• COVID-19
• Coagulation factors
• Community-acquired pneumonia
• Cytokines
• Hierarchical clustering
• Mortality

• Humans
• COVID-19/immunology
• COVID-19/mortality
• Community-Acquired Infections/mortality
• Community-Acquired Infections/immunology
• Male
• Female
• Middle Aged
• Aged
• SARS-CoV-2/immunology
• Thromboinflammation/immunology
• Cytokines/blood
• Canada/epidemiology
• Aged, 80 and over
• Adult
• Hospitalization
• Pneumonia/immunology
• Pneumonia/mortality
• Pneumonia, Viral/mortality
• Pneumonia, Viral/immunology
• Pneumonia, Viral/blood

• exosomes
• immune cells
• immunomodulation
• inflammation
• mesenchymal stem cells
• pulmonary disease

• Humans
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/immunology
• COVID-19/immunology
• COVID-19/therapy
• Lung/immunology
• Lung/pathology
• SARS-CoV-2/immunology
• Lung Diseases/immunology
• Lung Diseases/therapy
• Animals
• Cell Differentiation
• Cell Communication/immunology

• ALI
• Burn
• Camouflaged nanoparticles
• Nanomaterials
• Targeted treatment

• Acute Lung Injury/drug therapy
• Humans
• Nanostructures/chemistry
• Nanostructures/therapeutic use
• Burns/drug therapy
• Animals
• Lung
• Drug Delivery Systems/methods
• Nanoparticles/chemistry

• 52202343, 82172204 National Natural Science Foundation of China
• 2022zhyx-C01 the Research Fund of Anhui Institute of Translational Medicine
• 2021xkT028 the Basic and Clinical Cooperative Research and Promotion Program of Anhui Medical University
• 202104j07020027 the Anhui Key Research and Development Plan

• Mannosylated lipid nanoparticle
• acute respiratory distress syndrome
• alveolar macrophages
• inflammation
• microRNA

• Animals
• Mice
• Lung Injury
• Shock, Hemorrhagic
• Macrophages
• MicroRNAs
• Respiratory Distress Syndrome/drug therapy

• R01 HL142767 NHLBI NIH HHS

• Apremilast
• Heme-oxygenase
• Lipopolysaccharides
• Nitric oxide synthase-2
• Polymerase chain reaction
• Western blot

• connectivity map
• hub gene
• inflammation
• massive cerebral infarction
• microarray

• Acute respiratory distress syndrome
• Inflammatory response
• Mesenchymal stem cells
• Pulmonary edema
• Pulmonary fibrosis
• Tissue repair

• disease tolerance
• immunoparalysis
• lung infection
• mechanism
• metabolic adaptation

• ARDS
• COPD
• COVID-19
• Epigenetics
• Inflammation
• Lung cancer

• COVID-19/genetics
• Cytokines
• Epigenesis, Genetic
• Humans
• Inflammation/genetics
• Lung Diseases/genetics
• Lung Neoplasms/genetics
• MicroRNAs/genetics
• SARS-CoV-2

• R01 HL114933 NHLBI NIH HHS
• U01 ES025069 NIEHS NIH HHS
• U01 ES028182 NIEHS NIH HHS

Acute respiratory distress syndrome (ARDS) is a leading cause of death in critically ill patients due to hypoxemic respiratory failure. The specific pathogenesis underlying ARDS has not been fully elucidated. In this study, we constructed a triple regulatory network involving competing endogenous RNA (ceRNA) to investigate the potential mechanism of ARDS and evaluated the immune cell infiltration patterns in ARDS patients. Overall, we downloaded three microarray datasets that included 60 patients with sepsis-induced ARDS and 79 patients with sepsis alone from the public Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs, including 9 DElncRNAs, 9 DEmiRNAs, and 269 DEmRNAs) by R software. The DEGs were subjected to the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional enrichment analysis, and a protein–protein interaction (PPI) network was generated for uncovering interactive relationships among DEmRNAs. Then, a ceRNA network that contained 5 DElncRNAs, 7 DEmiRNAs, and 71 DEmRNAs was established according to the overlapping genes in both DEGs and predicted genes by public databases. Finally, we identified the TUG1/miR-140-5p/NFE2L2 pathway as the hub pathway in the whole network through Cytoscape. In addition, we evaluated the distribution of 22 subtypes of immune cells and recognized three differentially expressed immune cells in patients with sepsis-induced ARDS by “Cell Type Identification by Estimating Relative Subsets of Known RNA Transcripts (CIBERSORT)” algorithm, namely, naive B cells, regulatory T cells, and eosinophils. Correlations between differentially expressed immune cells and hub genes in the ceRNA network were also performed. In conclusion, we demonstrated a new potential regulatory mechanism underlying ARDS (the TUG1/miR-140-5p/NFE2L2 ceRNA regulatory pathway), which may help in further exploring the pathogenesis of ARDS.

