Megakaryocyte infection by SARS-CoV-2 drives the formation of pathogenic afucosylated IgG antibodies in mice (preprint)

Despite more than 90% of total plasma fucosylated IgG, specific IgGs with low core fucosylation are found sporadically in response to enveloped virus infections and to alloantigens on blood cells. IgG responses with low core fucosylation are directly pathogenic in SARS-CoV-2 and dengue infections. In COVID-19, formation of IgG with low core fucosylation (afucosylated IgG) against spike protein (S) predicts and directly mediates disease progression to severe form. Low fucosylation of IgG causes increased antibody-dependent cellular toxicity mediated by intense Fc{gamma}R-mediated stimulation of platelets, monocytes, macrophages, and natural killer cells. The mechanism of afucosylated IgG formation has remained elusive thus far in COVID-19, dengue infection, and other disorders. This study demonstrates that infection of megakaryocytes by SARS-CoV-2 drives the formation of pathogenic anti-S afucosylated IgGs, causing pulmonary vascular thrombosis, acute lung injury, and death in Fc{gamma}-expressing mice.

Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential (preprint)

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation.

We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post-injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, Foxm1, and were responsible for the rapid replenishment of all depleted EC populations by 7 days post-injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor-positive endothelial progenitors responsible for the regeneration of the lung microvasculature.

Renin-angiotensin system inhibitors mitigate radiation pneumonitis by activating ACE2-angiotensin-(1-7) axis via NF-κB/MAPK pathway.

Radiation pneumonitis (RP) affects both patients and physicians during radiation therapy for lung cancer. To date, there are no effective drugs for improving the clinical outcomes of RP. The activation of angiotensin-converting enzyme 2 (ACE2) improves experimental acute lung injury caused by severe acute respiratory syndrome coronavirus, acid inhalation, and sepsis. However, the effects and underlying mechanisms of ACE2 in RP remain unclear. Therefore, this study aimed to investigate the effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on RP and ACE2/angiotensin-(1-7)/Mas receptor pathway activation. We found that radiotherapy decreased the expression of ACE2 and that overexpression of ACE2 alleviated lung injury in an RP mouse model. Moreover, captopril and valsartan restored ACE2 activation; attenuated P38, ERK, and p65 phosphorylation; and effectively mitigated RP in the mouse model. Further systematic retrospective analysis illustrated that the incidence of RP in patients using renin-angiotensin system inhibitors (RASis) was lower than that in patients not using RASis (18.2% vs. 35.8% at 3 months, p = 0.0497). In conclusion, the current findings demonstrate that ACE2 plays a critical role in RP and suggest that RASis may be useful potential therapeutic drugs for RP.

Cepharanthine Dry Powder Inhaler for the Treatment of Acute Lung Injury.

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) induces a severe cytokine storm that may cause acute lung injury/acute respiratory distress syndrome (ALI/ARDS) with high clinical morbidity and mortality in infected individuals. Cepharanthine (CEP) is a bisbenzylisoquinoline alkaloid isolated and extracted from Stephania cepharantha Hayata. It exhibits various pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, anti-tumor, and antiviral activities. The low oral bioavailability of CEP can be attributed to its poor water solubility. In this study, we utilized the freeze-drying method to prepare dry powder inhalers (DPI) for the treatment of acute lung injury (ALI) in rats via pulmonary administration. According to the powder properties study, the aerodynamic median diameter (Da) of the DPIs was 3.2 µm, and the in vitro lung deposition rate was 30.26; thus, meeting the Chinese Pharmacopoeia standard for pulmonary inhalation administration. We established an ALI rat model by intratracheal injection of hydrochloric acid (1.2 mL/kg, pH = 1.25). At 1 h after the model's establishment, CEP dry powder inhalers (CEP DPIs) (30 mg/kg) were sprayed into the lungs of rats with ALI via the trachea. Compared with the model group, the treatment group exhibited a reduced pulmonary edema and hemorrhage, and significantly reduced content of inflammatory factors (TNF-α, IL-6 and total protein) in their lungs (p < 0.01), indicating that the main mechanism of CEP underlying the treatment of ALI is anti-inflammation. Overall, the dry powder inhaler can deliver the drug directly to the site of the disease, increasing the intrapulmonary utilization of CEP and improving its efficacy, making it a promising inhalable formulation for the treatment of ALI.

Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury.

Pneumonia is an acute inflammation of the lungs induced by pathogenic microorganisms, immune damage, physical and chemical factors, and other factors, and the latest outbreak of novel coronavirus pneumonia is also an acute lung injury (ALI) induced by viral infection. However, there are currently no effective treatments for inflammatory cytokine storms in patients with ALI/acute respiratory distress syndrome (ARDS). Protein kinase D (PKD) is a highly active kinase that has been shown to be associated with the production of inflammatory cytokines. Therefore, small-molecule compounds that inhibit PKD may be potential drugs for the treatment of ALI/ARDS. In the present study, we evaluated the ability of the small-molecule inhibitor CRT0066101 to attenuate lipopolysaccharide (LPS)-induced inflammatory cytokine production through in vitro cell experiments and a mouse pneumonia model. We found that CRT0066101 significantly reduced the protein and mRNA levels of LPS-induced cytokines (e.g., IL-6, TNF-α, and IL-1ß). CRT0066101 inhibited MyD88 and TLR4 expression and reduced NF-κB, ERK, and JNK phosphorylation. CRT0066101 also reduced NLRP3 activation, inhibited the assembly of the inflammasome complex, and attenuated inflammatory cell infiltration and lung tissue damage. Taken together, our data indicate that CRT0066101 exerts anti-inflammatory effects on LPS-induced inflammation through the TLR4/MyD88 signaling pathway, suggesting that CRT0066101 may have therapeutic value in acute lung injury and other MyD88-dependent inflammatory diseases.

The Role of Histone Deacetylases in Acute Lung Injury-Friend or Foe.

Acute lung injury (ALI), caused by intrapulmonary or extrapulmonary factors such as pneumonia, shock, and sepsis, eventually disrupts the alveolar-capillary barrier, resulting in diffuse pulmonary oedema and microatasis, manifested by refractory hypoxemia, and respiratory distress. Not only is ALI highly lethal, but even if a patient survives, there are also multiple sequelae. Currently, there is no better treatment than supportive care, and we urgently need to find new targets to improve ALI. Histone deacetylases (HDACs) are epigenetically important enzymes that, together with histone acetylases (HATs), regulate the acetylation levels of histones and non-histones. While HDAC inhibitors (HDACis) play a therapeutic role in cancer, inflammatory, and neurodegenerative diseases, there is also a large body of evidence suggesting the potential of HDACs as therapeutic targets in ALI. This review explores the unique mechanisms of HDACs in different cell types of ALI, including macrophages, pulmonary vascular endothelial cells (VECs), alveolar epithelial cells (AECs), and neutrophils.

Targeting immunometabolism against acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions triggered by multiple intra- and extra-pulmonary injury factors, characterized by complicated molecular mechanisms and high mortality. Great strides have been made in the field of immunometabolism to clarify the interplay between intracellular metabolism and immune function in the past few years. Emerging evidence unveils the crucial roles of immunometabolism in inflammatory response and ALI. During ALI, both macrophages and lymphocytes undergo robust metabolic reprogramming and discrete epigenetic changes after activated. Apart from providing ATP and biosynthetic precursors, these metabolic cellular reactions and processes in lung also regulate inflammation and immunity.In fact, metabolic reprogramming involving glucose metabolism and fatty acidoxidation (FAO) acts as a double-edged sword in inflammatory response, which not only drives inflammasome activation but also elicits anti-inflammatory response. Additionally, the features and roles of metabolic reprogramming in different immune cells are not exactly the same. Here, we outline the evidence implicating how adverse factors shape immunometabolism in differentiation types of immune cells during ALI and summarize key proteins associated with energy expenditure and metabolic reprogramming. Finally, novel therapeutic targets in metabolic intermediates and enzymes together with current challenges in immunometabolism against ALI were discussed.

