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Abstract Background Uncontrolled inflammation caused by macrophages and monocytes plays a crucial role in worsening acute respiratory distress syndrome (ARDS). Previous studies have highlighted the importance of IFIH1 in regulating macrophage polarisation in ARDS triggered by pneumonia. However, the mechanisms by which IFIH1 is activated in ARDS remain unclear. Methods In this study, we utilised multiomics sequencing and molecular interaction experiments to explore the molecular mechanisms underlying IFIH1 activation in ARDS. Through the use of conditional gene knockout mice and primary cells, we demonstrated the significant role of these mechanisms in the development of ARDS. Additionally, we validated the associations between these mechanisms and ARDS by quantitative PCR analysis of CD14+ cells obtained from the peripheral blood of 140 ARDS patients. Results Our investigation revealed that lipopolysaccharide, a critical component derived from Gram‐negative bacteria, activated IFIH1 by upregulating a novel transcript known as IFIH1‐binding RNA1 (IBR1) in monocytes and macrophages. Specifically, as an endogenous double‐stranded RNA, IBR1 bind to the helicase domain of IFIH1 because of its unique double‐stranded structure. Deletion of IBR1 significantly reduced the activation of IFIH1, M1 polarisation of macrophages, and inflammatory lung injury in ARDS. Moreover, IBR1 directly induced M1 polarisation of macrophages and ARDS, whereas deletion of IFIH1 inhibited IBR1‐induced macrophage M1 polarisation and inflammatory lung injury. Importantly, we observed a notable increase in IBR1 expression in ARDS patients with pneumonia caused by Gram‐negative bacteria. Furthermore, we demonstrated that the delivery of IFIH1 mutants through exosomes effectively counteracted IBR1, thereby reducing pulmonary inflammation and alleviating lung injury. Conclusions This study revealed a novel mechanism involving IBR1, an endogenous double‐stranded RNA (dsRNA) that binds to IFIH1, shedding light on the complex process of macrophage polarisation in ARDS. The administration of IFIH1 variants has the potential to eliminate pulmonary dsRNA and alleviate inflammatory lung injury in ARDS. Highlights In monocytes and macrophages, the endogenous double‐stranded RNA, IFIH1‐binding RNA 1 (IBR1), binds to the helicase domain of IFIH1 because of its unique double‐stranded structure. IBR1 plays a significant role in macrophage polarisation and the development of acute respiratory distress syndrome (ARDS) induced by Gram‐negative bacteria or lipopolysaccharide (LPS). Administration of IFIH1 variants has potential for eliminating pulmonary IBR1 and reducing inflammatory lung injury in ARDS patients.

Abstract Background and Aims Endocan is a marker of endothelial damage. Data regarding the association of this proteoglycan and acute respiratory distress syndrome (ARDS) is discrepant. Hence, this study sought to investigate the possible correlation between serum/plasma endocan concentration and ARDS. Methods A systematic review and meta‐analysis of international online databases was conducted following PRISMA guidelines. PubMed, SCOPUS, Embase, and Web of Science were searched in March 2023, with the leading search terms being “ARDS” OR “respiratory distress” AND “endocan” and other associated terms. Studies that measured endocan levels in patients with ARDS and compared it with non‐ARDS controls or within different severities of ARDS were included. We performed a random‐effect meta‐analysis for pooling the differences using standardized mean difference (SMD) and 95% confidence interval (CI). Results We included 14 studies involving 1,058 patients. Those developing ARDS had significantly higher levels of endocan compared to those without ARDS (SMD: 0.47, 95% CI: 0.10–0.84, p = 0.01). Our meta‐analysis of three studies found that endocan levels in ARDS nonsurvivors were significantly higher than in survivors (SMD: 0.31, 95% CI: 0.02–0.60, p = 0.03). Three studies investigated endocan levels in different severities of ARDS. Only one of these studies reported significantly higher endocan levels in patients with worsening acute respiratory failure at Day 15. The other two reported no significant association between ARDS severity and circulating endocan levels. Conclusion Blood endocan levels were significantly higher in patients with ARDS than those without. Additionally, among patients with ARDS, blood endocan values were significantly elevated in nonsurvivors compared to survivors. These findings could help researchers design future studies and solidify these findings and finally, clinicians to take advantage of measuring endocan in clinical settings for assessment of patients with ARDS.

Abstract Trimethoprim‐sulfamethoxazole (TMP‐SMX) acute respiratory distress syndrome (ARDS) is a rare, but severe complication of a commonly prescribed antibiotic. TMP‐SMX typically affects young, otherwise well patients with a specific human leukocyte antigen type (HLA‐B*07:02 and HLA‐C*07:02). The condition is poorly understood with a unique pathological appearance and mechanism that remains unclear. Mortality rate is greater than one third. We describe the case of a previously well 18‐year‐old woman treated with a prolonged course of TMP‐SMX for a complex urinary tract infection who developed rapidly progressive respiratory failure requiring prolonged intensive care admission, extra‐corporeal membranous oxygenation, and eventual lung transplantation. No targeted treatment exists, further research is required to better understand disease pathogenetic mechanisms and potential therapeutic interventions.

Abstract Endothelial dysfunction is a critical feature of acute respiratory distress syndrome (ARDS) associated with higher disease severity and worse outcomes. Preclinical in vivo models of sepsis and ARDS have failed to yield useful therapies in humans, perhaps due to interspecies differences in inflammatory responses and heterogeneity of human host responses. Use of microphysiological systems (MPS) to investigate lung endothelial function may shed light on underlying mechanisms and targeted treatments for ARDS. We assessed the response to plasma from critically ill sepsis patients in our lung endothelial MPS through measurement of endothelial permeability, expression of adhesion molecules, and inflammatory cytokine secretion. Sepsis plasma induced areas of endothelial cell (EC) contraction, loss of cellular coverage, and luminal defects. EC barrier function was significantly worse following incubation with sepsis plasma compared to healthy plasma. EC ICAM‐1 expression, IL‐6 and soluble ICAM‐1 secretion increased significantly more after incubation with sepsis plasma compared with healthy plasma. Plasma from sepsis patients who developed ARDS further increased IL‐6 and sICAM‐1 compared to plasma from sepsis patients without ARDS and healthy plasma. Our results demonstrate the proof of concept that lung endothelial MPS can enable interrogation of specific mechanisms of endothelial dysfunction that promote ARDS in sepsis patients.

