Lung Acute Respiratory Distress Syndrome Research Articles

Justification of the possibility of using liquid artificial lung ventilation for the treatment of acute respiratory distress syndrome of toxic genesis

Introduction. Pulmonotoxicants are chemicals that cause bronchospasm and damage to the alveolar capillary membrane. Lesions of the respiratory system with pulmonotoxicants in industrial accidents are especially relevant at the present time. Existing methods of treatment for the defeat of pulmonotoxicants and the development of acute respiratory distress syndrome (ARDS) are becoming ineffective, therefore, one of the tasks of modern medicine is to develop new methods of treating ARDS. One of these methods may be the creation of a "therapeutic window" by using perfluorocarbon (PFC) liquids. This article will present an experimental assessment of the use of liquid artificial lung ventilation (LALV) PFC liquids on the ARDS lung model. The study aims to explore the possibility of using liquid artificial lung ventilation to create a therapeutic window in the treatment of acute respiratory distress syndrome of a chemical nature. Materials and methods. The authors conducted a study on male Wistar rats aged 4 months, weighing 180–190 g. Toxic pulmonary edema was caused by endotracheal administration of 0.1 m HCl solution. The anesthetized patients were intubated using a cannula, after which the researchers intratracheally injected 0.1 M HCl solution at a dose of 2 ml/kg, a decrease in saturation below 80 was expected. Then the experts randomized the animals by weight into groups of 6 individuals each. They connected the animals of the control group to a ventilator. The animals of the experimental group were treated with PFC liquids for an hour, then transferred to a ventilator. Perfluorodecalin was used as a PFC liquid. The scientists recorded heart rate, blood oxygen saturation, rectal temperature, life expectancy and overall survival by group. Results. In the control group, after instillation of 0.1 M HCl solution and connection to a ventilator during the first 25–30 minutes, there was a gradual decrease in SpO2 to 74.0±5.6% (background — 95.0±3.5%) and an increase in heart rate to 182.0±8.6 beats/min., (background — 278.0±14.8 beats/min.) after which there was decompensation of the animal condition. In animals of the experimental group, after connecting to the LALV device, a sharp decrease in heart rate was recorded during the first 5 minutes to 61.0±8.5 beats/min. In turn, saturation did not change significantly throughout the LALV and was in the range from 95 to 100%. As a result of the experiments, it was noted that the average survival time in the experimental group was 256.0±34.5 minutes, which was significantly (p<0.001) more than 5 times higher than this indicator in the control animals — 45.3±4.3 minutes. There were no significant changes in the study of rectal temperature in the animals of the control group. In turn, the animals of the experimental group showed a sharp decrease in rectal temperature during the first 30 minutes from the beginning of LALV, on average by 5.8±1.60°С. As a result of the pathoanatomic autopsy, differences in lung mass coefficients were revealed in different groups. Thus, in the control group and the experimental groups, it was 1.67±0.06 and 2.4±0.045%, respectively. Conclusion. On the model of ARDS caused by endotracheal administration of 0.1M hydrochloric acid solution, it was shown that living with the use of PFC of low temperature liquids, unlike conventional mechanical ventilation, allows for a long time to maintain a stable condition of animals; evacuate a significant amount of edematous fluid from the lungs and thereby increase the duration of their survival. The data presented above indicate that the use of hypothermic LALV can be used to create a "therapeutic window" for ARDS, including its most severe form — the alveolar stage of toxic pulmonary edema. Ethics. Studies involving laboratory animals were conducted in compliance with the following regulations: the Helsinki Declaration of 2000 "On humane treatment of animals", Order No. 755 of the Ministry of Health of the USSR dated 08/12/1977 "Rules for carrying out work using experimental animals", Order No. 199n of the Ministry of Health of the Russian Federation dated 04/01/2016 "On approval of the rules of laboratory practice". The protocol of the study was approved by the Ethics Committee of the Izmerov Research Institute of Occupational Health. Protocol No. 4 dated May 25, 2022.

Contrasting predictors of severe primary graft dysfunction following transplant for chronic and acute respiratory failure.

