• GPR68
• HKSA
• OGM‐8345
• acidosis
• endothelial permeability
• inflammation
• lung injury

• Acute Lung Injury/microbiology
• Acute Lung Injury/metabolism
• Acute Lung Injury/pathology
• Animals
• Receptors, G-Protein-Coupled/antagonists & inhibitors
• Receptors, G-Protein-Coupled/metabolism
• Receptors, G-Protein-Coupled/genetics
• Mice
• Humans
• Staphylococcus aureus/pathogenicity
• Endothelial Cells/metabolism
• Endothelial Cells/microbiology
• Endothelial Cells/drug effects
• Mice, Inbred C57BL
• Staphylococcal Infections/metabolism
• Male
• Lung

• RO1HL152761 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• RO1HL167192 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• R01 HL167192 NHLBI NIH HHS
• RO1HL155051 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• R01 HL152761 NHLBI NIH HHS
• R01 HL155051 NHLBI NIH HHS
• HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)

• ascorbic acid
• critically ill
• pneumonia
• sepsis
• septic shock
• vitamin C

• National Heart, Lung, and Blood Institute

• Acute lung injury
• Albumin nanoparticle biodistribution
• BioUML
• Lipopolysaccharide injection
• Murine model
• Nanomedicine
• PBPK modeling

• ARDS
• IPF
• Mesenchymal stromal cell
• asthma
• lung
• pneumonia

• acute respiratory distress syndrome
• caveolae
• clathrin-mediated endocytosis
• endophilin
• glycosylphosphatidyl inositol-anchored protein enriched early endosomal compartment pathway
• macropinocytosis
• phagocytosis
• trafficking

• Humans
• Respiratory Distress Syndrome/therapy
• Endocytosis
• Acute Lung Injury/therapy
• Pinocytosis
• Phagocytosis

• Community-acquired bacterial pneumonia
• Intensive care unit
• Mesenchymal stem cells
• Sepsis
• Severe pneumonia

• Humans
• Community-Acquired Infections/drug therapy
• COVID-19
• Double-Blind Method
• Pneumonia, Bacterial
• SARS-CoV-2
• Thromboembolism
• Treatment Outcome
• Middle Aged
• Aged

• Acute lung injury
• Acute respiratory distress syndrome
• Animal model
• Drug delivery
• Nanomedicine
• Therapy

• Animals
• Humans
• Translational Science, Biomedical
• Acute Lung Injury/drug therapy
• Models, Animal

• NF-κB
• PGE2
• acute respiratory distress syndrome
• infectious disease
• influenza virus
• mesenchymal stem cell
• β-catenin

• Acute Respiratory Distress Syndrome
• Natural language processing
• Supervised machine learning

• 5-Methoxyflavone
• Acute lung injury
• LPS
• Methylated flavonoid
• Nrf2

• Chlamydia pneumoniae
• Legionella pneumophila
• Mycoplasma pneumoniae
• community-acquired atypical pneumonia

• Animals
• Anti-Bacterial Agents/pharmacology
• Coinfection
• Humans
• Influenza, Human
• Interferon-gamma/genetics
• Lung Injury/etiology
• Methicillin-Resistant Staphylococcus aureus
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Cells
• Respiratory Distress Syndrome
• Transcriptome
• Tumor Necrosis Factor-alpha/genetics

• R01 HL118408 NHLBI NIH HHS
• P30 CA036727 NCI NIH HHS
• P30 GM110768 NIGMS NIH HHS
• P20 GM103427 NIGMS NIH HHS

Metagenomic next-generation sequencing (mNGS) is an effective method that can be used for the identification of early pathogens in patients with suspected severe pneumonia. However, the potential of mNGS for evaluating the prognosis of acute respiratory distress syndrome (ARDS) in patients with severe pneumonia remains unclear. In the present report, hospital-acquired gram-negative bacteria infections were detected in a case using metagenomic next-generation sequencing (mNGS) in a sample of bronchoalveolar fluid. This was obtained from a 58-year-old male patient with traumatic wet lung after a neurosurgery. According to the results, of which the profiles of the resistance genes were detected by mNGS, drugs designed to control infection were adjusted, namely to polymyxin B (500,000 U/12 h), azithromycin (0.5 g/24 h) and ganciclovir (0.25 g/12 h). Following adjusting treatment for 8 days, the symptoms of lung infection and hypoxemia were markedly improved, resulting in the patient being transferred out of the intensive care unit 15 days after treatment. To conclude, observations from the present report suggest that mNGS is a useful method for the early identification of pathogens in patients with pneumonia caused by ARDS. However, further studies are required to identify the complementary role of mNGS in supporting conventional microbiological methods in routine clinical practice.

