Abstract Acute Respiratory Distress Syndrome Research Articles

Developing a Computational Model of Lungs for Patients With Acute Respiratory Distress Syndrome

Abstract Acute respiratory distress syndrome (ARDS) is a condition secondary to direct or indirect insult to lungs, leading to acute respiratory failure, and is associated with high mortality. Majority of the ARDS patients require mechanical ventilation, which acts as double-edged sword. Ventilator induced lung injury (VILI) is considered secondary to high inspiratory pressure and cyclical opening during inspiration, and collapse during expiration as suggested by ARDS network clinical trials. Other mechanism for VILI exist secondary to heterogeneous ventilation. To enumerate these mechanisms leading to VILI, a computational fluids dynamics (CFD) study was performed in this study to explore the flow patterns and the pressure distribution in a human tracheobronchial airway model from third to sixth generation branches. The authors validated the computational methodology and analyzed the results to obtain velocity profiles in the primary and secondary flow directions. The study investigated the role of various flow velocities corresponding to Reynolds number (Re) from 100 to 2000 on the pressure drops along branches and bifurcation zones. The identification of secondary flow patterns was critical in understanding the development of asymmetric velocity profiles in the triple bifurcation geometry. The observed patterns in pressure drops and velocity profiles over the laminar flow regime pave the path toward further development of a numerical model to aid treatment for patients with ARDS.

Infiltrative monocyte derived adenosine deaminase 2 is associated with COVID-19 related acute respiratory distress syndrome

Abstract Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 characterized by immune dysregulation. The pathogenesis for this, particularly the involvement of infiltrative monocytes, is poorly understood. Extracellular ATP released during inflammation and hypoxia is rapidly scavenged into adenosine, which is further converted into inosine by adenosine deaminase (ADA). ADA2 is an extracellular isoform of ADA secreted by activated monocytes and expressed by infiltrated CD16 +CXCR3 +monocytes. Herein, we aim to study the impact of monocyte-derived ADA2 in the pathogenesis of COVID-19 associated ARDS. Critically ill COVID-19 patients were assigned to the ARDS group based on Berlin criteria, while the non-ARDS group included COVID-19 patients without any or with low-flow oxygen therapy. We observed elevated ADA activity in the serum of ARDS patients, reflecting increased level of the secreted ADA2 protein, when compared to the non-ARDS group. ARDS patients exhibited high level of circulating IL-6, CXCL8 and CXCL10. Notably, correlation analysis revealed a significant association between circulating ADA activity and CXCL10, a chemokine for CXCR3 +monocytes. Post-mortem bulk RNAseq analysis of lung tissues showed increased expression of the ADA2 gene, CECR1, along with CXCL10 suggesting intrapulmonary accumulation of ADA2 positive macrophages. These observations were further supported by the analysis of single-nuclear and spatial transcriptomic atlas of lung tissues of severe COVID-19 patients, which demonstrated a strong expression of ADA2 in CD16 +monocytes. In summary, our data suggest a potential role of infiltrative monocyte-derived ADA2 in modulating the immune response in COVID-19 related ARDS. Supported by the German Center for Infection Research (TI 07.005 to STH)

Paradoxical role of IL-10 during influenza A virus and MRSA coinfection

Abstract Acute respiratory distress syndrome (ARDS) is a highly lethal inflammatory lung injury characterized by an excessive and dysregulated cytokine response. Viral or bacterial pneumonia is the most common cause of ARDS, but the events that trigger hypercytokinemia are unclear. Thus, no ARDS mechanism-specific treatments exist. Secondary methicillin-resistant Staphylococcus aureus (MRSA) pneumonia has contributed significantly to morbidity and mortality in recent influenza pandemics. By using a mouse model of influenza A virus (IAV) and MRSA coinfection, we have shown that IAV infection inhibits phagocyte oxidative burst-dependent MRSA clearance but nevertheless lethal oxidative lung damage ensues following MRSA infection. Cytokines regulate the balance between immune protection and immunopathology. Accordingly, we have shown that an IFN-γ and TNF-α dominant cytokine storm promotes lethal lung inflammation following IAV/MRSA coinfection. IL-10 is a potent anti-inflammatory cytokine; it counteracts many biological effects of IFN-γ. Therefore, we hypothesize that IL-10 is required to limit lung immunopathology during IAV/MRSA coinfection. Indeed, we found that IL-10-deficient mice are highly susceptible to coinfection, correlating with their IFN-γ hyperproduction. Interestingly, mice lacking IL-10 receptor alpha in myeloid cells (Lyz2 CreIl0ra fl/fl) are also highly susceptible to coinfection, despite their improved bacterial clearance. This increased susceptibility is associated with hyperproduction of inflammatory cytokines. Ongoing studies will examine the impact of IL-10 on neutrophils and mononuclear phagocytes to elucidate their respective contribution to bacterial clearance and immunopathology. R01 HL118408