Lung transplantation represents a pivotal intervention for individuals grappling with end-stage lung diseases, and the role of lung transplantation in acute respiratory distress syndrome (ARDS) patients has garnered increased attention especially after the coronavirus disease 2019 (COVID-19) pandemic. Multiple studies have demonstrated a high incidence of primary graft dysfunction (PGD) in patients with ARDS compared to contemporaneous controls undergoing transplantation for chronic end-stage lung diseases although underlying mechanisms or risk factors remain unknown. This retrospective study investigates the contrasting risk factors for PGD grade 3 in patients with ARDS and chronic respiratory failure undergoing lung transplantation. The study included 293 patients who underwent lung transplantation from January 2018 through June 2023. We performed a multivariate logistic regression analysis using variables from the univariate logistic regression analyses to predict PGD grade 3. Our findings reveal distinct predictors for PGD grade 3 in the two cohorts. ARDS patients had higher incidence of PGD grade 3 than non-ARDS patients (30.2% vs. 9.6%, P<0.001). Multivariate logistic regression analysis showed ischemic time [odds ratio (OR) =0.60; 95% confidence interval (CI): 0.40-0.90; P=0.01] as predictor of PGD grade 3 for non-ARDS patients, and age (OR =0.72; 95% CI: 0.52-0.99; P=0.048), pre-operative albumin (OR <0.01; 95% CI: <0.01-0.74; P=0.042) for ARDS patients. Interestingly, there was no notable difference in post-transplant survival between the two groups. This study highlights differing risk profiles for severe PGD in ARDS and non-ARDS lung transplant recipients, underscoring the need for tailored approaches in managing these patients. It paves the way for further research to refine strategies aimed at reducing PGD incidence and enhancing transplant outcomes in these distinct populations.

High Levels of Triggering Receptor Expressed in Myeloid Cells-Like Transcript-1 Positive, but Not Glycoprotein 1b+, Microparticles Are Associated With Poor Outcomes in Acute Respiratory Distress Syndrome.

To identify triggering receptor expressed in myeloid cells-like transcript-1 positive (TLT-1+) microparticles (MPs) and evaluate if their presence is associated with clinical outcomes and/or disease severity in acute respiratory distress syndrome (ARDS). Retrospective cohort study. ARDS Network clinical trials. A total of 564 patients were diagnosed with ARDS. None. Using flow cytometry, we demonstrated the presence of TLT-1+ platelet-derived microparticles (PMP) that bind fibrinogen in plasma samples from fresh donors. We retrospectively quantified TLT-1, glycoprotein (Gp) 1b, or αIIbβIIIa immunopositive microparticles in plasma samples from patients with ARDS enrolled in the ARMA, KARMA, and LARMA (Studies 01 and 03 lower versus higher tidal volume, ketoconazole treatment, and lisofylline treatment Clincial Trials) ARDS Network clinical trials and evaluated the relationship between these measures and clinical outcomes. No associations were found between Gp1b+ MPs and clinical outcomes for any of the cohorts. When stratified by quartile, associations were found for survival, ventilation-free breathing, and thrombocytopenia with αIIbβIIIa+ and TLT-1+ MPs (χ2p < 0.001). Notably, 63 of 64 patients in this study who failed to achieve unassisted breathing had TLT+ PMP in the 75th percentile. In all three cohorts, patients whose TLT+ MP counts were higher than the median had higher Acute Physiology and Chronic Health Evaluation III scores, were more likely to present with thrombocytopenia and were 3.7 times (p < 0.001) more likely to die than patients with lower TLT+ PMP after adjusting for other risk factors. Although both αIIbβIIIa+ and TLT+ microparticles (αIIbβIIIa, TLT-1) were associated with mortality, TLT-1+ MPs demonstrated stronger correlations with Acute Physiology and Chronic Health Evaluation III scores, unassisted breathing, and multiple system organ failure. These findings warrant further exploration of the mechanistic role of TLT-1+ PMP in ARDS or acute lung injury progression.

PNSC928, a plant-derived compound, specifically disrupts CtBP2-p300 interaction and reduces inflammation in mice with acute respiratory distress syndrome

BackgroundPrior research has highlighted the involvement of a transcriptional complex comprising C-terminal binding protein 2 (CtBP2), histone acetyltransferase p300, and nuclear factor kappa B (NF-κB) in the transactivation of proinflammatory cytokine genes, contributing to inflammation in mice with acute respiratory distress syndrome (ARDS). Nonetheless, it remains uncertain whether the therapeutic targeting of the CtBP2-p300-NF-κB complex holds potential for ARDS suppression.MethodsAn ARDS mouse model was established using lipopolysaccharide (LPS) exposure. RNA-Sequencing (RNA-Seq) was performed on ARDS mice and LPS-treated cells with CtBP2, p300, and p65 knockdown. Small molecules inhibiting the CtBP2-p300 interaction were identified through AlphaScreen. Gene and protein expression levels were quantified using RT-qPCR and immunoblots. Tissue damage was assessed via histological staining.Key findingsWe elucidated the specific role of the CtBP2-p300-NF-κB complex in proinflammatory gene regulation. RNA-seq analysis in LPS-challenged ARDS mice and LPS-treated CtBP2-knockdown (CtBP2KD), p300KD, and p65KD cells revealed its significant impact on proinflammatory genes with minimal effects on other NF-κB targets. Commercial inhibitors for CtBP2, p300, or NF-κB exhibited moderate cytotoxicity in vitro and in vivo, affecting both proinflammatory genes and other targets. We identified a potent inhibitor, PNSC928, for the CtBP2-p300 interaction using AlphaScreen. PNSC928 treatment hindered the assembly of the CtBP2-p300-NF-κB complex, substantially downregulating proinflammatory cytokine gene expression without observable cytotoxicity in normal cells. In vivo administration of PNSC928 significantly reduced CtBP2-driven proinflammatory gene expression in ARDS mice, alleviating inflammation and lung injury, ultimately improving ARDS prognosis.ConclusionOur results position PNSC928 as a promising therapeutic candidate to specifically target the CtBP2-p300 interaction and mitigate inflammation in ARDS management.