Abstract Background When influenza A‐related pneumonia is complicated by bacteria, aspergillus, and other infections, the disease is aggravated, while there is no research on the role of Epstein–Barr virus (EBV) on patients with influenza A‐related pneumonia. This study aimed to evaluate the relationship between the isolation of EBV and influenza A‐related pneumonia. Methods This is a clinical study based on the baseline data of a retrospective cohort. A total of 113 cases of influenza A‐related pneumonia who underwent polymerase chain reaction test for isolation of EBV‐DNA in lower respiratory tract specimens during six influenza seasons from 2013–2014 to 2018–2019 were enrolled. According to the results of EBV‐DNA, patients were divided into EBV‐positive group and EBV‐negative group, and the role of EBV‐DNA on patients with influenza A‐related pneumonia was analyzed. Regression analysis was used to explore the potential risk factors for the development of moderate‐to‐severe acute respiratory distress syndrome (ARDS) in patients with influenza A‐related pneumonia during hospitalization. Results Among 113 patients with influenza A‐related pneumonia, there were 53 patients with EBV‐positive and 60 patients with EBV‐negative. The EBV‐positive group had higher intensive care unit admission rate, hospital stay, invasive mechanical ventilation rate, extracorporeal membrane oxygenation rate, Sequential Organ Failure Assessment (SOFA) score, and moderate‐to‐severe ARDS rate. Patients were divided into severe group and mild group. Patients in severe group had lower lymphocyte count, platelet count, and albumin level, while the levels of aspartate aminotransferase, alanine transaminase, creatine kinase, lactic dehydrogenase, and total bilirubin were higher in severe group. The levels of D‐dimer, serum ferritin, C‐reactive protein, and procalcitonin were higher in severe group than those in the mild group. Multivariate logistic regression analysis revealed that the isolation of EBV (odds ratio = 2.713, 95% confidence interval: 1.094–6.729, P = 0.031) and lymphocyte count (odds ratio = 3.585, 95% confidence interval: 1.157–11.101, P = 0.027) were independent risk factors for moderate‐to‐severe ARDS in patients with influenza A‐related pneumonia. Conclusion The isolation rate of EBV in the lower respiratory tract was 46.9%. The length of hospital stays, intensive care unit admission rate, invasive mechanical ventilation rate, extracorporeal membrane oxygenation rate, SOFA score, and the proportion of moderate‐to‐severe ARDS in the EBV‐positive group were higher than those in the EBV‐negative group, while there was no effect on the death during hospitalization. The isolation of EBV in the lower respiratory tract and low lymphocyte count are independent risk factors for the development of moderate‐to‐severe ARDS in patients with influenza A‐related pneumonia.

Abstract Background Severe community‐acquired pneumonia (SCAP) is one of the world's most common diseases and a major etiology of acute respiratory distress syndrome (ARDS). Cuproptosis is a novel form of regulated cell death that can occur in various diseases. Methods Our study explored the degree of immune cell infiltration during the onset of severe CAP and identified potential biomarkers related to cuproptosis. Gene expression matrix was obtained from GEO database indexed GSE196399. Three machine learning algorithms were applied: The least absolute shrinkage and selection operator (LASSO), the random forest, and the support vector machine‐recursive feature elimination (SVM‐RFE). Immune cell infiltration was quantified by single‐sample gene set enrichment analysis (ssGSEA) scoring. Nomogram was constructed to verify the applicability of using cuproptosis‐related genes to predict the onset of severe CAP and its deterioration toward ARDS. Results Nine cuproptosis‐related genes were differentially expressed between the severe CAP group and the control group: ATP7B, DBT, DLAT, DLD, FDX1, GCSH, LIAS, LIPT1, and SLC31A1. All 13 cuproptosis‐related genes were involved in immune cell infiltration. A three‐gene diagnostic model was constructed to predict the onset of severe CAP: GCSH, DLD, and LIPT1. Conclusion Our study confirmed the involvement of the newly discovered cuproptosis‐related genes in the progression of SCAP.

Abstract Aims The coronavirus disease 2019 (COVID‐19) pandemic has resulted in more than 6 million deaths worldwide. Studies on the impact of obesity on patients hospitalized with COVID‐19 pneumonia have been conflicting, with some studies describing worse outcomes in patients with obesity, while other studies reporting no difference in outcomes. Previous studies on obesity and critical illness have described improved outcomes in patients with obesity, termed the “obesity paradox.” The study assessed the impact of obesity on the outcomes of COVID‐19 hospitalizations, using a nationally representative database. Materials and Methods ICD‐10 code U071 was used to identify all hospitalizations with the principal diagnosis of COVID‐19 infection in the National Inpatient Database 2020. ICD‐10 codes were used to identify outcomes and comorbidities. Hospitalizations were grouped based on body mass index (BMI). Multivariable logistic regression was used to adjust for demographic characteristics and comorbidities. Results A total of 56,033 hospitalizations were identified. 48% were male, 49% were white and 22% were black. Patients hospitalized with COVID‐19 pneumonia in the setting of obesity and clinically severe obesity were often younger. Adjusted for differences in comorbidities, there was a significant increase in mortality, incidence of mechanical ventilation, shock, and sepsis with increased BMI. The mortality was highest among hospitalizations with BMI ≥60, with an adjusted odds ratio of 2.66 (95% Confidence interval 2.18–3.24) compared to hospitalizations with normal BMI. There were increased odds of mechanical ventilation across all BMI groups above normal, with the odds of mechanical ventilation increasing with increasing BMI. Conclusion The results show that obesity is independently associated with worse patient outcomes in COVID‐19 hospitalizations and is associated with higher in‐patient mortality and higher rates of mechanical ventilation. The underlying mechanism of this is unclear, and further studies are needed to investigate the cause of this.