Localized immune dysregulation is associated with lung injury in severe pediatric COVID-19

Abstract Acute respiratory distress syndrome (ARDS) is a common and devastating consequence of SARS-CoV-2 infection in adults, however severe lung injury is a rare manifestation of COVID-19 in children. Aberrant local immune responses are known to drive lung pathology in adults, but little is known about localized immune responses in children with respiratory failure due to COVID-19. We obtained blood and respiratory tract samples from children (n=35, aged 1 month to 18 years) admitted to the hospital for COVID-19, stratifying by presence of respiratory failure (n=15). We defined the cytokine and chemokine profile of severe disease using a 71 analyte Luminex panel. Children with respiratory failure were found to have increased circulating levels of leukemia inhibitory factor (LIF), a growth factor upregulated during pulmonary inflammation. The local environment revealed significant inflammation with increased levels of pro-inflammatory cytokines including IL-6, IL-8, and IL-33 among others. Application of high dimensional flow cytometry to define immune cell subsets revealed elevated proportions of monocytes in both circulating and local environments. Monocytes demonstrated decreased expression of HLA-DR and CD86, suggesting an immunoparalysis phenotype, previously associated with severe COVID-19 in adults. Further, effector memory T cells in the airway exhibited an exhausted phenotype with high levels of PD-1 expression. Together this analysis reveals a highly inflammatory and dysregulated immune response underlies SARS-CoV-2 induced pediatric lung injury. These findings suggest a shared pathway with adult COVID-19 ARDS and provide new insights into the immune mechanisms associated with severe COVID-19 in children. Supported by grants from NIH (K23AI141686)

Uridine alleviates LPS-induced ARDS and improves insulin sensitivity by decreasing oxidative stress and inflammatory processes.

Acute respiratory distress syndrome (ARDS) refers to the injury of alveolar epithelial cells and capillary endothelial cells due to various injury factors. Research on the pathogenesis of ARDS has made great progress, but the exact pathogenesis of ARDS has not been fully elucidated. Up to now, the prevention and treatment of ARDS is still an important scientific problem that needs to be solved urgently. In this work, we analyzed the effect of uridine on ARDS. An ARDS model was successfully constructed by lipopolysaccharide (LPS) stimulation. Western-blotting, IFA, ELISA, RT-PCT and CLSM were conducted to investigate the effect of uridine on ARDS and insulin resistance, and the results showed that lung histopathological alterations were significantly attenuated by uridine treatment. Further work showed that the levels of proinflammatory cytokines were significantly down-regulated in the lung tissue after treatment with uridine. Additionally, the numbers of total cells and neutrophils in the bronchoalveolar lavage fluid (BALF) were also decreased in the uridine-treated ARDS mice. We further explored the potential mechanism by which uridine could treat ARDS, and the results indicated that NF-κB signaling was down-regulated by uridine treatment. Next, we studied insulin sensitivity in the ARDS mice, and found that insulin signaling was significantly down-regulated, and uridine could enhance insulin sensitivity in the ARDS mice model. Furthermore, we found that the levels of inflammation and oxidative stress were decreased by uridine treatment, which may be the potential mechanism by which uridine could improve insulin sensitivity. Taken together, the current work provides evidence that uridine can serve as a potential drug to treat ARDS and insulin resistance.