Stress–strain curve and elastic behavior of the fibrotic lung with usual interstitial pneumonia pattern during protective mechanical ventilation

Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress–strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO2/FiO2 ratio) during a PEEP trial performed within 24 h from intubation. Patient’s stress–strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8–33.2] cmH2O versus 11.4 [10.3–14.6] cmH2O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress–strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.

Mesenchymal stromal cell therapy for COVID-19 acute respiratory distress syndrome: a double-blind randomised controlled trial.

Mesenchymal stromal cells (MSC) have immunomodulatory and tissue-regenerative properties and have shown promising results in acute respiratory distress syndrome (ARDS) of multiple causes, including COVID-19. We conducted a randomised (1:1), placebo-controlled, double-blind clinical trial to assess the efficacy and safety of one bone marrow-derived MSC infusion in twenty patients with moderate to severe ARDS caused by COVID-19. The primary endpoint (increase in PaO2/FiO2 ratio from baseline to day 7, MSC 83.3 versus placebo 57.6) was not statistically significant, although a clinical improvement at day 7 in the WHO scale was observed in MSC patients (5, 50% vs 0, 0%, p = 0.033). Median time to discontinuation of supplemental oxygen was also shorter in the experimental arm (14 versus 23 days, p = 0.007), resulting in a shorter hospital stay (17.5 versus 28 days, p = 0.042). No significant differences were observed for other efficacy or safety secondary endpoints. No infusion or treatment-related serious adverse events occurred during the one-year follow-up. This study did not meet the primary endpoint of PaO2/FiO2 increase by day 7, although itsuggests that MSC are safe in COVID-19 ARDS and may accelerate patients' clinical recovery and hospital discharge. Larger studies are warranted to elucidate their role in ARDS and other inflammatory lung disorders.Trial Registration: EudraCT Number: 2020-002193-27, registered on July 14th, 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002193-27/ES . NCT number: NCT04615429, registered on November 4th, 2020, https://clinicaltrials.gov/ct2/show/NCT04615429 .

MANAGEMENT OF ARDS IN DROWNING PATIENT IN INTENSIVE CARE UNIT

Acute Respiratory Distress Syndrome (ARDS) occured in drowning patients in both fresh or salt water. This is a consequence of aspiration of fluid into the lungs. This condition can be made worse by the possibility of hypothermia, arrhythmia, or neurological impacts as a result of anoxia. A male, 16 years old, 60 kg without comorbid was drowned in a well, came on referral from a another hospital, he was admitted to the ward for 2 days. The patient arrived in emergency room and the patient is in respiratory failure state and ARDS. This patient was given intubation in the emergency room, after this patient is stable he was transfered to ICU. In the ICU, the patient was given mechanical ventilation therapy on 4th day and then he was given weaning gradually, on 7th day the patient was given extubation. In general, treatment outcome of drowned patient really depends on how effective and fast the maangement of the respiratory distress in the incident location and until taken to hospital. Mechanical ventilation therapy follows the general ARDS management pattern, using PEEP and lung protection strategies. Monitoring and caution is needed during the weaning process to prevent recurrence of pulmonary edema and re-intubation.