Abstract Introduction The use of the pulmonary artery catheter has decreased overtime; central venous blood gases are generally used in place of mixed venous samples. We want to evaluate the accuracy of oxygen and carbon dioxide related parameters from a central versus a mixed venous sample, and whether this difference is influenced by mechanical ventilation. Materials and Methods We analyzed 78 healthy female piglets ventilated with different mechanical power. Results There was a significant difference in oxygen‐derived parameters between samples taken from the central venous and mixed venous blood (Sv¯O2 = 74.6%, ScvO2 = 83%, p

Abstract Introduction Bladder paraganglioma is exceedingly rare, accounting for

Abstract Introduction High flow nasal cannula (HFNC) reduces the need for intubation in patients with hypoxaemic acute respiratory failure (ARF), but its added value in patients with severe coronavirus disease 2019 (COVID‐19) and a do‐not‐intubate (DNI) order is unknown. We aimed to assess (variables associated with) survival in these patients. Materials and methods We described a multicentre retrospective observational cohort study in five hospitals in the Netherlands and assessed the survival in COVID‐19 patients with severe acute respiratory failure and a DNI order who were treated with high flow nasal cannula. We also studied variables associated with survival. Results and discussion One‐third of patients survived after 30 days. Survival was 43.9% in the subgroup of patients with a good WHO performance status and only 16.1% in patients with a poor WHO performance status. Patients who were admitted to the hospital for a longer period prior to HFNC initiation were less likely to survive. HFNC resulted in an increase in ROX values, reflective of improved oxygenation and/or decreased respiratory rate. Conclusion Our data suggest that a trial of HFNC could be considered to increase chances of survival in patients with ARF due to COVID‐19 pneumonitis and a DNI order, especially in those with a good WHO performance status.

Abstract Introduction Acute respiratory distress syndrome (ARDS) is characterized by hypoxemia and increased lung permeability and would result in acute respiratory failure and with high mortality. In patients who survive from acute lung injury (ALI)/ARDS, it is an active process of the transition from injury to resolution depending on the coordinated immune system. The roles of regulatory CD4+T cells (Tregs) are now gradually being clarified during inflammation and resolution of ARDS. However, clear conclusions about roles of Tregs in ALI/ARDS are only a few. Objective This review provides an overview of phenotype, differentiation, and suppressive mechanisms of Tregs and focuses on keys of biology of Tregs in alveolar space during the inflammatory response and resolution of ALI/ARDS. Data Source Literature search of Web of Science, PubMed, and EMBASE was made to find relative articles about Tregs in ALI/ARDS. We used the following search terms: Tregs, ALI, ARDS, inflammation, and resolution. Conclusion More and more studies have indicated Tregs involved in the processes of inflammation and resolution of ALI/ARDS. A deep understanding of the roles of Tregs may indicate new treatments for patients of ARDS. Therapies aimed at expansion or adaptive transfer of Tregs could be an effective therapy to ARDS patients.

Abstract Highly pathogenic coronavirus (CoV) infection induces a defective innate antiviral immune response coupled with the dysregulated release of proinflammatory cytokines and finally results in acute respiratory distress syndrome (ARDS). A timely and appropriate triggering of innate antiviral response is crucial to inhibit viral replication and prevent ARDS. However, current medical countermeasures can rarely meet this urgent demand. Here, an antiviral nanobiologic named CoVR‐MV is developed, which is polymerized of CoVs receptors based on a biomimetic membrane vesicle system. The designed CoVR‐MV interferes with the viral infection by absorbing the viruses with maximized viral spike target interface, and mediates the clearance of the virus through its inherent interaction with macrophages. Furthermore, CoVR‐MV coupled with the virus promotes a swift production and signaling of endogenous type I interferon via deregulating 7‐dehydrocholesterol reductase (DHCR7) inhibition of interferon regulatory factor 3 (IRF3) activation in macrophages. These sequential processes re‐modulate the innate immune responses to the virus, trigger spontaneous innate antiviral defenses, and rescue infected Syrian hamsters from ARDS caused by SARS‐CoV‐2 and all tested variants.

Abstract Panton‐Valentine leucocidin toxin‐producing methicillin‐resistant staphylococcus aureus is an important uncommon cause of community‐acquired pneumonia; we describe a case of necrotizing pneumonia presenting as respiratory failure necessitating early initiation of extracorporeal membrane oxygenation, acute kidney injury and rhabdomyolysis, awareness, prompt recognition and appropriate management are crucial due to possible significant pathology.

Abstract Pulmonary hydatid cysts (PHC) and their complications are still a health concern in endemic countries. Here we described a 17‐year‐old male presented with a large PHC with a spontaneous rupture. He developed acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. He was treated with albendazole, broad‐spectrum antibiotics, and corticosteroids. The patient's general condition did not allow any attempt for surgical resection of the cyst. He was discharged in stable condition after one month and referred to a thoracic surgeon for resection of the cyst. As far as we know ARDS after hydatid cyst rupture was rarely reported, and through this case report we aimed to raise awareness of this possible life‐threatening complication.

Abstract Hemodialyzed patients with COVID‐19 are at risk for severe complications from acute respiratory distress syndrome, requiring admission to the intensive‐care unit for invasive mechanical ventilation. Post tracheotomy stenosis can be a life‐threatening condition that commonly occurs after iatrogenic injury secondary to tracheotomy or tracheal intubation. We report a case of a 44‐year‐old female patient on maintenance haemodialysis who presented a COVID‐19‐related ARDS that required mechanical ventilation for 4 weeks, followed by a persistent stridor and finally succumbed, 1 month after being discharged from intensive care unit, from a severe respiratory distress due to a tracheal stenosis. Our aim is to highlight the importance of the early recognition and management of post tracheotomy stenosis in patients with persistent respiratory difficulty as stridor after prolonged intubation requiring tracheotomy, in order to improve the prognosis of these patients.