Sodium butyrate prevented mortality in Acute Respiratory Distress Syndrome through induction of anti-inflammatory response by regulation of epigenetic pathway

Abstract Acute Respiratory Distress Syndrome (ARDS) is a life-threatening disease that has been identified following pneumonia, inflammation, as well as accompained with COVID19 cases. In this study, we investigated the effect of Sodium Butyrate (BUT) in ARDS induced by Staphylococcus Enterotoxin B (SEB). To that end, C3H/HeJ mice were administered BUT through oral gavage with a dose of 200mg/kg and 30mins later followed by a dual dose of SEB, starting with an intranasal dose of 7ug (i.n.) and 2hrs later with another dose of 2ug intraperitoneally (i.p.). The adminstration of BUT continued as same daily and the sacrifice was 72 hrs after SEB exposure. Our data demonstrated that the mortality rate was 80% in SEB+VEH mice compared to 0% mortality in SEB+BUT mice. Plethysmography data indicated a significant improvement in the clinical pulomonary functions. ELISA results indicated that the cytokine storm parameters including IFNγ were significantly decreased after BUT treatment compared to SEB+VEH. Furthermore, flow cytometry data indicated that CD4+ T cells, Vβ8+ T cells and NK T cells were significantly decreased in SEB+BUT compared to SEB+VEH. Analysis of miRNA from MNCs of lungs indicated that anti-inflammatory genes related to T-regulatory cells (Tregs) and Myeloid Derived Suppressor Cells (MDSCs) were targeted by many downregulated miRNAs which were then validated by qRT-PCR. Furthermore, flowcytometry data indicated a significant increase in T regs and MDSCs. Together, our data indicated that BUT prevented mortality and improved Lungs clinical functions in ARDS through modulation of the miRNAs in MNCs in lungs leading to induction of anti-inflammatory genes and suppression of inflammatory T cell subsets as well as increase in Tregs and MDSCs. Supported by NIH P01AT003961, P20GM103641, R01AI129788, R01ES030144, R01AI160896 and R01AI123947

Identifying distinct T cell subsets in the context of pediatric ARDS

Abstract Acute respiratory distress syndrome (ARDS) is a condition defined by sudden respiratory failure caused by severe lung injury, with disease etiology that can differ across pediatric and adult patients. While T lymphocytes have been implicated in ARDS, the role of T cell subsets in pediatric ARDS (pARDS) is not fully understood. In this study, we sought to characterize the potential role of T cells in pARDS caused by viral lower respiratory tract infection (LRTI). To do this, we performed single cell RNA-Seq on tracheal aspirate samples from three categories of mechanically ventilated pediatric patients: 1) LRTI patients with pARDS, 2) LRTI patients without pARDS, and 3) ventilated patients without underlying LRTI or pARDS. All LRTI patients were diagnosed with respiratory viral infections, 70 percent of which were respiratory syncytial virus (RSV). Within the T lymphocytes, we identified populations of CD8+ T cells, CD4+ regulatory T cells, and γδ T cells that each expressed unique gene signatures with distinct distribution across disease states. We compared these data to T cell subsets within healthy lung tissue at multiple ages, and within the periphery of healthy adults. These analyses identified age, location, and disease-specific differences within T cell subsets, highlighting the unique role of T cells in pARDS. Supported by grants from NIH (R01 AI54470, R01 AI121832)

A Nomogram for Predicting the Mortality of Patients with Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is an acute lung injury associated with high morbidity and mortality. This study aimed to establish an accurate prediction model for mortality risk in ARDS. 70% of patients from the Medical Information Mart for Intensive Care Database (MIMIC-III) were selected as the training group, and the remaining 30% as the testing group. Patients from a Chinese hospital were used for external validation. Univariate and multivariate regressions were used to screen the independent predictors. The receiver operating characteristic curve (ROC) analysis, the Hosmer–Lemeshow test, and the calibration curve were used for evaluating the performance of the model. Age, hemoglobin, heart failure, renal failure, Simplified Acute Physiology Score II (SAPS II), immune function impairment, total bilirubin (TBIL), and PaO2/FiO2 were identified as independent predictors. The algorithm of the prediction model was: ln (Pr/(1 + Pr)) = −3.147 + 0.037 ∗ age − 0.068 ∗ hemoglobin + 0.522 ∗ heart failure (yes) + 0.487 ∗ renal failure (yes) + 0.029 ∗ SAPS II + 0.697 ∗ immune function impairment (yes) + 0.280 ∗ TBIL (abnormal) − 0.006 ∗ PaO2/FiO2 (Pr represents the probability of death occurring). The AUC of the model was 0.791 (0.766–0.816), and the internal and the external validations both confirmed the good performance of the model. A nomogram for predicting the risk of death in ARDS patients was developed and validated. It may help clinicians early identify ARDS patients with high risk of death and thereby help reduce the mortality and improve the survival of ARDS.