Application effect analysis of lateral prone position ventilation in patients with acute respiratory distress syndrome

To investigate the effect of lateral prone position ventilation in patients with acute respiratory distress syndrome (ARDS). A prospective control study was conducted. A total of 75 patients with moderate to severe ARDS admitted to the department of critical care medicine of Jingxian Hospital in Anhui province from January 2020 to December 2022 were selected as the research objects. According to the envelope method, the patients were divided into the lateral prone position ventilation group (38 cases) and the traditional prone position ventilation (PPV) group (37 cases), using lateral prone position ventilation and traditional PPV, respectively. The mechanical ventilation parameters were set according to the ARDS treatment guidelines and lung protective ventilation requirements in both groups, and the time of prone position for the first 3 times was not less than 16 hours per day. General data of patients were recorded, including heart rate (HR), mean arterial pressure (MAP), airway resistance and lung static compliance (Cst) before prone position (T0), 1 hour (T1), 4 hours (T2), 8 hours (T3), and before the end of prone position (T4), oxygenation index (PaO2/FiO2) before the first prone position (t0) and 12 hours (t1), 24 hours (t2), 48 hours (t3), and 72 hours (t4) after the intensive care unit (ICU) admission, as well as the incidence of pressure injury (PI) and vomiting, tracheal intubation time, and mechanical ventilation time. Repeated measures analysis of variance was used to compare the effects of different prone positions on patients before and after the prone position. There were no significant differences in age, gender, body mass index (BMI), acute physiology and chronic health evaluation II (APACHE II), underlying diseases, HR, MAP, pH value, PaO2/FiO2, blood lactic acid (Lac), arterial blood pressure of carbon dioxide (PaCO2) and other general information between the two groups. The HR (intergroup effect: F = 0.845, P = 0.361; time effect: F = 1.373, P = 0.247; interaction: F = 0.245, P = 0.894), MAP (intergroup effect: F = 1.519, P = 0.222; time effect: F = 0.169, P = 0.954; interaction: F = 0.449, P = 0.773) and airway resistance (intergroup effect: F = 0.252, P = 0.617; time effect: F = 0.578, P = 0.679; interaction: F = 1.467, P = 0.212) of T0-T4 between two groups showed no significant difference. The Cst of T0-T4 between the two groups showed no significant difference in the intergroup effect (F = 0.311, P = 0.579) and the interaction (F = 0.364, P = 0.834), while the difference in the time effect was statistically significant (F = 120.546, P < 0.001). The PaO2/FiO2 of t0-t4 between the two groups showed no significant difference in the intergroup effect (F = 0.104, P = 0.748) and the interaction (F = 0.147, P = 0.964), while the difference in the time effect was statistically significant (F = 17.638, P < 0.001). The group factors and time factors were tested separately, and there were no significant differences in the HR, MAP, airway resistance, Cst, PaO2/FiO2 between the two groups at different time points (all P > 0.05). The Cst at T1-T4 and PaO2/FiO2 at t1-t4 in the two groups were significantly higher than those at T0/t0 (all P < 0.05). There were no significant differences in the tracheal intubation time [days: 6.75 (5.78, 8.33) vs. 7.00 (6.30, 8.45)] and mechanical ventilation time [days: 8.30 (6.70, 9.20) vs. 7.40 (6.80, 8.75)] between the lateral prone position ventilation group and the traditional PPV group (both P > 0.05). However, the incidences of PI [7.9% (3/38) vs. 27.0% (10/37)] and vomiting [10.5% (4/38) vs. 29.7% (11/37)] in the lateral prone position ventilation group were significantly lower than those in the traditional PPV group (both P < 0.05). Both lateral prone position ventilation and traditional PPV can improve Cst and oxygenation in patients with moderate to severe ARDS. The two types of prone position have little influence on HR, MAP and airway resistance of patients, and there is no difference in the influence on tracheal intubation time and mechanical ventilation time of patients. However, the lateral prone position ventilation mode can reduce the incidence of PI and vomiting, and is worthy of clinical promotion and application.

Apoptotic neutrophil-mediated inflammatory microenvironment regulation for the treatment of ARDS

Acute respiratory distress syndrome (ARDS) is a critical respiratory disease characterized by uncontrolled acute lung inflammation with high mortality. At present, effective therapeutic drugs for clinical practice are still lacking. Neutrophil apoptosis and subsequent efferocytosis by macrophages can modulate the lung inflammatory microenvironment of ARDS, thereby promoting the repair of injured lungs. Inspired by the spontaneous process and immunomodulatory properties of apoptotic neutrophils, an apoptotic neutrophil-mediated drug delivery system (T-NP@ApoNEs) for ARDS treatment was constructed. After intravenous injection, T-NP@ApoNEs could adhere to the inflammatory vascular endothelial cells and thus accumulate in the inflamed lung, which were then efficiently phagocytized by macrophages through efferocytosis. Apoptotic neutrophils and pre-loaded anti-inflammatory drug TPCA-1 could synergistically regulate the inflammatory microenvironment of ARDS lungs. It exhibited significant effects on reducing neutrophil infiltration, inhibiting cytokine storm, and promoting macrophage polarization into anti-inflammatory phenotype. In summary, the apoptotic neutrophil-mediated drug delivery strategy may provide an effective therapeutic modality for ARDS.