Abstract Background New drugs for veterinary patients with acute respiratory distress syndrome (ARDS) are urgently needed. Early or late postinfection treatment of influenza‐infected mice with the liponucleotide cytidine diphosphocholine (CDP‐choline) resulted in decreased hypoxemia, pulmonary edema, lung dysfunction, and inflammation without altering viral replication. These findings suggested CDP‐choline could have benefit as adjunctive treatment for ARDS in veterinary patients (VetARDS). Objectives Determine if parenterally administered CDP‐choline can attenuate mild VetARDS in dogs with aspiration pneumonia. Animals Dogs admitted to a veterinary intensive care unit (ICU) for aspiration pneumonia. Methods Subjects were enrolled in a randomized, double‐blinded, placebo‐controlled trial of treatment with vehicle (0.1 mL/kg sterile 0.9% saline, IV; n = 8) or CDP‐choline (5 mg/kg in 0.1 mL/kg 0.9% saline, IV; n = 9) q12h over the first 48 hours after ICU admission. Results No significant differences in signalment or clinical findings were found between placebo‐ and CDP‐choline‐treated dogs on admission. All dogs exhibited tachycardia, tachypnea, hypertension, hypoxemia, hypocapnia, lymphopenia, and neutrophilia. CDP‐choline administration resulted in rapid, progressive, and clinically relevant increases in oxygenation as determined by pulse oximetry and ratios of arterial oxygen partial pressure (PaO2 mmHg) to fractional inspired oxygen (% FiO2) and decreases in alveolar‐arterial (A‐a) gradients that did not occur in placebo (saline)‐treated animals. Treatment with CDP‐choline was also associated with less platelet consumption over the first 48 hours, but had no detectable detrimental effects. Conclusions and Clinical Importance Ctyidine diphosphcholine acts rapidly to promote gas exchange in dogs with naturally occurring aspiration pneumonia and is a potential adjunctive treatment in VetARDS patients.

Abstract Optimal oxygenation in the intensive care unit requires adequate pulmonary gas exchange, oxygen‐carrying capacity in the form of hemoglobin, sufficient delivery of oxygenated hemoglobin to the tissue, and an appropriate tissue oxygen demand. In this Case Study in Physiology, we describe a patient with COVID‐19 whose pulmonary gas exchange and oxygen delivery were severely compromised by COVID‐19 pneumonia requiring extracorporeal membrane oxygenation (ECMO) support. His clinical course was complicated by a secondary superinfection with staphylococcus aureus and sepsis. This case study is provided with two goals in mind (1) We outline how basic physiology was used to address life‐threatening consequences of a novel infection—COVID‐19. (2) We describe a strategy of whole‐body cooling to lower the cardiac output and oxygen consumption, use of the shunt equation to optimize flow to the ECMO circuit, and transfusion to improve oxygen‐carrying capacity when ECMO alone failed to provide sufficient oxygenation.

Abstract We previously identified a missense single nucleotide polymorphism rs2228315 (G>A, Met62Ile) in the selectin‐P‐ligand gene (SELPLG), encoding P‐selectin glycoprotein ligand 1 (PSGL‐1), to be associated with increased susceptibility to acute respiratory distress syndrome (ARDS). These earlier studies demonstrated that SELPLG lung tissue expression was increased in mice exposed to lipopolysaccharide (LPS)‐ and ventilator‐induced lung injury (VILI) suggesting that inflammatory and epigenetic factors regulate SELPLG promoter activity and transcription. In this report, we used a novel recombinant tandem PSGL1 immunoglobulin fusion molecule (TSGL‐Ig), a competitive inhibitor of PSGL1/P‐selectin interactions, to demonstrate significant TSGL‐Ig‐mediated decreases in SELPLG lung tissue expression as well as highly significant protection from LPS‐ and VILI‐induced lung injury. In vitro studies examined the effects of key ARDS stimuli (LPS, 18% cyclic stretch to simulate VILI) on SELPLG promoter activity and showed LPS‐mediated increases in SELPLG promoter activity and identified putative promoter regions associated with increased SELPLG expression. SELPLG promoter activity was strongly regulated by the key hypoxia‐inducible transcription factors, HIF‐1α, and HIF‐2α as well as NRF2. Finally, the transcriptional regulation of SELPLG promoter by ARDS stimuli and the effect of DNA methylation on SELPLG expression in endothelial cell was confirmed. These findings indicate SELPLG transcriptional regulation by clinically‐relevant inflammatory factors with the significant TSGL‐Ig‐mediated attenuation of LPS and VILI highly consistent with PSGL1/P‐selectin as therapeutic targets in ARDS.

Key message NPPE imaging findings were reported to show a preferential central and nondependent distribution. However, in our case, NPPE showed a peripheral accent pattern, resembling the ARDS pattern of COVID‐19 pneumonia 4 months ago. Capillary damage from COVID‐19 might still exist.