• Adrenal Cortex Hormones
• Female
• Humans
• Male
• Methylprednisolone/therapeutic use
• Middle Aged
• Probability
• Respiratory Distress Syndrome
• Respiratory Insufficiency/chemically induced
• Retrospective Studies
• SARS-CoV-2
• COVID-19 Drug Treatment

• Taiwan Ministry of Science and Technology
• National Taiwan University Hospital

• ARDS
• India
• Predictors
• Recovery
• Sepsis

• Acute lung injury and inflammation
• Bacterial pneumonia
• Cannabinoid-2 receptor
• Pseudomonas aeruginosa

Community-acquired pneumonia caused by Mycoplasma pneumoniae or Chlamydia pneumoniae is usually mild. Mycoplasma pneumoniae-related and C. pneumoniae-related acute respiratory distress syndromes (ARDSs) are rare. Moreover, to our knowledge, there are no published reports on ARDS caused by M. pneumoniae and C. pneumoniae coinfection. Here, we report a case of an immunocompetent young woman who was co-infected with M. pneumoniae and C. pneumoniae and was started on treatment with piperacillin and clarithromycin. Two days later, she developed ARDS. She recovered rapidly following a change of antibiotic treatment to levofloxacin and was discharged on day 12. We conducted exome sequencing followed by alternative filtering to search for candidate ARDS-related genes. We identified an intronic variant of unknown significance within leucine-rich repeat-containing 16A (LRRC16A), a gene previously identified as a significant locus for platelet count with a possible role in ARDS. This is a rare case of ARDS in a young adult caused by M. pneumoniae and C. pneumoniae coinfection. This case suggests that ARDS in young adults may be correlated with variants in LRRC16A. This requires confirmation by further case reports.

• ARDS
• COVID-19
• Inflammatory cell death
• Inflammatory cytokine
• Inflammatory storm program

• Animals
• COVID-19/immunology
• COVID-19/therapy
• COVID-19 Vaccines/immunology
• Clinical Protocols
• Cytokine Release Syndrome
• Humans
• Immunity
• Immunomodulation
• Inflammation
• SARS-CoV-2/physiology
• Signal Transduction

• Animals
• Lipopolysaccharides
• Azithromycin/pharmacology
• Dexamethasone/pharmacology
• Dexamethasone/therapeutic use
• Mice
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Disease Models, Animal
• Neutrophils/drug effects
• Neutrophils/metabolism
• Diterpenes/pharmacology
• Diterpenes/therapeutic use
• Thioglycolates/pharmacology
• Humans
• Lung/drug effects
• Lung/pathology
• Lung/metabolism
• Cytokines/metabolism
• Bronchoalveolar Lavage Fluid
• Male
• Leukocyte Disorders/drug therapy
• Leukocyte Disorders/chemically induced
• Female
• Polycyclic Compounds

• Nabriva Therapeutics

• ARDS
• ARDS risk factors
• Acute respiratory distress syndrome
• Lung protective ventilation

• Clinical
• Diagnosis
• Laboratory
• MERS-CoV
• Radiological
• SARS-CoV-2

The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 has become a sudden public emergency of international concern and seriously threatens millions of people’s life health. Two current studies have indicated a favorable role for mesenchymal stem/stromal cells (MSCs) in clinical remission of COVID-19 associated pulmonary diseases, yet the systematical elaboration of the therapeutics and underlying mechanism is far from satisfaction. In the present review, we summarize the therapeutic potential of MSCs in COVID-19 associated pulmonary diseases such as pneumonia induced acute lung injury, acute respiratory distress syndrome, and pulmonary fibrosis. Furthermore, we review the underlying mechanism of MSCs including direct- and trans-differentiation, autocrine and paracrine anti-inflammatory effects, homing, and neovascularization, as well as constitutive microenvironment. Finally, we discuss the prospects and supervision of MSC-based cytotherapy for COVID-19 management before large-scale application in clinical practice. Collectively, this review supplies overwhelming new references for understanding the landscapes of MSCs in the remission of COVID-19 associated pulmonary diseases.