Oridonin inhibits inflammation of epithelial cells via dual-targeting of CD31 Keap1 to ameliorate acute lung injury.

Introdcution: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of COVID-19 mortality. However, drug delivery to lung tissues is impeded by endothelial cell barriers, limiting the efficacy of existing treatments. A prompt and aggressive treatment strategy is therefore necessary. Methods: We assessed the ability of anti-CD31-ORI-NPs to penetrate endothelial cell barriers and specifically accumulate in lung tissues using an animal model. We also compared the efficacy of anti-CD31-ORI-NPs to that of free oridonin in ameliorating acute lung injury and evaluated the cytotoxicity of both treatments on endothelial cells. Results: Compared to free ORI, the amount of anti-CD31-ORI-NPs accumulated in lung tissues increase at least three times. Accordingly, anti-CD31-ORI-NPs improve the efficacy three times on suppressing IL-6 and TNF-a secretion, ROS production, eventually ameliorating acute lung injury in animal model. Importantly, anti-CD31-ORI-NPs significantly decrease the cytotoxicity at least two times than free oridonin on endothelial cells. Discussion: Our results from this study will not only offer a novel therapeutic strategy with high efficacy and low toxicity, but also provide the rational design of nanomaterials of a potential drug for acute lung injury therapy.

Acute Lung Injury in aortic dissection : new insights in anesthetic management strategies.

Acute aortic dissection (AAD) is a severe cardiovascular disease characterized by rapid progress and a high mortality rate. The incidence of acute aortic dissection is approximately 5 to 30 per 1 million people worldwide. In clinical practice, about 35% of AAD patients are complicated with acute lung injury (ALI). AAD complicated with ALI can seriously affect patients' prognosis and even increase mortality. However, the pathogenesis of AAD combined with ALI remains largely unknown. Given the public health burden of AAD combined with ALI, we reviewed the anesthetic management advances and highlighted potential areas for clinical practice.

Recuperative herbal formula Jing Si maintains vasculature permeability balance, regulates inflammation and assuages concomitants of "Long-Covid".

Coronavirus disease 2019 (COVID-19) is a worldwide health threat that has long-term effects on the patients and there is currently no efficient cure prescribed for the treatment and the prolonging effects. Traditional Chinese medicines (TCMs) have been reported to exert therapeutic effect against COVID-19. In this study, the therapeutic effects of Jing Si herbal tea (JSHT) against COVID-19 infection and associated long-term effects were evaluated in different in vitro and in vivo models. The anti-inflammatory effects of JSHT were studied in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and in Omicron pseudotyped virus-induced acute lung injury model. The effect of JSHT on cellular stress was determined in HK-2 proximal tubular cells and H9c2 cardiomyoblasts. The therapeutic benefits of JSHT on anhedonia and depression symptoms associated with long COVID were evaluated in mice models for unpredictable chronic mild stress (UCMS). JSHT inhibited the NF-ƙB activities, and significantly reduced LPS-induced expression of TNFα, COX-2, NLRP3 inflammasome, and HMGB1. JSHT was also found to significantly suppress the production of NO by reducing iNOS expression in LPS-stimulated RAW 264.7 cells. Further, the protective effects of JSHT on lung tissue were confirmed based on mitigation of lung injury, repression in TMRRSS2 and HMGB-1 expression and reduction of cytokine storm in the Omicron pseudotyped virus-induced acute lung injury model. JSHT treatment in UCMS models also relieved chronic stress and combated depression symptoms. The results therefore show that JSHT attenuates the cytokine storm by repressing NF-κB cascades and provides the protective functions against symptoms associated with long COVID-19 infection.