Effects of Ankle Pumping Exercises on Limb Edema in Critically ill Patients with Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS) is an acute respiratory disease in which the respiratory activity of the lungs is compromised due to secretion of fluid in the alveoli of lungs and thus depriving the blood stream with optimal oxygen supply. Objective: To determine the effects of ankle pumping exercises on limb edema in critically ill patients with acute respiratory distress syndrome Methods: A sample of 67 patients was selected by using non-probability convenient sampling from different hospital settings. Ventilated patients or those having endotracheal tube, age between 40-65 years, and either gender were included in the study. Results:   The effect of Range of Motion (ROM) on ARDS patients was as high as 91 %. There were 61(91.0) responders who experienced edema reduced by ankle pumping 54(80.6) found prone position and 13(19.4) found supine position effective 53(79.1) having resonant sound and 14(20.9) with hyper stony dullness 24(35.8) person having added sound and 43(64.2) crepitus sound in this study. In this study, 20 out of 67 patients who were admitted to the intensive care unit (ICU) developed acute onset of severe dyspnea, hypoxemia, and cyanosis and decreased respiratory system compliance, despite supplemental oxygen and mechanical ventilation. Edema had been reduced by ankle pumping in 61 subjects. Conclusions:  Patients with ARDS report improvement in symptoms with physiotherapy treatment, ROM exercises had remarkable effects on such patients.

Impact of Plasma 5 Hydroxyindoleacetic Acid, a Serotonin Metabolite, on Clinical Severity in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is characterized by dysregulated vascular permeability. The clinical outcomes remain poor, and the disease burden is widespread. We demonstrated that plasma 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, is a pivotal severity indicator of ARDS. Serotonin is an effector of cellular contraction and a modulator of vascular permeability. Plasma 5-HIAA levels were significantly elevated in severe ARDS cases with shock status (p = 0.047) and positively correlated with SOFA (p < 0.0001) and APACHE-II score (p < 0.0001). In the longitudinal analysis, plasma 5-HIAA levels were also a strong independent predictor of mortality rate (p = 0.005). This study indicates that plasma 5-HIAA is a biomarker of ARDS severity and highlights the importance of evaluating vascular leakage levels for ARDS treatment.

Acute Respiratory Distress Syndrome: Focus on Viral Origin and Role of Pulmonary Lymphatics.

Acute respiratory distress syndrome (ARDS) is a serious affection of the lung caused by a variety of pathologies. Great interest is currently focused on ARDS induced by viruses (pandemic influenza and corona viruses). The review describes pulmonary changes in ARDS and specific effects of the pandemic viruses in ARDS, and summarizes treatment options. Because the known pathogenic mechanisms cannot explain all aspects of the syndrome, the contribution of pulmonary lymphatics to the pathology is discussed. Organization and function of lymphatics in a healthy lung and in resorption of pulmonary edema are described. A future clinical trial may provide more insight into the role of hyaluronan in ARDS but the development of promising pharmacological treatments is unlikely because drugs play no important role in lymphedema therapy.

Outcomes in Ventilated Burn Patients With Acute Respiratory Distress Syndrome: An Evaluation of Early High-PEEP Strategy Using Berlin Criteria.