• Mesenchymal stem/stromal cells
• COVID-19
• Acute lung injury
• Acute respiratory distress syndrome
• Pulmonary fibrosis
• Molecular mechanism

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are most often caused by bacterial pneumonia and characterized by severe dyspnea and high mortality. Knowledge about the lung injury effects of current clinical bacterial strains is lacking. The aim of this study was to investigate the ability of representative pathogenic bacteria isolated from patients to cause ALI/ARDS in mice and identify the major virulence factor.

Seven major bacterial species were isolated from clinical sputum and unilaterally instilled into the mouse airway. A histology study was performed to determine the lung injury effect. Virulence genes were examined by PCR. Sequence types of P. aeruginosa strains were identified by MLST. LC-MS/MS was used to analysis the bacterial exoproducts proteome. LasB was purified through a DEAE-cellulose column, and its toxicity was tested both in vitro and in vivo.

Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus agalactiae, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli were randomly separated and tested 3 times. Among them, gram-negative bacteria have much more potential to cause acute lung injury than gram-positive bacteria. However, P. aeruginosa is the only pathogen that induces diffuse alveolar damage, hemorrhage and hyaline membranes in the lungs of mice. The lung injury effect is associated with the excreted LasB elastase. Purified LasB recapitulated lung injury similar to P. aeruginosa infection in vivo. We found that this was due to the powerful degradation effect of LasB on the extracellular matrix of the lung and key proteins in the coagulation cascade without inducing obvious cellular apoptosis. We also report for the first time that LasB could induce DIC-like coagulopathy in vitro.

P. aeruginosa strains are most capable of inducing ALI/ARDS in mice among major clinical pathogenic bacteria tested, and this ability is specifically attributed to their LasB production.

• ALI/ARDS
• LasB elastase
• Pseudomonas aeruginosa
• unilateral lung injury

• Aminoacyl-tRNA synthetases
• COVID-19
• biogenic amines
• co-infections
• microbial metabolism
• necrotizing factor
• protein biosynthesis
• shikimate pathway
• tryptamine
• tryptophan metabolism

• ARDS
• COVID-19
• NF-κB
• lung inflammation
• selective serotonin reuptake inhibitor

• COVID-19
• SARS-CoV-2
• alveolar regeneration
• in vitro lung models
• interstitial pulmonary fibrosis
• lung-on-chip
• organoids
• precision-cut lung slices

Microvesicles (MVs) are cell-derived extracellular vesicles that have emerged as markers and mediators of acute lung injury (ALI). One of the most common pathogens in pneumonia-induced ALI is Streptococcus pneumoniae (Spn), but the role of MVs during Spn lung infection is largely unknown. In the first line of defense against Spn and its major virulence factor, pneumolysin (PLY), are the alveolar epithelial cells (AEC). In this study, we aim to characterize MVs shed from PLY-stimulated AEC and explore their contribution in mediating crosstalk with neutrophils. Using in vitro cell and ex vivo (human lung tissue) models, we demonstrated that Spn in a PLY-dependent manner stimulates AEC to release increased numbers of MVs. Spn infected mice also had higher levels of epithelial-derived MVs in their alveolar compartment compared to control. Furthermore, MVs released from PLY-stimulated AEC contain mitochondrial content and can be taken up by neutrophils. These MVs then suppress the ability of neutrophils to produce reactive oxygen species, a critical host-defense mechanism. Taken together, our results demonstrate that AEC in response to pneumococcal PLY release MVs that carry mitochondrial cargo and suggest that these MVs regulate innate immune responses during lung injury.