Alveolar Mitochondrial Quality Control During Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a leading cause of respiratory failure and death in patients in the intensive care unit. Experimentally, acute lung injury resolution depends on the repair of mitochondrial oxidant damage by the mitochondrial quality control (MQC) pathways, mitochondrial biogenesis, and mitophagy, but nothing is known about this in the human lung. In a case–control autopsy study, we compared the lungs of subjects dying of ARDS (n = 8; cases) and age-/gender-matched subjects dying of nonpulmonary causes (n = 7; controls). Slides were examined by light microscopy and immunofluorescence confocal microscopy, randomly probing for co-localization of citrate synthase with markers of oxidant stress, mitochondrial DNA damage, mitophagy, and mitochondrial biogenesis. ARDS lungs showed diffuse alveolar damage with edema, hyaline membranes, and neutrophils. Compared with controls, a high degree of mitochondrial oxidant damage was seen in type 2 epithelial (AT2) cells and alveolar macrophages by 8-hydroxydeoxyguanosine and malondialdehyde co-staining with citrate synthase. In ARDS, antioxidant protein heme oxygenase-1 and DNA repair enzyme N-glycosylase/DNA lyase (Ogg1) were found in alveolar macrophages but not in AT2 cells. Moreover, MAP1 light chain-3 (LC3) and serine/threonine-protein kinase (Pink1) staining were absent in AT2 cells, suggesting a mitophagy failure. Nuclear respiratory factor-1 staining was missing in the alveolar region, suggesting impaired mitochondrial biogenesis. Widespread hyperproliferation of AT2 cells in ARDS could suggest defective differentiation into type 1 cells. ARDS lungs show profuse mitochondrial oxidant DNA damage but little evidence of MQC activity in AT2 epithelium. Because these pathways are important for acute lung injury resolution, our findings support MQC as a novel pharmacologic target for ARDS resolution.

Basement membrane product, endostatin, as a link between inflammation, coagulation and vascular permeability in COVID-19 and non-COVID-19 acute respiratory distress syndrome.

Immune cell recruitment, endothelial cell barrier disruption, and platelet activation are hallmarks of lung injuries caused by COVID-19 or other insults which can result in acute respiratory distress syndrome (ARDS). Basement membrane (BM) disruption is commonly observed in ARDS, however, the role of newly generated bioactive BM fragments is mostly unknown. Here, we investigate the role of endostatin, a fragment of the BM protein collagen XVIIIα1, on ARDS associated cellular functions such as neutrophil recruitment, endothelial cell barrier integrity, and platelet aggregation in vitro. In our study we analyzed endostatin in plasma and post-mortem lung specimens of patients with COVID-19 and non-COVID-19 ARDS. Functionally, we investigated the effect of endostatin on neutrophil activation and migration, platelet aggregation, and endothelial barrier function in vitro. Additionally, we performed correlation analysis for endostatin and other critical plasma parameters. We observed increased plasma levels of endostatin in our COVID-19 and non-COVID-19 ARDS cohort. Immunohistochemical staining of ARDS lung sections depicted BM disruption, alongside immunoreactivity for endostatin in proximity to immune cells, endothelial cells, and fibrinous clots. Functionally, endostatin enhanced the activity of neutrophils, and platelets, and the thrombin-induced microvascular barrier disruption. Finally, we showed a positive correlation of endostatin with soluble disease markers VE-Cadherin, c-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in our COVID-19 cohort. The cumulative effects of endostatin on propagating neutrophil chemotaxis, platelet aggregation, and endothelial cell barrier disruption may suggest endostatin as a link between those cellular events in ARDS pathology.

Effects and mechanism of annexin A1-overexpressing human adipose-derived mesenchymal stem cells in the treatment of mice with acute respiratory distress syndrome

Effects and mechanism of annexin A1-overexpressing human adipose-derived mesenchymal stem cells in the treatment of mice with acute respiratory distress syndrome

Complement as a vital nexus of the pathobiological connectome for acute respiratory distress syndrome: An emerging therapeutic target.