Human adenovirus lung disease: outbreaks, models of immune-response-driven acute lung injury and pandemic potential.

PURPOSE OF REVIEW: An overview of epidemic, human adenovirus (HAdV) lung infections with proposed studies of the viral/host immune response interface to better understand mechanisms of immunopathogenesis, for development of improved responses to a potential HAdV pandemic. RECENT FINDINGS: Emergent HAdV strains 7, 3, 4, 14 are the most common types associated with infection outbreaks. Recent outbreaks have revealed increased community spread, beyond epidemic group settings. The ongoing circulation of these virulent HAdV strains might allow for further HAdV adaptation, with increased HAdV spread and disease severity in the population that could theoretically result in expansion to a pandemic level. SUMMARY: Public health screening has revealed spread of HAdV outbreak strains to the general community. Despite expanded awareness of viral respiratory diseases during the SARS-CoV-2 pandemic, there has been limited, systematic monitoring of HAdV infection in the population. The shift in clinical laboratories to a focus on molecular diagnostics and away from classical methods of viral characterization has reduced the distribution of outbreak HAdV strains to the research community to study mechanisms of pathogenesis. This change risks reduced development of new preventive and therapeutic strategies that could be needed in the event of more widespread HAdV epidemics.

The effects and mechanisms of the anti-COVID-19 traditional Chinese medicine, Dehydroandrographolide from Andrographis paniculata (Burm.f.) Wall, on acute lung injury by the inhibition of NLRP3-mediated pyroptosis.

BACKGROUND: Dehydroandrographolide (Deh) from Andrographis paniculata (Burm.f.) Wall has strong anti-inflammatory and antioxidant activities. PURPOSE: To explore the role of Deh in acute lung injury (ALI) of coronavirus disease 19 (COVID-19) and its inflammatory molecular mechanism. METHODS: Liposaccharide (LPS) was injected into a C57BL/6 mouse model of ALI, and LPS + adenosine triphosphate (ATP) was used to stimulate BMDMs in an in vitro model of ALI. RESULTS: In an in vivo and in vitro model of ALI, Deh considerably reduced inflammation and oxidative stress by inhibiting NLRP3-mediated pyroptosis and attenuated mitochondrial damage to suppress NLRP3-mediated pyroptosis through the suppression of ROS production by inhibiting the Akt/Nrf2 pathway. Deh inhibited the interaction between Akt at T308 and PDPK1 at S549 to promote Akt protein phosphorylation. Deh directly targeted PDPK1 protein and accelerated PDPK1 ubiquitination. 91-GLY, 111-LYS, 126-TYR, 162-ALA, 205-ASP and 223-ASP may be the reason for the interaction between PDPK1 and Deh. CONCLUSION: Deh from Andrographis paniculata (Burm.f.) Wall presented NLRP3-mediated pyroptosis in a model of ALI through ROS-induced mitochondrial damage through inhibition of the Akt/Nrf2 pathway by PDPK1 ubiquitination. Therefore, it can be concluded that Deh may be a potential therapeutic drug for the treatment of ALI in COVID-19 or other respiratory diseases.

Esculin alleviates LPS-induced acute lung injury via inhibiting neutrophil recruitment and migration.

