expected survival of 65%. These data suggest that high-dose MPT may be a viable salvage therapy in refractory COVID-19 ARDS.

Engineered Extracellular Vesicles Derived from Dermal Fibroblasts Attenuate Inflammation in a Murine Model of Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) represents a significant burden to the healthcare system, with ≈200000 cases diagnosed annually in the USA. ARDS patients suffer from severe refractory hypoxemia, alveolar-capillary barrier dysfunction, impaired surfactant function, and abnormal upregulation of inflammatory pathways that lead to intensive care unit admission, prolonged hospitalization, and increased disability-adjusted life years. Currently, there is no cure or FDA-approved therapy for ARDS. This work describes the implementation of engineered extracellular vesicle (eEV)-based nanocarriers for targeted nonviral delivery of anti-inflammatory payloads to the inflamed/injured lung. The results show the ability of surfactant protein A (SPA)-functionalized IL-4- and IL-10-loaded eEVs to promote intrapulmonary retention and reduce inflammation, both in vitro and in vivo. Significant attenuation is observed in tissue damage, proinflammatory cytokine secretion, macrophage activation, influx of protein-rich fluid, and neutrophil infiltration into the alveolar space as early as 6 h post-eEVs treatment. Additionally, metabolomics analyses show that eEV treatment causes significant changes in the metabolic profile of inflamed lungs, driving the secretion of key anti-inflammatory metabolites. Altogether, these results establish the potential of eEVs derived from dermal fibroblasts to reduce inflammation, tissue damage, and the prevalence/progression of injury during ARDS via nonviral delivery of anti-inflammatory genes/transcripts.

Single-cell analysis reveals dysregulated inflammatory response in peripheral blood immunity in patients with acute respiratory distress syndrome.

Introduction: Acute respiratory distress syndrome (ARDS) remains a major clinical challenge for patients in intensive care units. Determining the differential mechanisms underlying ARDS with different etiologies is a key goal to improve the effectiveness of ARDS therapy. Despite growing evidence that different immune cell types are involved in ARDS, the role of altered immune cell subpopulations in disease progression is unelucidated. Methods: In this study, we combined scRNA-seq and bulk-level sequencing to analyze the transcriptomes of peripheral blood mononuclear cells from healthy volunteers and patients with septic ARDS (sep-ARDS) and pneumonic ARDS (PNE-ARDS). Results: Our data revealed differential alterations at the cellular and molecular levels and within biological signaling pathways in ARDS with different etiologies. The dynamics of neutrophils, macrophages (Macs), classical dendritic cells (cDCs), myeloid-derived suppressive cells (MDSCs), and CD8+ T cells varied significantly among groups of different samples, with neutrophils and cDCs at higher, and Macs at significantly lower, amounts in the patients with sep-ARDS. Furthermore, MDSCs were highly enriched only in the sep-ARDS patients, whereas a higher abundance of CD8+ T cells was observed in patients with PNE-ARDS. In addition, these cell subpopulations were found to be significantly involved in apoptosis, inflammatory, and immune-related pathways. In particular, a significant enhancement of the oxidative stress response was observed in the neutrophil subpopulation. Conclusion: Our study shows that the composition of cells involved in the main peripheral circulation differs in patients with ARDS with different etiologies. Studying the role and mechanism of action of these cells during ARDS will provide new opportunities for the treatment of this condition.

4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway.

Acute respiratory distress syndrome (ARDS) is a high-mortality pulmonary disorder characterized by an intense inflammatory response and a cytokine storm. As of yet, there is no proven effective therapy for ARDS. Itaconate, an immunomodulatory derivative accumulated during inflammatory macrophage activation, has attracted widespread attention for its potent anti-inflammatory and anti-oxidative properties. This study pointed to explore the protective impacts of 4-octyl itaconate (4-OI) on ARDS. The results showed that lung injury was attenuated markedly after 4-OI pre-treatment, as represented by decreased pulmonary edema, inflammatory cell infiltration, and production of inflammatory factors. LPS stimulation induced NLRP3-mediated pyroptosis in vitro and in vivo, as represented by the cleavage of gasdermin D (GSDMD), IL-18 and IL-1β release, and these changes could be prevented by 4-OI pretreatment. Mechanistically, 4-OI eliminated mitochondrial reactive oxygen species (mtROS) and mtDNA escaping to the cytosol through the opening mitochondrial permeability transition pore (mPTP) in alveolar macrophages (AMs) under oxidative stress. In addition, 4-OI pretreatment markedly downregulated cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) expression, and interferon regulatory factor 3 (IRF3) phosphorylation in vitro and in vivo. Meanwhile, inhibition of STING/IRF3 pathway alleviated NLRP3-mediated pyroptosis induced by LPS in vitro. Taken together, this study indicated that 4-OI ameliorated ARDS by rescuing mitochondrial dysfunction and inhibiting NLRP3-mediated macrophage pyroptosis in a STING/IRF3-dependent manner, which further revealed the potential mechanism of itaconate in preventing inflammatory diseases.