Acute respiratory distress syndrome (ARDS) remains a formidable sequela, complication, and mortality risk in patients with large burns with or without inhalation injury. Alveolar recruitment using higher Positive end expiratory pressures (PEEP) after the onset of ARDS has been tried with varying success. Studies have identified benefits for several rescue maneuvers in ARDS patients with refractory hypoxemia. A prophylactic strategy utilizing an early recruitment maneuver, however, has not, to our knowledge, been explored in ventilated burn patients. This study was designed to evaluate the natural progression and clinical outcomes of ARDS severity (mild, moderate, and severe) using Berlin criteria in ventilated burn patients treated with an early high-PEEP ventilator strategy. A single-center retrospective review of burn patients who were mechanically ventilated for greater than 48 hours utilizing an early high-PEEP >10 mmHg (10.36) ventilator strategy was performed at the Level 1 trauma and regional burn center in Wright State University. ARDS severity was defined according to the Berlin criteria and then compared to published results of ARDS severity, clinical outcomes, and mortality. Demographic data, as well as respiratory and clinical outcomes, were evaluated. Eighty-three patients met inclusion criteria and were evaluated. Utilizing the Berlin definition as a benchmark, 42.1% of patients met ARDS criteria on admission, and most patients (85.5%) developed ARDS within the first seven days: 28 (34%) mild, 32 (38.6%) moderate, and 11 (13.3%) severe ARDS. The mean percent total body surface area was 24.6 + 22.1, with 68.7% of patients diagnosed with inhalation injury. The highest incidence of ARDS was 57.8% on day 2 of admission. Most cases remained in the mild to moderate ARDS category with severe ARDS (2.4%) being less common by hospital day 7. Overall, 30-day in-hospital and inhalation injury mortality rates were 9.6% and 15.8%, respectively. No correlation was observed between plateau pressures (22.8), mean arterial pressures (84.4), or vasopressor requirements; and oxygen requirements down trended quickly over the first 24 to 48 hours. In our study, implementing prophylactic, immediate high-PEEP in mechanically ventilated burn patients was associated with trends toward decreased severity and rapid resolution of ARDS in the first week following burn injury. This correlated with low 30-day in-hospital mortality in this population. This short and less severe course suggests that early high-PEEP support may be a viable protective strategy in the treatment of ventilated burn patients with ARDS.

Comparisons of Outcomes between Patients with Direct and Indirect Acute Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation.

Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome caused by direct (local damage to lung parenchyma) or indirect lung injury (insults from extrapulmonary sites with acute systemic inflammatory response), the clinical and biological complexity can have a profound effect on clinical outcomes. We performed a retrospective analysis of 152 severe ARDS patients receiving extracorporeal membrane oxygenation (ECMO). Our objective was to assess the differences in clinical characteristics and outcomes of direct and indirect ARDS patients receiving ECMO. Overall hospital mortality was 53.3%. A total of 118 patients were assigned to the direct ARDS group, and 34 patients were assigned to the indirect ARDS group. The 28-, 60-, and 90-day hospital mortality rates were significantly higher among indirect ARDS patients (all p < 0.05). Cox regression models demonstrated that among direct ARDS patients, diabetes mellitus, immunocompromised status, ARDS duration before ECMO, and SOFA score during the first 3 days of ECMO were independently associated with mortality. In indirect ARDS patients, SOFA score and dynamic compliance during the first 3 days of ECMO were independently associated with mortality. Our findings revealed that among patients receiving ECMO, direct and indirect subphenotypes of ARDS have distinct clinical outcomes and different predictors for mortality.

Using Dictyostelium to Develop Therapeutics for Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) involves damage to lungs causing an influx of neutrophils from the blood into the lung airspaces, and the neutrophils causing further damage, which attracts more neutrophils in a vicious cycle. There are ∼190,000 cases of ARDS per year in the US, and because of the lack of therapeutics, the mortality rate is ∼40%. Repelling neutrophils out of the lung airspaces, or simply preventing neutrophil entry, is a potential therapeutic. In this minireview, we discuss how our lab noticed that a protein called AprA secreted by growing Dictyostelium cells functions as a repellent for Dictyostelium cells, causing cells to move away from a source of AprA. We then found that AprA has structural similarity to a human secreted protein called dipeptidyl peptidase IV (DPPIV), and that DPPIV is a repellent for human neutrophils. In animal models of ARDS, inhalation of DPPIV or DPPIV mimetics blocks neutrophil influx into the lungs. To move DPPIV or DPPIV mimetics into the clinic, we need to know how this repulsion works to understand possible drug interactions and side effects. Combining biochemistry and genetics in Dictyostelium to elucidate the AprA signal transduction pathway, followed by drug studies in human neutrophils to determine similarities and differences between neutrophil and Dictyostelium chemorepulsion, will hopefully lead to the safe use of DPPIV or DPPIV mimetics in the clinic.