Abstract Aims We continuously monitored right ventricular pressures and the estimated diastolic pulmonary artery pressure (ePAD) for up to 30 days in mechanically ventilated patients with severe COVID‐19 acute respiratory distress syndrome in order to detect and treat right ventricular and pulmonary artery hypertension. Methods and Results We retrospectively evaluated right ventricular pressures and the ePAD measured in 30 invasively ventilated COVID‐19 acute respiratory distress syndrome patients between 1 October 2020 and 31 March 2021. We divided the patients into two groups, survivors and non‐survivors based on their 60 day mortality. Primary outcome variables were the values of right ventricular pressures and the ePAD over time after insertion of the right ventricular probe. Right ventricular systolic pressure [RVSP, (IQR; 25th to 75th percentile)] was significantly lower on the first and the last measurement day in the survivors compared with the non‐survivors [Day 1: 38 (27–45) vs. 46 (44–49), P = 0.036; last day: 36 (27–44) vs. 51 (40–57) mmHg, P = 0.006]. 16/22 survivors and 7/8 non‐survivors received sildenafil orally, one survivor received additionally inhaled nitric oxide and one survivor and one non‐survivor each inhaled iloprost. On the last measurement day, both right ventricular pressure amplitude [31 (26–37) vs. 38 (35–47) mmHg, P = 0.027] and ePAD [22 (16–26) vs. 31 (23–34) mmHg, P = 0.043] were significantly lower in the survivors compared with the non‐survivors. Four patients in the survivor group developed excessive high RVSP in the course of their disease (peak: 57/61/78/105 mmHg). After sildenafil 20 mg every 8 h, additional inhaled nitric oxide (20 ppm) in one and additional inhaled iloprost 20 μg every 4 h in another patient RVSP consecutively decreased substantially in all four patients until the end of the measurement period (47/23/42/47 mmHg). Conclusions The RVSP and right ventricular pressure amplitude both were significantly lower in the survivors compared with those in the non‐survivors with a significant decrease in RVSP over time in the survivors suggesting successful lowering by pulmonary vasodilators. The ePAD as an indicator of left heart failure was significantly higher in non‐survivors compared to the surviving patients.

Abstract We report a case of out‐of‐hospital cardiac arrest occurred in a 61‐year‐old recreational female diver. After resuscitation, the patient was referred to the hospital. With data provided by witnesses and appropriate medical investigations, drowning related to a failed rebreather system was the most plausible explanation. Patient outcome was favorable.

Abstract Selective serotonin reuptake inhibitors (SSRIs) have anti‐inflammatory properties that may have clinical utility in treating severe pulmonary manifestations of COVID‐19. SSRIs exert anti‐inflammatory effects at three mechanistic levels: (a) inhibition of proinflammatory transcription factor activity, including NF‐κB and STAT3; (b) downregulation of lung tissue damage and proinflammatory cell recruitment via inhibition of cytokines, including IL‐6, IL‐8, TNF‐α, and IL‐1β; and (c) direct suppression inflammatory cells, including T cells, macrophages, and platelets. These pathways are implicated in the pathogenesis of COVID‐19. In this review, we will compare the pathogenesis of lung inflammation in pulmonary diseases including COVID‐19, ARDS, and chronic obstructive pulmonary disease (COPD), describe the anti‐inflammatory properties of SSRIs, and discuss the applications of SSRIS in treating COVID‐19‐associated inflammatory lung disease.

Abstract Fibrin deposition in the alveolar spaces during pulmonary involvement of COVID‐19 impairs the O2/CO2 exchange and leads to respiratory symptoms. In this report, Recombinant Tissue Plasminogen Activator (r‐tPA) has been nebulized to 3 critically ill COVID‐19 patients in order to resolve the deposited fibrin while avoiding the risk of bleeding. Based on these observations, nebulization of r‐tPA may be a potential therapeutic approach and new area of research for future studies.

Abstract Yellow nail syndrome is a rare lymphatic abnormality without clear pathogenesis. Hereby, we report a 70‐year‐old Sudanese female patient who presented with recurrent cough, recurrent lower limb swelling, and yellowish nail discoloration diagnosed as yellow nail syndrome but unfortunately passed away due to acute respiratory distress syndrome (ARDS).

Background Lung injury, a severe adverse outcome of lipopolysaccharide‐induced acute respiratory distress syndrome, is attributed to excessive neutrophil recruitment and effector response. Poldip2 (polymerase δ‐interacting protein 2) plays a critical role in regulating endothelial permeability and leukocyte recruitment in acute inflammation. Thus, we hypothesized that myeloid Poldip2 is involved in neutrophil recruitment to inflamed lungs. Methods and Results After characterizing myeloid‐specific Poldip2 knockout mice, we showed that at 18 hours post‐lipopolysaccharide injection, bronchoalveolar lavage from myeloid Poldip2‐deficient mice contained fewer inflammatory cells (8 [4–16] versus 29 [12–57]×104/mL in wild‐type mice) and a smaller percentage of neutrophils (30% [28%–34%] versus 38% [33%–41%] in wild‐type mice), while the main chemoattractants for neutrophils remained unaffected. In vitro, Poldip2‐deficient neutrophils responded as well as wild‐type neutrophils to inflammatory stimuli with respect to neutrophil extracellular trap formation, reactive oxygen species production, and induction of cytokines. However, neutrophil adherence to a tumor necrosis factor‐α stimulated endothelial monolayer was inhibited by Poldip2 depletion (225 [115–272] wild‐type [myePoldip2+/+] versus 133 [62–178] myeloid‐specific Poldip2 knockout [myePoldip2‐/‐] neutrophils) as was transmigration (1.7 [1.3–2.1] versus 1.1 [1.0–1.4] relative to baseline transmigration). To determine the underlying mechanism, we examined the surface expression of β2‐integrin, its binding to soluble intercellular adhesion molecule 1, and Pyk2 phosphorylation. Surface expression of β2‐integrins was not affected by Poldip2 deletion, whereas β2‐integrins and Pyk2 were less activated in Poldip2‐deficient neutrophils. Conclusions These results suggest that myeloid Poldip2 is involved in β2‐integrin activation during the inflammatory response, which in turn mediates neutrophil‐to‐endothelium adhesion in lipopolysaccharide‐induced acute respiratory distress syndrome.