The hallmark of acute respiratory distress syndrome (ARDS) pathobiology is unchecked inflammation-driven diffuse alveolar damage and alveolar-capillary barrier dysfunction. Currently, therapeutic interventions for ARDS remain largely limited to pulmonary-supportive strategies, and there is an unmet demand for pharmacologic therapies targeting the underlying pathology of ARDS in patients suffering from the illness. The complement cascade (ComC) plays an integral role in the regulation of both innate and adaptive immune responses. ComC activation can prime an overzealous cytokine storm and tissue/organ damage. The ARDS and acute lung injury (ALI) have an established relationship with early maladaptive ComC activation. In this review, we have collected evidence from the current studies linking ALI/ARDS with ComC dysregulation, focusing on elucidating the new emerging roles of the extracellular (canonical) and intracellular (non-canonical or complosome), ComC (complementome) in ALI/ARDS pathobiology, and highlighting complementome as a vital nexus of the pathobiological connectome for ALI/ARDS via its crosstalking with other systems of the immunome, DAMPome, PAMPome, coagulome, metabolome, and microbiome. We have also discussed the diagnostic/therapeutic potential and future direction of ALI/ARDS care with the ultimate goal of better defining mechanistic subtypes (endotypes and theratypes) through new methodologies in order to facilitate a more precise and effective complement-targeted therapy for treating these comorbidities. This information leads to support for a therapeutic anti-inflammatory strategy by targeting the ComC, where the arsenal of clinical-stage complement-specific drugs is available, especially for patients with ALI/ARDS due to COVID-19.

Year in Review 2015: Recruitment manoeuvres in ARDS

Refractory hypoxaemia is a problem in patients with acute respiratory distress syndrome (ARDS). Although mechanical ventilation is the mainstay of management of ARDS, this therapy itself can cause damage to the lungs due to high tidal volume and high airway pressures. Lung protective strategies are used to reduce damage to the lungs due to mechanical ventilation. Use of small tidal volumes can cause alveolar derecruitment and arterial hypoxaemia. Lung recruitment manoeuvre (RM) opens up collapsed segments of the ARDS lung but the collapse may reappear once the RM is complete. Although RM has been shown to improve oxygenation there is still no clear data showing improvement in clinical outcome. This review summarises the different techniques used for RM, physiological effects of RM on lung mechanics along with monitoring RM at the bedside.

MiR-199a-3p-regulated alveolar macrophage-derived secretory autophagosomes exacerbate lipopolysaccharide-induced acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a prevalent illness in intensive care units. Extracellular vesicles and particles released from activated alveolar macrophages (AMs) assist in ARDS lung injury and the inflammatory process through mechanisms that are unclear. This study investigated the role of AM-derived secretory autophagosomes (SAPs) in lung injury and microRNA (MiR)-199a-3p-regulated inflammation associated with ARDS in vitro and in a murine model. The ARDS model in mouse was established by intratracheal LPS lipopolysaccharide (LPS) injection. The agomirs or antagomirs of MiR-199a-3p were injected into the caudal vein to figure out whether MiR-199a-3p could influence ARDS inflammation and lung injury, whereas the mimics or inhibitors of MiR-199a-3p, siRNA of Rab8a, or PAK4 inhibitor were transfected or applied to RAW264.7 cells to evaluate the mechanism of SAP release. Culture supernatants of RAW264.7 cells treated with LPS or bronchoalveolar lavage fluid from mice were collected for the isolation of SAPs. We found that MiR-199a-3p was over-expressed in the lungs of ARDS mice. The MiR-199a-3p antagomir alleviated, whereas the MiR-199a-3p agomir exacerbated LPS-induced inflammation in mice by promoting AM-derived SAP secretion. In addition, MiR-199a-3p over-expression exacerbated LPS-induced ARDS via activating Rab8a, and Rab8a silencing significantly suppressed the promoting influence of the MiR-199a-3p mimic on SAP secretion. Furthermore, MiR-199a-3p mimic activated Rab8a by directly inhibiting PAK4 expression. The novel finding of this study is that MiR-199a-3p participated in the regulation of SAP secretion and the inflammatory process via targeting of PAK4/Rab8a, and is a potential therapeutic candidate for ARDS treatment.

Whole Transcriptomic Analysis of Key Genes and Signaling Pathways in Endogenous ARDS.