Ventilator-Induced Lung Injury as a Dynamic Balance Between Epithelial Cell Damage and Recovery.

Acute respiratory distress syndrome (ARDS) has a high mortality rate that is due in part to ventilator-induced lung injury (VILI). Nevertheless, the majority of patients eventually recover, which means that their innate reparative capacities eventually prevail. Since there are currently no medical therapies for ARDS, minimizing its mortality thus amounts to achieving an optimal balance between spontaneous tissue repair versus the generation of VILI. In order to understand this balance better, we developed a mathematical model of the onset and recovery of VILI that incorporates two hypotheses: (1) a novel multi-hit hypothesis of epithelial barrier failure, and (2) a previously articulated rich-get-richer hypothesis of the interaction between atelectrauma and volutrauma. Together, these concepts explain why VILI appears in a normal lung only after an initial latent period of injurious mechanical ventilation. In addition, they provide a mechanistic explanation for the observed synergy between atelectrauma and volutrauma. The model recapitulates the key features of previously published in vitro measurements of barrier function in an epithelial monolayer and in vivo measurements of lung function in mice subjected to injurious mechanical ventilation. This provides a framework for understanding the dynamic balance between factors responsible for the generation of and recovery from VILI.

Anti-inflammatory activity of non-selective PDE inhibitor aminophylline on the lung tissue and respiratory parameters in animal model of ARDS

Acute respiratory distress syndrome (ARDS) is a common complication of critical illness characterized by lung inflammation, epithelial and endothelial dysfunction, alveolar-capillary leakage, and worsening respiratory failure. The present study aimed to investigate the anti-inflammatory effects of non-selective phosphodiesterase (PDE) inhibitor aminophylline. New Zealand white rabbits were randomly divided into 3 groups: animals with respiratory failure defined as PaO2/FiO2 ratio (P/F) below < 26.7 kPa, and induced by saline lung lavage (ARDS), animals with ARDS treated with intravenous aminophylline (1 mg/kg; ARDS/AMINO), and healthy ventilated controls (Control). All animals were oxygen ventilated for an additional 4 h and respiratory parameters were recorded regularly. Post mortem, the lung tissue was evaluated for oedema formation, markers of inflammation (tumor necrosis factor, TNFα, interleukin (IL)-1β, -6, -8, -10, -13, -18), markers of epithelial damage (receptor for advanced glycation end products, RAGE) and endothelial injury (sphingosine 1-phosphate, S1P), oxidative damage (thiobarbituric acid reactive substances, TBARS, 3-nitrotyrosine, 3NT, total antioxidant capacity, TAC). Aminophylline therapy decreased the levels of pro-inflammatory cytokines, markers of epithelial and endothelial injury, oxidative modifications in lung tissue, reduced lung oedema, and improved lung function parameters compared to untreated ARDS animals. In conclusion, non-selective PDE inhibitor aminophylline showed a significant anti-inflammatory activity suggesting a potential of this drug to be a valuable component of ARDS therapy.

Aerosolized Pulmonary Delivery of mRNA Constructs Attenuates Severity of Escherichia coli Pneumonia in the Rat.

Acute respiratory distress syndrome (ARDS), a rapid onset inflammatory lung disease with no effective specific therapy, typically has pathogenic etiology termed pneumonia. In previous studies nuclear factor-κB (NF-κB) inhibitor α super-repressor (IκBα-SR) and extracellular superoxide dismutase 3 (SOD3) reduced pneumonia severity when prophylactically delivered by viral vector. In this study, mRNA coding for green fluorescent protein, IκBα-SR, or SOD3 was complexed with cationic lipid, passed through a vibrating mesh nebulizer, and delivered to cell culture or directly to rats undergoing Escherichia coli pneumonia. Injury level was then assessed at 48 h. In vitro, expression was observed as early as 4 h in lung epithelial cells. IκBα-SR and wild-type IκBα mRNAs attenuated inflammatory markers, while SOD3 mRNA induced protective and antioxidant effects. In rat E. coli pneumonia, IκBα-SR mRNA reduced arterial carbon dioxide (pCO2) and reduced lung wet/dry ratio. SOD3 mRNA improved static lung compliance and alveolar-arterial oxygen gradient (AaDO2) and decreased bronchoalveolar lavage (BAL) bacteria load. White cell infiltration and inflammatory cytokine concentrations in BAL and serum were reduced by both mRNA treatments compared to scrambled mRNA controls. These findings indicate nebulized mRNA therapeutics are a promising approach to ARDS therapy, with rapid expression of protein and observable amelioration of pneumonia symptoms.