Abstract Global knockout of the nonmuscle isoform of myosin light‐chain kinase (nmMLCK), a primary cellular regulator of cytoskeletal machinery, is strongly protective in preclinical murine models of inflammatory lung injury. The current study was designed to assess the specific contribution of endothelial cell (EC) nmMLCK to the severity of murine inflammatory lung injury produced by lipopolysaccharide (LPS) and mechanical ventilation ventilator‐induced lung injury or ventilation (VILI). Responses to combined LPS/VILI exposure were assessed in: (i) wild‐type (WT) C57BL/6J mice; (ii) transgenic mice with global deletion of nmMLCK (nmMylk−/−); (iii) transgenic nmMylk−/− mice with overexpression of nmMLCK restricted to the endothelium (nmMylk−/−/ec‐tg+). Lung inflammation indices included lung histology, bronchoalveolar lavage (BAL) polymorphonuclear leukocytes (PMNs), lung protein biochemistry, tissue albumin levels, Evans blue dye (EBD) lung extravasation, and plasma cytokines (interleukin‐6 [IL‐6], keratinocyte chemoattractant [KC]/IL‐8, IL‐1bβ, extracellular nicotinamide phosphoribosyltransferase, tumor necrosis factor‐α). Compared to WT C57BL/6J mice, the severity of LPS/VILI‐induced lung injury was markedly reduced in mice with global nmMLCK deletion reflected by reductions in histologic inflammatory lung injury, BAL PMN counts, mitogen‐activated protein kinase, and NF‐kB pathway activation in lung homogenates, plasma cytokine levels, and parameters of lung permeability (increased BAL protein, tissue albumin levels, EBD lung extravasation). In contrast, mice with restricted overexpression of nmMLCK in EC (nmMylk−/−/ec‐tg+) showed significant persistence of LPS/VILI‐induced lung injury severity compared to WT mice. In conclusion, these studies strongly endorse the role of EC nmMLCK in driving the severity of preclinical inflammatory lung injury. Precise targeting of EC nmMLCK may represent an attractive therapeutic strategy to reduce lung inflammation and both lung and systemic vascular permeability.

Abstract Acute respiratory distress syndrome (ARDS) is a major clinical problem without available therapies. Known risks for ARDS include severe sepsis, SARS‐CoV‐2, gram‐negative bacteria, trauma, pancreatitis, and blood transfusion. During ARDS, blood fluids and inflammatory cells enter the alveoli, preventing oxygen exchange from air into blood vessels. Reduced pulmonary endothelial barrier function, resulting in leakage of plasma from blood vessels, is one of the major determinants in ARDS. It is, however, unknown why systemic inflammation particularly targets the pulmonary endothelium, as endothelial cells (ECs) line all vessels in the vascular system of the body. In this study, we examined ECs of pulmonary, umbilical, renal, pancreatic, and cardiac origin for upregulation of adhesion molecules, ability to facilitate neutrophil (PMN) trans‐endothelial migration (TEM) and for endothelial barrier function, in response to the gram‐negative bacterial endotoxin LPS. Interestingly, we found that upon LPS stimulation, pulmonary ECs showed increased levels of adhesion molecules, facilitated more PMN‐TEM and significantly perturbed the endothelial barrier, compared to other types of ECs. These observations could partly be explained by a higher expression of the adhesion molecule ICAM‐1 on the pulmonary endothelial surface compared to other ECs. Moreover, we identified an increased expression of Cadherin‐13 in pulmonary ECs, for which we demonstrated that it aids PMN‐TEM in pulmonary ECs stimulated with LPS. We conclude that pulmonary ECs are uniquely sensitive to LPS, and intrinsically different, compared to ECs from other vascular beds. This may add to our understanding of the development of ARDS upon systemic inflammation.

Abstract During the 2020 Spring Festival in China, the outbreak of a novel coronavirus, named COVID‐19 by WHO, brought on a worldwide panic. According to the clinical data of infected patients, radiologic evidence of lung edema is common and deserves clinical attention. Lung edema is a manifestation of acute lung injury (ALI) and may progress to hypoxemia and potentially acute respiratory distress syndrome (ARDS). Patients diagnosed with ARDS have poorer prognosis and potentially higher mortality. Although no effective treatment is formally approved for COVID‐19 infection, support of ventilation with oxygen therapy and sometimes mechanical ventilation is often required. Treatment with systemic and/or local glucocorticoids might be helpful to alleviate the pulmonary inflammation and edema, which may decrease the development and/or consequences of ARDS. In this article, we focus on the lung edema and ALI of patients with this widely transmitted COVID‐19 infection in order to provide clinical indications and potential therapeutic targets for clinicians and researchers.

Background: Uncontrolled inflammation caused by macrophages and monocytes plays a crucial role in worsening acute respiratory distress syndrome (ARDS). Previous studies have highlighted the importance of IFIH1 in regulating macrophage polarisation in ARDS triggered by pneumonia. However, the mechanisms by which IFIH1 is activated in ARDS remain unclear., Methods: In this study, we utilised multiomics sequencing and molecular interaction experiments to explore the molecular mechanisms underlying IFIH1 activation in ARDS. Through the use of conditional gene knockout mice and primary cells, we demonstrated the significant role of these mechanisms in the development of ARDS. Additionally, we validated the associations between these mechanisms and ARDS by quantitative PCR analysis of CD14 + cells obtained from the peripheral blood of 140 ARDS patients., Results: Our investigation revealed that lipopolysaccharide, a critical component derived from Gram-negative bacteria, activated IFIH1 by upregulating a novel transcript known as IFIH1-binding RNA1 (IBR1) in monocytes and macrophages. Specifically, as an endogenous double-stranded RNA, IBR1 bind to the helicase domain of IFIH1 because of its unique double-stranded structure. Deletion of IBR1 significantly reduced the activation of IFIH1, M1 polarisation of macrophages, and inflammatory lung injury in ARDS. Moreover, IBR1 directly induced M1 polarisation of macrophages and ARDS, whereas deletion of IFIH1 inhibited IBR1-induced macrophage M1 polarisation and inflammatory lung injury. Importantly, we observed a notable increase in IBR1 expression in ARDS patients with pneumonia caused by Gram-negative bacteria. Furthermore, we demonstrated that the delivery of IFIH1 mutants through exosomes effectively counteracted IBR1, thereby reducing pulmonary inflammation and alleviating lung injury., Conclusions: This study revealed a novel mechanism involving IBR1, an endogenous double-stranded RNA (dsRNA) that binds to IFIH1, shedding light on the complex process of macrophage polarisation in ARDS. The administration of IFIH1 variants has the potential to eliminate pulmonary dsRNA and alleviate inflammatory lung injury in ARDS., Highlights: In monocytes and macrophages, the endogenous double-stranded RNA, IFIH1-binding RNA 1 (IBR1), binds to the helicase domain of IFIH1 because of its unique double-stranded structure. IBR1 plays a significant role in macrophage polarisation and the development of acute respiratory distress syndrome (ARDS) induced by Gram-negative bacteria or lipopolysaccharide (LPS). Administration of IFIH1 variants has potential for eliminating pulmonary IBR1 and reducing inflammatory lung injury in ARDS patients., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