Objective To analyze the differentially expressed genes (DEGs) in rats with endogenous acute respiratory distress syndrome (ARDS) lung injury and explore the pathogenesis and early diagnostic molecular markers using whole transcriptomic data. Methods Twelve 8-week-old male Sprague Dawley rats were selected and randomly and equally divided into ARDS lung injury group and normal control group. RNA was extracted from the left lung tissues of both the groups and sequenced using the paired-end sequencing mode of the Illumina Hiseq sequencing platform. The DEGs of miRNA, cirRNA, lncRNA, and mRNA were screened using DESeq2 software, and the ceRNA regulatory network was constructed using Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using the mRNA DEGs. STRING and Cytoscape software were used to construct the protein interaction network and identify the 15 key genes, which were verified using quantitative real-time polymerase chain reaction (qRT-PCR). Results Based on different screening conditions, and compared with the control group, the ARDS lung injury group showed 836 mRNA DEGs (386 upregulated and 450 downregulated), 110 lncRNA DEGs (53 upregulated and 57 downregulated), 19 circRNA DEGs (3 upregulated and 16 downregulated), and 6 miRNA DEGs (5 upregulated and 1 downregulated gene). GO showed that the DEGs of mRNA were mainly involved in biological processes, such as defense response to lipopolysaccharide and other organisms, leukocyte chemotaxis, neutrophil chemotaxis, and cytokine-mediated signaling. KEGG enrichment analysis showed that the DEGs played their biological roles mainly by participating in IL-17, TNF, and chemokine signaling pathways. The PPI analysis showed a total of 281 node proteins and 634 interaction edges. The top 15 key genes, which were screened, included Cxcl10, Mx1, Irf7, Isg15, Ifit3, Ifit2, Rsad2, Ifi47, Oasl, Dhx58, Usp18, Cmpk2, Herc6, Ifit1, and Gbp4. The ceRNA network analysis showed 69 nodes and 73 correlation pairs, where the key gene nodes were miR-21-3p, Camk2g, and Stx2. Conclusions The chemotaxis, migration, and degranulation of inflammatory cells, cytokine immune response, autophagy, and apoptosis have significant biological functions in the occurrence and development of endogenous acute lung injury during ARDS. Thus, the camk2g/miR-21-3p/lncRNA/circRNA network, CXCL10/CXCR3, and IL-17 signaling pathways might provide novel insights and targets for further studying the lung injury mechanism and clinical treatment.

Identification and validation of autophagy-related genes in exogenous sepsis-induced acute respiratory distress syndrome.

ObjectiveTo analyze the differential expression of autophagy‐related genes of sepsis‐induced acute respiratory distress syndrome (ARDS) as potential markers for early diagnosis.MethodsMale Sprague–Dawley rats (aged 8 weeks) were selected and randomly divided into sepsis‐induced ARDS group (n = 6) and a normal control group (n = 6). Lung tissue samples were collected for high‐throughput sequencing using Illumina HiSeq sequencing platform in the paired‐end sequencing mode. Differentially expressed genes (DEGs) were screened by DESeq. 2 software [|log2FC | ≥1 and p < .05] and autophagy‐related genes were identified using Mouse Genome Informatics. Co‐expressed autophagy‐related DEGs from these two datasets were filtered by construction of a Venn diagram. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these autophagy‐related DEGs and a protein interaction network was constructed using STRING and Cytoscape software to identify hub genes, which were verified by real‐time quantitative polymerase chain reaction (qRT‐PCR).ResultsA total of 42 autophagy‐related DEGs (26 upregulated genes and 16 downregulated genes) were identified. The GO and KEGG pathway analyses showed enrichment in 969 biological processes (BPs), three cellular components (CCs), eight molecular functions (MFs) and 27 signaling pathways. The protein interaction (PPI) network revealed 42 node proteins and 75 interacting edges, with an average node degree of 3.52, and an average local clustering coefficient of 0.509. Among the top 10 hub genes with the RNA‐Seq, six hub genes (Stat3, Il10, Ifng, Hmox1, Hif1a, and Nod2) were validated by qRT‐PCR (all p < .05).Conclusion42 potential autophagy‐related genes associated with sepsis‐induced ARDS lung injury were identified and six hub genes (Stat3, Il10, Ifng, Hmox1, Hif1a, and Nod2) may affect the development of ARDS by regulating autophagy. These results expanded our understanding of ARDS and might be useful in treatment of exogenous sepsis‐induced ARDS.

Mechanical power in AVM-2 versus conventional ventilation modes in various ARDS lung models. Bench study