Mechanisms of impaired alveolar fluid clearance.

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.

The safety and efficacy of mesenchymal stromal cells in ARDS: a meta-analysis of randomized controlled trials

Mesenchymal stromal cells (MSC) have shown potential efficacy in both animal and human trials of acute respiratory distress syndrome (ARDS). Especially during the COVID-19 pandemic, MSC was intensely studied for treating COVID-19-induced ARDS. The purpose of this study is to evaluate the safety and efficacy of MSC in ARDS via a meta-analysis of randomized controlled trials (RCTs). Therefore, a meta-analysis of RCTs of MSC as a therapy for ARDS was conducted. The protocol of this review was registered on Open Science Framework. With no language restriction and according to the “PICOs” principle, searches were conducted on Pubmed and Embase to retrieve any clinical literature on MSC for ARDS. Any RCT, which compared MSC to controls for ARDS, where MSC and controls were intravenously infused, of any dosage, was eligible for inclusion. A total of 13 RCTs, which evaluated MSC versus control for treating ARDS, enrolling a total of 655 cases, met the inclusion criteria and appeared in this meta-analysis. A heterogeneity assessment was carried out using the χ2 test, where a P value less than 0.05 was considered significant. The choice of a fixed-effect or a random-effect model was decided by the I2 value in each of the analyses. This meta-analysis indicated that there was no significant difference in terms of adverse events between MSC and control for ARDS (OR = 0.64, 95% CI [0.34, 1.20], P = 0.17, and I2 = 0%). In comparison with control, MSC could reduce the mortality of ARDS (OR = 0.66, 95% CI [0.46, 0.96], P = 0.03, and I2 = 10%). Based on the results of our meta-analysis, the safety of MSC was demonstrated to be non-inferior to that of standard treatment, and MSC may reduce the mortality rate of ARDS. Though the heterogeneity in the main results was low (I2 < 25%), more high-quality and large-scale clinical trials are needed to further confirm our findings.

Extracorporeal Membrane Oxygenation versus Conventional Ventilator Support in COVID-19 Patients with Acute Respiratory Distress Syndrome

Background: Acute respiratory distress syndrome (ARDS) is an undesirable outcome of severe coronavirus disease 2019 (COVID-19). Although venovenous extracorporeal membrane oxygenation (VV-ECMO) has been widely accepted as a rescue therapy for severe ARDS, its use in COVID19-associated ARDS is still debated. Objective: To compare the clinical outcomes of COVID-19 patients treated with VV-ECMO or conventional ventilator support. Materials and Methods: The authors conducted a retrospective study in Bangkok Heart Hospital, Thailand, between March and September 2021. Patients were divided into ECMO and non-ECMO or conventional ventilator support groups. The primary outcome was in-hospital mortality, and the secondary outcomes were complications, length of ICU stay, recovery time after extubation, and total length of hospital stay. Results: Of the 3,053 COVID-19 patients, 36 (1.18%) developed severe ARDS, which 12 were treated with VV-ECMO and 24 with a conventional ventilator. In-hospital mortality was non-significantly lower in the ECMO group at 58.3% versus 83.3% (p=0.126). Upper gastrointestinal bleeding was non-significantly more common in the ECMO group at 41.7% versus 25.0% (p=0.306) but there were no cases of deep vein thrombosis in the ECMO group at 0% versus 20.8% (p=0.088). There were no significant differences in any other complications. Six patients, including four in the ECMO group and two in the non-ECMO group underwent cytokine removal via HA330 hemoperfusion, but interleukin-6 did not decrease in these patients. Conclusion: VV-ECMO in COVID-19-associated ARDS patients did not significantly decreased mortality compared to conventional ventilator therapy. A multidisciplinary team should develop an optimal treatment plan for each COVID-19-associated ARDS patient. Keywords: SARS-CoV-2; Intensive care unit, Artificial respiration