A wide variety of inflammatory mediators, mainly cytokines and chemokines, are induced during SARS CoV-2 infection. Among these proinflammatory mediators, chemokines tend to play a pivotal role in virus-mediated immunopathology. The C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1) is a potent proinflammatory cytokine and strong chemoattractant of monocytes, macrophages and CD4+ T cells bearing C-C chemokine receptor type-2 (CCR2). Besides controlling immune cell trafficking, CCL2 is also involved in multiple pathophysiological processes including systemic hyperinflammation associated cytokine release syndrome (CRS), organ fibrosis and blood coagulation. These pathological features are commonly manifested in severe and fatal cases of COVID-19. Given the crucial role of CCL2 in COVID-19 pathogenesis, the CCL2:CCR2 axis may constitute a potential therapeutic target to control virus-induced hyperinflammation and multi-organ dysfunction. Herein we describe recent advances on elucidating the role of CCL2 in COVID-19 pathogenesis, prognosis, and a potential target of anti-inflammatory interventions., (© 2024 The Author(s). Reviews in Medical Virology published by John Wiley & Sons Ltd.)

Abstract Background and Aims Most published reports of COVID‐19 Intensive Care Unit (ICU) patients are from large tertiary hospitals and often present short‐term or incomplete outcome data. There are reports indicating that ICUs with fewer beds are associated with higher mortality. This study aimed to investigate the definitive outcome and patient characteristics of the complete first wave of COVID‐19 patients admitted to ICU in a secondary hospital. Methods In this prospective observational study, all patients with respiratory failure and a positive SARS‐CoV‐2 test admitted to Västerås Hospital ICU between 24 March and July 22, 2020 were included. The primary outcome was defined as 90‐day mortality. Secondary outcomes included ICU length of stay, hospital length of stay, number of days with invasive ventilation, need for vasopressors/inotropes, and use of renal replacement therapy. Results Fifty‐three patients were included. Median age (range) was 59 (33‐76) and 74% were men. Obesity and hypertension were the most common comorbidities and 45% of the patients were born outside Europe. Ninety‐day mortality was 30%. Median ICU length of stay (interquartile range) was 14 (5‐24) days and the duration of invasive mechanical ventilation 16 (12‐26) days. No patients received dialysis at 90‐day follow‐up. Conclusion In this cohort of COVID‐19 patients treated in a secondary hospital ICU, mortality rates were low compared to early studies from China, Italy, and the United States, but similar to other government‐funded hospitals in Scandinavia. A preparatory reorganization enabled an increase in ICU capacity, hence avoiding an overwhelmed intensive care organization.

Abstract Extracorporeal membrane oxygenation is indispensable for critically severe COVID‐19 patients. However, it would be inapplicable to patients with a rare blood type or blood transfusion refusal. In that case, severely conservative fluid management with the sacrifice of renal functions and hydrocortisone therapy should be considered for better oxygenation.

Abstract Even in the absence of disease‐specific radiological signs of granulomatosis with polyangiitis (GPA), severe intrapulmonary GPA may be present. Rapidly establishing the diagnosis with a confirmatory biopsy is key to initiate lifesaving therapy.

Abstract Methylprednisolone pulse therapy has significant anti‐inflammatory effects in multiple sclerosis. Acute respiratory distress syndrome as a probable adverse effect of methylprednisolone pulse therapy in MS patients should be considered.

Abstract High‐dose short‐term corticosteroid therapy is effective and produces favorable clinical outcome in patients with severe 2019‐nCoV infection who are candidates for mechanical ventilation with close monitor/ing for the adverse effect of corticosteroids.

Abstract Introduction Current knowledge on the use of extracorporeal membrane oxygenation (ECMO) in COVID‐19 remains limited to small series and registry data. In the present retrospective monocentric study, we report on our experience, our basic principles, and our results in establishing and managing ECMO in critically ill COVID‐19 patients. Methods A cohort study was conducted in patients with severe acute respiratory distress syndrome (ARDS) related to COVID‐19 pneumonia admitted to the ICU of the Geneva University Hospitals and supported by VV‐ECMO from March 14 to May 31. The VV‐ECMO implementation criteria were defined according to an institutional algorithm validated by the local crisis unit and the Swiss Society of Intensive Care Medicine. Results Out of 137 ARDS patients admitted to our ICU, 10 patients (age 57 ± 4 years, BMI 31.5 ± 5 kg/m2, and SAPS II score 56 ± 3) were put on VV‐ECMO. The mean duration of mechanical ventilation before ECMO and mean time under ECMO were 7 ± 3 days and 19 ± 11 days, respectively. The ICU and hospital length of stay were 26 ± 11 and 35 ± 10 days, respectively. The survival rate for patients on ECMO was 40%. The comparative analysis between survivors and non‐survivors highlighted that survivors had a significantly shorter mechanical ventilation duration before ECMO (4 ± 2 days vs. 9 ± 2 days, p = 0.01). All the patients who had more than 150 h of mechanical ventilation before the application of ECMO ultimately died. Conclusion The present results suggest that VV‐ECMO can be safely utilized in appropriately selected COVID‐19 patients with refractory hypoxemia. The main information for clinicians is that late VV‐ECMO therapy (i.e., beyond the seventh day of mechanical ventilation) seems futile.