Introduction Mechanical power has been linked to ventilator induced lung injury and mortality in acute respiratory distress syndrome (ARDS). Adaptive Ventilator Mode-2 is a closed-loop pressure-controlled mode with an optimal targeting scheme based on the inspiratory power equation that adjusts the respiratory rate and tidal volume to achieve a target minute ventilation. Conceptually, this mode should reduce the mechanical power delivered to the patients and thus reduce the incidence of ventilator induced lung injury. Methods A bench study using a lung simulator was conducted. We constructed three passive single compartment ARDS models (Mild, Moderate, Severe) with compliance of 40, 30, 20 ml/cmH2O respectively, and resistance of 10 cmH2O/L/s, with IBW 70 kg. We compared three different ventilator modes: AVM-2, Pressure Regulated Volume Control (PRVC), and Volume Controlled Ventilation (VCV) in six different scenarios: 3 levels of minute ventilation 7, 10.5, and 14 Lit/min (Experiment 1, 2, and 3 respectively), each with 3 different PEEP levels 10, 15, and 20 cmH2O (Experiment A, B, and C respectively) termed 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 3C respectively for a total of 81 experiments. The AVM-2 mode automatically selects the optimal tidal volume and respiratory rate per the dialed percent minute ventilation with an I:E ratio of 1:1. In the PRVC and VCV (constant flow) we selected target tidal volume 6ml/kg/IBW (420 ml) and respiratory rate adjusted to match the minute ventilation for the AVM-2 mode. I:E ratio was kept 1:2. The mechanical power delivered by the ventilator for each mode was computed and compared between the three modes in each experiment. Statistical analysis was done using Kruskal-Wallis test to analyze the difference between the three modes, post HOC Tukey test was used to analyze the difference between each mode where P &lt; 0.05 was considered statistically significant. The Power Compliance Index was calculated and compared in each experiment. Multiple regression analysis was performed in each mode to test the correlation of the variables of mechanical power to the total calculated power. Results There were statistically significant differences (P &lt; 0.001) between all the three modes regarding the ventilator delivered mechanical power. AVM-2 mode delivered significantly less mechanical power than VCV which in turn was less than PRVC. The Power Compliance index was also significantly lower (P &lt; 0.01) in the AVM-2 mode compared to the other conventional modes. Multiple regression analysis indicated that in AVM-2 mode, the driving pressure (P = 0.004), tidal volume (P &lt; 0.001), respiratory rate (P = 0.011) and PEEP (P &lt; 0.001) were significant predictors in the model. In the VCV mode, the respiratory rate (P 0&lt; 0.001) and PEEP (P &lt; 0.001) were significant predictors, but the driving pressure was a non-significant predictor (P = 0.08). In PRVC mode, the respiratory rate (P &lt; 0.001), PEEP (P &lt; 0.001) and driving pressure (P &lt; 0.001) were significant predictors. Conclusion AVM2 mode delivered less mechanical power compared to two conventional modes using low tidal volume in an ARDS lung model with different severities. This might translate to the reduction of the incidence of ventilator induced lung injury. Results need to be validated in clinical studies.

New Insights into the Alveolar Epithelium as a Driver of Acute Respiratory Distress Syndrome.

The alveolar epithelium serves as a barrier between the body and the external environment. To maintain efficient gas exchange, the alveolar epithelium has evolved to withstand and rapidly respond to an assortment of inhaled, injury-inducing stimuli. However, alveolar damage can lead to loss of alveolar fluid barrier function and exuberant, non-resolving inflammation that manifests clinically as acute respiratory distress syndrome (ARDS). This review discusses recent discoveries related to mechanisms of alveolar homeostasis, injury, repair, and regeneration, with a contemporary emphasis on virus-induced lung injury. In addition, we address new insights into how the alveolar epithelium coordinates injury-induced lung inflammation and review maladaptive lung responses to alveolar damage that drive ARDS and pathologic lung remodeling.

The Remarkable Roles of the Receptor for Advanced Glycation End Products (RAGE) and Its Soluble Isoforms in COVID-19: The Importance of RAGE Pathway in the Lung Injuries.

The respiratory symptoms of acute respiratory distress syndrome (ARDS) in the coronavirus disease 2019 (COVID-19) patients is associated with accumulation of pre-inflammatory molecules such as advanced glycation end-products (AGES), calprotectin, high mobility group box family-1 (HMGB1), cytokines, angiotensin converting enzyme 2 (ACE2), and other molecules in the alveolar space of lungs and plasma. The receptor for advanced glycation end products (RAGEs), which is mediated by the mitogen-activated protein kinase (MAPK), plays a critical role in the severity of chronic inflammatory diseases such as diabetes mellitus (DM) and ARDS. The RAGE gene is most expressed in the alveolar epithelial cells (AECs) of the pulmonary system. Several clinical trials are now being conducted to determine the possible association between the levels of soluble isoforms of RAGE (sRAGE and esRAGE) and the severity of the disease in patients with ARDS and acute lung injury (ALI). In the current article, we reviewed the most recent studies on the RAGE/ligands axis and sRAGE/esRAGE levels in acute respiratory illness, with a focus on COVID-19–associated ARDS (CARDS) patients. According to the research conducted so far, sRAGE/esRAGE measurements in patients with CARDS can be used as a powerful chemical indicator among other biomarkers for assessment of early pulmonary involvement. Furthermore, inhibiting RAGE/MAPK and Angiotensin II receptor type 1 (ATR1) in CARDS patients can be a powerful strategy for diminishing cytokine storm and severe respiratory symptoms.