Gavage approach to oxygen supplementation with oxygen therapeutic Ox66™ in a hypoventilation rodent model of respiratory distress

Acute respiratory distress syndrome (ARDS) features pulmonary dysfunction capable of causing life-threatening hypoxaemia. Ventilation and hyperoxic therapies force oxygen through dysfunctional alveoli but risk exacerbating damage. Ox66™ is an ingestible, solid-state oxygen product designed for oxygen supplementation. Eighteen anaesthetized, ventilated rats were subjected to a 40% reduction in tidal volume to produce a hypoventilatory simulation of the hypoxia in ARDS (HV-ARDS). After 60 min, animals were randomized to receive either normal saline (Saline; volume control) or Ox66™ gavage. Cardiovascular function and blood oximetry/chemistry were measured alongside interstitial oxygenation (PISFO2) of the peripheral spinotrapezius muscle. HV-ARDS reduced mean arterial pressure by ∼20% and PISFO2 by ∼35% for both groups. Ox66™ gavage treatment at 60 min improved PISFO2 over Saline (p < .0001), restoring baseline values, however, the effect was temporary. A second bolus at 120 min repeated the OX66™ PISFO2 response, which remained elevated over Saline (p < .01) until study end and was supported by systemic parameters of lactate, PaO2, SO2, and base deficit. Saline remained hypotensive, whereas Ox66™ became normotensive. Vasoconstriction was observed in the Saline, but not Ox66™ group. Supplemental oxygenation through Ox66™ gavage increased peripheral tissue oxygenation, warranting further study for disorders featuring dysfunction of pulmonary perfusion like ARDS.

Investigation of the MSC Paracrine Effects on Alveolar-Capillary Barrier Integrity in the In Vitro Models of ARDS.

Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical disorder with high mortality rates and no specific pharmacological treatment available yet. It is characterized by excessive inflammation in the alveolar compartment resulting in edema of the airspaces due to loss of integrity in the alveolar epithelial-endothelial barrier leading to the development of hypoxemia and often severe respiratory failure. Changes in the permeability of the alveolar epithelial-endothelial barrier contribute to excessive inflammation, the formation of lung edema and impairment of the alveolar fluid clearance. In recent years, Mesenchymal Stromal Cells (MSCs) have attracted attention as a cell therapy for ARDS. MSCs are known to secrete a variety of biologically active factors (growth factors, cytokines, and extracellular vesicles). These paracrine factors have been shown to be major effectors of the anti-inflammatory and regenerative properties observed in multiple in vitro and in vivo studies. This chapter provides a simple protocol on how to investigate the paracrine effect of MSCs on the alveolar epithelial-endothelial barrier functions.

Soluble PD-L1 improved direct ARDS by reducing monocyte-derived macrophages

Acute respiratory distress syndrome (ARDS) is common in intensive care units (ICUs), although it is associated with high mortality, no effective pharmacological treatments are currently available. Despite being poorly understood, the role of programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) axis in ARDS may provide significant insights into the immunosuppressive mechanisms that occur after ARDS. In the present study, we observed that the level of soluble PD-L1 (sPD-L1), a potential activator of the PD-1 pathway, was upregulated in survivors of direct ARDS than in non-survivors. Administration of sPD-L1 in mice with direct ARDS relieved inflammatory lung injury and improved the survival rate, indicating the protective role of sPD-L1 in direct ARDS. Using high-throughput mass cytometry, we found a marked decrease in the number of lung monocyte-derived macrophages (MDMs) with proinflammatory markers, and the protective role of sPD-L1 diminished in ARDS mice with monocyte/macrophage depletion. Furthermore, PD-1 expression increased in the MDMs of patients and mice with direct ARDS. Finally, we showed that sPD-L1 induced MDM apoptosis in patients with direct ARDS. Taken together, our results demonstrated that the engagement of sPD-L1 on PD-1 expressing macrophages resulted in a decrease in pro-inflammatory macrophages and eventually improved direct ARDS. Our study identified a prognostic indicator for patients with direct ARDS and a potential target for therapeutic development in direct ARDS.