• IL-36γ
• Pseudomonas aeruginosa
• proteolytic environment
• thrombospondin-1

• Animals
• Female
• Host-Pathogen Interactions
• Inflammation/microbiology
• Interleukin-1/classification
• Interleukin-1/immunology
• Lung/immunology
• Lung/microbiology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophil Infiltration
• Neutrophils/enzymology
• Neutrophils/immunology
• Pseudomonas Infections/immunology
• Pseudomonas Infections/microbiology
• Pseudomonas aeruginosa/immunology
• Pseudomonas aeruginosa/pathogenicity
• Thrombospondin 1/genetics
• Thrombospondin 1/immunology

• R01 HL135062 NHLBI NIH HHS
• F32 HL152504 NHLBI NIH HHS
• R01 HL123515 NHLBI NIH HHS
• K24 HL143285 NHLBI NIH HHS
• R01 HL136143 NHLBI NIH HHS
• R01 HL125435 NHLBI NIH HHS
• R01 HL142084 NHLBI NIH HHS
• P01 HL114453 NHLBI NIH HHS
• R21 HL148088 NHLBI NIH HHS
• R01 HL086884 NHLBI NIH HHS
• R01 HL142997 NHLBI NIH HHS
• IK2 BX004886 BLRD VA
• HHS | National Institutes of Health (NIH)
• Pitt | Vascular Medicine Institute, University of Pittsburgh (VMI)

• Cytokine storm
• Nanoparticles
• Nanotheranostics
• SARS-CoV-2
• Viral pathogenesis
• Viral transmission

• Wellcome Trust

• COVID-19
• acute respiratory distress syndrome
• extracellular vesicles
• inhalation treatment
• intravenous treatment
• lung diseases
• mesenchymal stem cells

• COVID-19
• Methylxanthines
• Pentoxifylline and caffeine

• Anti-Inflammatory Agents, Non-Steroidal/pharmacology
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• COVID-19
• Caffeine/pharmacology
• Caffeine/therapeutic use
• Coronavirus Infections/complications
• Coronavirus Infections/drug therapy
• Humans
• Infant, Newborn
• Infant, Premature
• Inflammation/drug therapy
• Inflammation/etiology
• Pandemics
• Pentoxifylline/pharmacology
• Pentoxifylline/therapeutic use
• Pneumonia, Viral/complications
• Pneumonia, Viral/drug therapy
• Xanthines/pharmacology
• Xanthines/therapeutic use
• COVID-19 Drug Treatment

• Acute lung injury
• Acute respiratory distress syndrome
• Alveolar cell regeneration
• Arterial blood gas analysis
• BALB/c mouse
• Bone marrow-derived mesenchymal stem cells
• Cell-based therapy
• Highly pathogenic avian influenza a/H5N1 virus
• Inflammatory cytokines

To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients.

A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed.

An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048).

Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT 04251871 at www.clinicaltrials.gov)

Supplementary material is available in the online version of this article at 10.1007/s11655-020-3426-7.

• COVID-19
• Chinese medicine
• SARS-CoV-2
• acute respiratory distress syndrome

• Algorithms
• Biomarkers
• COVID-19
• Comorbidity
• Coronavirus Infections/diagnosis
• Coronavirus Infections/physiopathology
• Critical Care
• Decision Support Systems, Clinical/organization & administration
• Humans
• Image Processing, Computer-Assisted
• Immunoassay/methods
• Machine Learning
• Pandemics
• Pneumonia, Viral/diagnosis
• Pneumonia, Viral/physiopathology
• Point-of-Care Systems
• Predictive Value of Tests
• Risk Factors
• Severity of Illness Index
• Software
• Treatment Outcome

• U01 DE017793 NIDCR NIH HHS
• 5U01DE017793-2 NIDCR NIH HHS
• 3U01DE017793-02S1 NIDCR NIH HHS

• COVID-19
• Cell therapy
• Immunosenescence
• Immunotherapy
• Inflammaging
• Vaccine