OBJECTIVES: Acute lung injury (ALI) poses a serious threat to human health globally, particularly with the Coronavirus 2019 (COVID-19) pandemic. Excessive recruitment and infiltration of neutrophils is the major etiopathogenesis of ALI. Esculin, also known as 6,7-dihydroxycoumarin, is a remarkable compound derived from traditional Chinese medicine Cortex fraxini. Accumulated evidence indicates that esculin has potent anti-inflammatory effects, but its pharmaceutical effect against ALI and potential mechanisms are still unclear. METHODS: This study evaluated the protective effect of esculin against ALI by histopathological observation and biochemical analysis of lung tissues and bronchoalveolar lavage fluid (BALF) in lipopolysaccharide (LPS)-challenged ALI mice in vivo. The effects of esculin on N-formyl-met-leu-phe (fMLP)-induced neutrophil migration and chemotaxis were quantitatively assessed using a Transwell assay and an automated cell imaging system equipped with a Zigmond chamber, respectively. The drug affinity responsive target stability (DARTS) assay, in vitro protein binding assay and molecular docking were performed to identify the potential therapeutic target of esculin and the potential binding sites and pattern. RESULTS: Esculin significantly attenuated LPS-induced lung pathological injury, reduced the levels of pro-inflammatory cytokines in both BALF and lung, and suppressed the activation of NF-κB signaling. Esculin also significantly reduced the number of total cells and neutrophils as well as myeloperoxidase (MPO) activity in the BALF. Esculin impaired neutrophil migration and chemotaxis as evidenced by the reduced migration distance and velocity. Furthermore, esculin remarkably inhibited Vav1 phosphorylation, suppressed Rac1 activation and the PAK1/LIMK1/cofilin signaling axis. Mechanistically, esculin could interact with ß2 integrin and then diminish its ligand affinity with intercellular adhesion molecule-1 (ICAM-1). CONCLUSIONS: Esculin inhibits ß2 integrin-dependent neutrophil migration and chemotaxis, blocks the cytoskeletal remodeling process required for neutrophil recruitment, thereby contributing to its protective effect against ALI. This study demonstrates the new therapeutic potential of esculin as a novel lead compound.

Targeting neutrophils extracellular traps (NETs) reduces multiple organ injury in a COVID-19 mouse model.

BACKGROUND: COVID-19 is characterized by severe acute lung injury, which is associated with neutrophil infiltration and the release of neutrophil extracellular traps (NETs). COVID-19 treatment options are scarce. Previous work has shown an increase in NETs release in the lung and plasma of COVID-19 patients suggesting that drugs that prevent NETs formation or release could be potential therapeutic approaches for COVID-19 treatment. METHODS: Here, we report the efficacy of NET-degrading DNase I treatment in a murine model of COVID-19. SARS-CoV-2-infected K18-hACE2 mice were performed for clinical sickness scores and lung pathology. Moreover, the levels of NETs were assessed and lung injuries were by histopathology and TUNEL assay. Finally, the injury in the heart and kidney was assessed by histopathology and biochemical-specific markers. RESULTS: DNase I decreased detectable levels of NETs, improved clinical disease, and reduced lung, heart, and kidney injuries in SARS-CoV-2-infected K18-hACE2 mice. Furthermore, our findings indicate a potentially deleterious role for NETs lung tissue in vivo and lung epithelial (A549) cells in vitro, which might explain part of the pathophysiology of severe COVID-19. This deleterious effect was diminished by the treatment with DNase I. CONCLUSIONS: Together, our results support the role of NETs in COVID-19 immunopathology and highlight NETs disruption pharmacological approaches as a potential strategy to ameliorate COVID-19 clinical outcomes.

Therapeutic potential of curcumin in ARDS and COVID-19.

Curcumin is a safe, non-toxic, readily available and naturally occurring compound, an active constituent of Curcuma longa (turmeric). Curcumin could potentially treat diseases, but faces poor physicochemical and pharmacological characteristics. To overcome these limitations, we developed a stable, water-soluble formulation of curcumin called cyclodextrin-complexed curcumin (CDC). We have previously shown that direct delivery of CDC to the lung following lipopolysaccharides exposure reduces acute lung injury (ALI) and effectively reduces lung injury, inflammation and mortality in mice following Klebsiella pneumoniae. Recently, we found that administration of CDC led to a significant reduction in angiotensin-converting enzyme 2 and signal transducer and activator of transcription 3 expression in gene and protein levels following pneumonia, indicating its potential in treating coronavirus disease 2019 (COVID-19). In this review, we consider the clinical features of ALI and acute respiratory distress syndrome (ARDS) and the role of curcumin in modulating the pathogenesis of bacterial/viral-induced ARDS and COVID-19.