Extracellular vesicle-cargo miR-185-5p reflects type II alveolar cell death after oxidative stress

Acute respiratory distress syndrome (ARDS) is a devastating syndrome responsible for significant morbidity and mortality. Diffuse alveolar epithelial cell death, including but not limited to apoptosis and necroptosis, is one of the hallmarks of ARDS. Currently, no detectable markers can reflect this feature of ARDS. Hyperoxia-induced lung injury is a well-established murine model that mimics human ARDS. We found that hyperoxia and its derivative, reactive oxygen species (ROS), upregulate miR-185-5p, but not miR-185-3p, in alveolar cells. This observation is particularly more significant in alveolar type II (ATII) than alveolar type I (ATI) cells. Functionally, miR-185-5p promotes expression and activation of both receptor-interacting kinase I (RIPK1) and receptor-interacting kinase III (RIPK3), leading to phosphorylation of mixed lineage kinase domain-like (MLKL) and necroptosis. MiR-185-5p regulates this process probably via suppressing FADD and caspase-8 which are both necroptosis inhibitors. Furthermore, miR-185-5p also promotes intrinsic apoptosis, reflected by enhancing caspase-3/7 and 9 activity. Importantly, extracellular vesicle (EV)-containing miR-185-5p, but not free miR-185-5p, is detectable and significantly elevated after hyperoxia-induced cell death, both in vitro and in vivo. Collectively, hyperoxia-induced miR-185-5p regulates both necroptosis and apoptosis in ATII cells. The extracellular level of EV-cargo miR-185-5p is elevated in the setting of profound epithelial cell death.

Lung Pathology in Patients with Acute Respiratory Distress Syndrome Associated with the Novel SARS-Cov-2 Virus

Acute Respiratory Distress Syndrome (ARDS) is a well-recognized clinical problem first described in the late sixties. However, its relevance seems to have increased since the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) outbreak, as 14% (CI 95% 2% to 59%) of patients admitted to the hospital present with this syndrome. Conceptually, a syndrome is a group of symptoms and signs that correspond to several diseases. Although defining disease is much harder than may appear at first glance, we can view it as the association between a syndrome and a pathology pattern. Diffuse alveolar damage (DAD) is the morphological hallmark of ARDS, although studies performed in autopsies and patients have demonstrated that it is present in only half of ARDS patients. The SARS-CoV-2 outbreak and the high incidence of ARDS associated with this infection have triggered a natural question: is the lung pathology similar in patients with ARDS associated with traditional risk factors than to SARS-CoV-2 infection? This review aims to analyze the lung pathology results of patients infected with the novel SARS Cov-2. As this article targets non-intensive care physicians, we will first describe the main characteristics of the novel SARS-Cov-2 and the ARDS definition, and then the lung pathology results from the UCI in this group of patients.

α2A-adrenoceptor deficiency attenuates lipopolysaccharide-induced lung injury by increasing norepinephrine levels and inhibiting alveolar macrophage activation in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a severe condition with high morbidity and mortality and few interventions. The role of sympathetic stress in the pathogenesis of ARDS has attracted recent research attention. Blockade of α-2 or α2A-adrenoceptor (α2A-AR) has been shown to attenuate lung injury induced by lipopolysaccharide (LPS) in rats. However, the mechanism is unclear. We confirmed the role of α2A-AR in ARDS using knockout mice and alveolar macrophages following LPS stimulation to assess the underlying mechanisms. We found that α2A-AR deficiency decreased the permeability of the alveolar capillary barrier in ARDS mice and suppressed lung inflammation by reducing inflammatory cell infiltration and the production of TNF-α, interleukin (IL)-6, and CXCL2/MIP-2. LPS stimulation decreased NF-κB activation in lung tissues of α2A-AR deficient mice and increased norepinephrine concentrations. In vitro, we found that norepinephrine inhibited the production of TNF-α, IL-6, and CXCL2/MIP-2 and promoted the secretion of IL-10 from LPS-stimulated murine alveolar macrophages. Blockade of α2A-AR by a specific antagonist further inhibited the production of TNF-α, IL-6, and IL-10. Furthermore, norepinephrine down-regulated NF-κB activation in stimulated alveolar macrophages. Altogether, these results suggest that α2A-AR deficiency ameliorates lung injury by increasing norepinephrine concentrations in lung tissues and inhibiting the activation of alveolar macrophages.