• U01 DE017793 NIDCR NIH HHS

Infection with avian influenza A H5N1 virus results in acute lung injury (ALI) and has a high mortality rate (52.79%) because there are limited therapies available for treatment. Drug repositioning is an economical approach to drug discovery. We developed a method for drug repositioning based on high-throughput RNA sequencing and identified several drugs as potential treatments for avian influenza A H5N1 virus. Using high-throughput RNA sequencing, we identified a total of 1,233 genes differentially expressed in A549 cells upon H5N1 virus infection. Among these candidate genes, 79 drug targets (corresponding to 59 approved drugs) overlapped with the DrugBank target database. Twenty-two of the 41 commercially available small-molecule drugs reduced H5N1-mediated cell death in cultured A549 cells, and fifteen drugs that protected A549 cells when administered both pre- and post-infection were tested in an H5N1-infection mouse model. The results showed significant alleviation of acute lung injury by amitriptyline HCl (an antidepressant drug), flavin adenine dinucleotide (FAD; an ophthalmic agent for vitamin B2 deficiency), azacitidine (an anti-neoplastic drug) and calcitriol (an active form of vitamin D). All four agents significantly reduced the infiltrating cell count and decreased the lung injury score in H5N1 virus-infected mice based on lung histopathology, significantly improved mouse lung edema by reducing the wet-to-dry weight ratio of lung tissue and significantly improved the survival of H5N1 virus-infected mice. This study not only identifies novel potential therapies for influenza H5N1 virus-induced lung injury but also provides a highly effective and economical screening method for repurposing drugs that may be generalizable for the prevention and therapy of other diseases.

Highly pathogenic avian influenza (HPAI) A virus H5N1 causes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), with mortality as high as 52.79%. No vaccine for HPAI virus is available, and current treatments for influenza A H5N1 virus-induced ALI have limitations. Drug repurposing may be an effective approach for developing novel therapeutic strategies. In this study, we identified 4 drugs, the antidepressant amitriptyline HCl, the ophthalmic flavin adenine dinucleotide, the anti-neoplastic azacitidine and the vitamin D-deficiency treatment calcitriol, as being highly effective for the treatment of H5N1 virus-induced ALI using a transcriptomic-based high-throughput repurposing drug screening. These approved drugs might constitute novel potential remedies for treating influenza H5N1 virus infection, and this screening method may be generalizable for drug repositioning to identify new indications for other diseases.

• Acute Lung Injury/drug therapy
• Acute Lung Injury/etiology
• Acute Lung Injury/immunology
• Amitriptyline/administration & dosage
• Animals
• Azacitidine/administration & dosage
• Calcitriol/administration & dosage
• Disease Models, Animal
• Drug Repositioning
• Female
• Flavin-Adenine Dinucleotide/administration & dosage
• Humans
• Influenza A Virus, H5N1 Subtype/physiology
• Influenza, Human/complications
• Influenza, Human/virology
• Lung/immunology
• Lung/virology
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL

• National Natural Science Foundation of China
• Ministry of Science and Technology of the People's Republic of China
• Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences

Influenza virus A (IVA) is one of the predominant causative agents of the seasonal flu and has become an important cause of morbidity worldwide. Great efforts have been paid to develop vaccines against IVA. However, due to antigenic drift in influenza virus A and rapid emergence of drug-resistant strains, current available vaccines or anti-IVA chemotherapeutics are consistently inefficient. Hence, various more broadly effective drugs have become important for the prevention and treatment of IVA. Of these drugs, baicalin, a flavonoid isolated from Radix Scutellaria, is a promising example. However, little is known in regards to its pharmacological mechanism. Here, it was demonstrated that baicalin inhibits the H1N1 and H3N2 viruses in A549 cells. Subsequently, it was found that miR-146a was markedly downregulated by treatment of baicalin. Additionally, further experiments revealed that miR-146a was able to promote the replication of H1N1 and H3N2 by targeting TNF receptor-associated factor 6 (TRAF6), a pivotal adaptor in the interferon (IFN) production signaling pathway, to downregulate type I IFN production, and enrichment of miR-146a eliminated the anti-IVA effects of baicalin on the H1N1 and H3N2 viruses. Additionally, in vivo experiments demonstrated that baicalin could protect mice during H1N1 infection. Taken together, our findings firstly illustrated the anti-IVA molecular mechanism of baicalin and provide new evidence for targeting miRNAs to prevent and treat viral infection, such as the H1N1 and H3N2 viruses.

• MTT
• apoptosis
• capillary Western blot
• macrophages
• phagocytosis

• acute lung injury
• acute respiratory distress syndrome (ARDS)
• endomicroscopy
• inflammation
• microimaging
• probe-based confocal laser endomicroscopy
• repair
• virtual biopsy