Abstract The new coronavirus SARS‐CoV‐2 is a global pandemic and a severe public health crisis. SARS‐CoV‐2 is highly contagious and shows high mortality rates, especially in elderly and patients with pre‐existing medical conditions. At the current stage, no effective drugs are available to treat these patients. In this review, we analyse the rationale of targeting RGD‐binding integrins to potentially inhibit viral cell infection and to block TGF‐β activation, which is involved in the severity of several human pathologies, including the complications of severe COVID‐19 cases. Furthermore, we demonstrate the correlation between ACE2 and TGF‐β expression and the possible consequences for severe COVID‐19 infections. Finally, we list approved drugs or drugs in clinical trials for other diseases that also target the RGD‐binding integrins or TGF‐β. These drugs have already shown a good safety profile and, therefore, can be faster brought into a trial to treat COVID‐19 patients.

Abstract Cell‐free hemoglobin (CFH) is associated with severe lung injury in human patients and is sufficient to induce airspace inflammation and alveolar–capillary barrier dysfunction in an experimental model of acute lung injury. The mechanisms through which this occurs are unknown. One key pathway which regulates inflammation during acute lung injury is the NLRP3 inflammasome. Because CFH can act as a damage‐associated molecular pattern, we hypothesized that CFH may activate the NLRP3 inflammasome during acute lung injury. Primary mouse alveolar macrophages and cultured murine macrophages exposed to CFH (0–1 mg/ml) for 24 hr demonstrated robust upregulation of the NLRP3 inflammasome components NLRP3, caspase‐1, and caspase‐11. Maximal induction of the NLRP3 inflammasome by CFH required TLR4. Compared to wild‐type controls, mice lacking NLRP3 developed less airspace inflammation (2.7 × 105 cells/ml in bronchoalveolar lavage fluid versus. 1.1 × 105/ml, p = .006) after exposure to intratracheal CFH. Together, these data demonstrate that CFH can stimulate the NLRP3 inflammasome in macrophages and that this pathway may be important in the pathogenesis of CFH‐induced acute lung injury.

Abstract Coronavirus Disease 2019 (COVID‐19) is a public health emergency of international concern with increasing cases globally, including in Indonesia. COVID‐19 clinical manifestations ranging from asymptomatic, acute respiratory illness, respiratory failure that necessitate mechanical ventilation and support in an intensive care unit (ICU), to multiple organ dysfunction syndromes. Some patients might present with happy hypoxia, a condition where patients have low oxygen saturations (SpO2

Abstract We report a case series of seven mechanically ventilated patients with acute respiratory distress syndrome (ARDS) caused by coronavirus disease (COVID‐19) who received early treatment with high‐dose, short‐term systemic corticosteroids to prevent cytokine overproduction. Of the seven patients, four were male and median age was 69 years. They were intubated within seven days after admission when their respiratory status rapidly worsened. At that time, we administered 1000 or 500 mg/day for three days of methylprednisolone intravenously, followed by 1 mg/kg and tapered off. The median duration for the total administration of corticosteroids was 13 days. This high‐dose, short‐term corticosteroid therapy enabled extubation of the patients within seven days. Many questions on the clinical management of COVID‐19 remain unanswered, and data on corticosteroid therapy as a choice of treatment are mixed. We present the clinical course of our cases, review the previous evidence, and discuss management.

Abstract Recent studies have demonstrated a strong link between acute respiratory distress syndrome (ARDS) and the levels of iron and iron‐related proteins in the lungs. However, the role of iron overload in ARDS development has yet to be characterized. In this study, we compared the highly iron‐overloaded hepcidin knockout mice (HKO) to their iron‐sufficient wild‐type (WT) littermates in a model of sterile acute lung injury (ALI) induced by treatment with oropharyngeal (OP) LPS. There were no major differences in systemic inflammatory response or airway neutrophil infiltration between the two groups at the time of maximal injury (days 2 and 3) or during the recovery phase (day 7). Hepcidin knockout mice had transiently increased bronchoalveolar lavage fluid (BALF) protein and MPO activity in the lung and BALF on day 3, indicating worse vascular leakage and increased neutrophil activity, respectively. The increased ALI severity in iron‐overloaded mice may be a result of increased apoptosis of lung tissue, as evidenced by an increase in cleaved capsase‐3 protein in lung homogenates from HKO mice versus WT mice on day 3. Altogether, our data suggest that even severe iron overload has a relatively minor and transient effect in LPS‐induced ALI.

We present a novel computational model for the dynamics of alveolar recruitment/derecruitment (RD), which reproduces the underlying characteristics typically observed in injured lungs. The basic idea is a pressure- and time-dependent variation of the stress-free reference volume in reduced dimensional viscoelastic elements representing the acinar tissue. We choose a variable reference volume triggered by critical opening and closing pressures in a time-dependent manner from a straightforward mechanical point of view. In the case of (partially and progressively) collapsing alveolar structures, the volume available for expansion during breathing reduces and vice versa, eventually enabling consideration of alveolar collapse and reopening in our model. We further introduce a method for patient-specific determination of the underlying critical parameters of the new alveolar RD dynamics when integrated into the tissue elements, referred to as terminal units, of a spatially resolved physics-based lung model that simulates the human respiratory system in an anatomically correct manner. Relevant patient-specific parameters of the terminal units are herein determined based on medical image data and the macromechanical behavior of the lung during artificial ventilation. We test the whole modeling approach for a real-life scenario by applying it to the clinical data of a mechanically ventilated patient. The generated lung model is capable of reproducing clinical measurements such as tidal volume and pleural pressure during various ventilation maneuvers. We conclude that this new model is an important step toward personalized treatment of ARDS patients by considering potentially harmful mechanisms-such as cyclic RD and overdistension-and might help in the development of relevant protective ventilation strategies to reduce ventilator-induced lung injury (VILI)., (© 2023 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)