Xuanfei Baidu Decoction regulates NETs formation via CXCL2/CXCR2 signaling pathway that is involved in acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening symptoms in Coronavirus Disease 2019 (COVID-19) patients. Xuanfei Baidu Decoction (XFBD) is a recommend first-line traditional Chinese medicine (TCM) formula therapeutic strategy for COVID-19 patients. Prior studies demonstrated the pharmacological roles and mechanisms of XFBD and its derived effective components against inflammation and infections through multiple model systems, which provided the biological explanations for its clinical use. Our previous work revealed that XFBD inhibited macrophages and neutrophils infiltration via PD-1/IL17A signaling pathway. However, the subsequent biological processes are not well elucidated. Here, we proposed a hypothesis that XFBD can regulate the neutrophils-mediated immune responses, including neutrophil extracellular traps (NETs) formation and the generation of platelet-neutrophil aggregates (PNAs) after XFBD administration in lipopolysaccharide (LPS)-induced ALI mice. The mechanism behind it was also firstly explained, that is XFBD regulated NETs formation via CXCL2/CXCR2 axis. Altogether, our findings demonstrated the sequential immune responses of XFBD after inhibiting neutrophils infiltration, as well as shedding light on exploiting the therapy of XFBD targeting neutrophils to ameliorate ALI during the clinical course.

NETs Promote Inflammatory Injury by Activating cGAS-STING Pathway in Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) threatens the survival of critically ill patients, the mechanisms of which are still unclear. Neutrophil extracellular traps (NETs) released by activated neutrophils play a critical role in inflammatory injury. We investigated the role of NETs and the underlying mechanism involved in acute lung injury (ALI). We found a higher expression of NETs and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) in the airways, which was reduced by Deoxyribonuclease I (DNase I) in ALI. The administration of the STING inhibitor H-151 also significantly relieved inflammatory lung injury, but failed to affect the high expression of NETs in ALI. We isolated murine neutrophils from bone marrow and acquired human neutrophils by inducing HL-60 to differentiate. After the PMA interventions, exogenous NETs were obtained from such extracted neutrophils. Exogenous NETs intervention in vitro and in vivo resulted in airway injury, and such inflammatory lung injury was reversed upon degrading NETs with or inhibiting cGAS-STING with H-151 as well as siRNA STING. In conclusion, cGAS-STING participates in regulating NETs-mediated inflammatory pulmonary injury, which is expected to be a new therapeutic target for ARDS/ALI.

Orally administered BZL-sRNA-20 oligonucleotide targeting TLR4 effectively ameliorates acute lung injury in mice.

The global COVID-19 pandemic emerged at the end of December 2019. Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are common lethal outcomes of bacterial lipopolysaccharide (LPS), avian influenza virus, and SARS-CoV-2. Toll-like receptor 4 (TLR4) is a key target in the pathological pathway of ARDS and ALI. Previous studies have reported that herbal small RNAs (sRNAs) are a functional medical component. BZL-sRNA-20 (Accession number: B59471456; Family ID: F2201.Q001979.B11) is a potent inhibitor of Toll-like receptor 4 (TLR4) and pro-inflammatory cytokines. Furthermore, BZL-sRNA-20 reduces intracellular levels of cytokines induced by lipoteichoic acid (LTA) and polyinosinic-polycytidylic acid (poly (I:C)). We found that BZL-sRNA-20 rescued the viability of cells infected with avian influenza H5N1, SARS-CoV-2, and several of its variants of concern (VOCs). Acute lung injury induced by LPS and SARS-CoV-2 in mice was significantly ameliorated by the oral medical decoctosome mimic (bencaosome; sphinganine (d22:0)+BZL-sRNA-20). Our findings suggest that BZL-sRNA-20 could be a pan-anti-ARDS ALI drug.

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.