• acute respiratory distress syndrome—ARDS
• bioinformatic analysis
• competitive endogenous RNA (ceRNA) network
• immune infiltration
• sepsis

• Antigen Presenting Cell
• B cells
• COVID-19
• DC
• Macrophages
• SARS-CoV-2

• Antibodies, Monoclonal
• Antigen-Presenting Cells
• COVID-19
• Humans
• SARS-CoV-2

Uncontrolled severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 infection is closely related to disorders of the innate immune and delayed adaptive immune systems. Dendritic cells (DCs) “bridge” innate immunity and adaptive immunity. DCs have important roles in defending against SARS-CoV-2 infection. In this review, we summarize the latest research concerning the role of DCs in SARS-CoV-2 infection. We focus on the complex interplay between DCs and SARS-CoV-2: pyroptosis-induced activation; activation of the renin–angiotensin–aldosterone system; and activation of dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin. We also discuss the decline in DC number, the impaired antigen-presentation capability, and the reduced production of type-I interferon of DCs in severe SARS-CoV-2 infection. In addition, we discuss the potential mechanisms for pathological activation of DCs to understand the pattern of SARS-CoV-2 infection. Lastly, we provide a brief overview of novel vaccination and immunotherapy strategies based on DC targeting to overcome SARS-CoV-2 infection.

• COVID-19
• SARS-CoV-2
• dendritic cells
• immunopathogenesis
• severe acute respiratory syndrome coronavirus 2

• Acute Lung Injury/metabolism
• Animals
• Dendritic Cells/metabolism
• Lipopolysaccharides/metabolism
• Lipopolysaccharides/pharmacology
• Mice
• Neuroimmunomodulation
• Sepsis/metabolism

• budesonide
• inhaled
• neonate
• respiratory distress
• therapeutic

• Acute lung injury
• Azilsartan
• Inflammation
• LPS
• Nrf2
• Oxidative stress

• LPS
• acute lung injury
• conventional dendritic cells
• resveratrol

Background: Acute respiratory distress syndrome (ARDS) is a frequent and serious complication of sepsis without specific and sensitive diagnostic signatures.

Methods: The mRNA profiles, including 60 blood samples with sepsis-induced ARDS and 86 blood samples with sepsis alone, were obtained from the Gene Expression Omnibus (GEO). The differently expressed genes (DEGs) were analyzed by limma package of R language. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were carried out using the clusterProfiler package of R. Eventually, multivariate logistic regression model was established through the glm function of R, and support vector machine (SVM) model was constructed via the e1071 package of R.

Results: A total of 242 DEGs in GSE32707 and 102 DEGs in GSE66890 were identified. Notably, five genes exhibited significant differences between the two datasets and were considered to be closely associated with the occurrence of ARDS induced by sepsis. Furthermore, functional enrichment analysis based on the DEGs showed there were 80 overlapped GO terms and one KEGG pathway which were significantly enriched in the two datasets. The logistic regression model and SVM model constructed could efficiently distinguish sepsis patients with or without ARDS.

Conclusion: In brief, our study suggested that NKG7, SPTA1, FGL2, RGS2, and IFI27 might be potential diagnostic signatures for sepsis-induced ARDS, which contributed to the future exploration in mechanism of ARDS occurrence and development.

• ARDS
• GO and KEGG analysis
• SVM model
• logistic regression model
• sepsis

• Acute lung injury
• HMGB1/TLR4
• Mitochondrial abnormalities
• NLRP-3 inflammasome
• Pyroptosis
• Sepsis

• Acute Lung Injury/drug therapy
• Acute Lung Injury/etiology
• Animals
• Escin
• Lipopolysaccharides
• Male
• NF-kappa B
• Rats
• Sepsis/complications
• Sepsis/drug therapy
• Ubiquinone/analogs & derivatives

• ALI
• SB203580
• p38/MAPK signaling
• sepsis
• taurine

Systemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited.

To evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome.

Paired bronchoalveolar lavage fluid and plasma samples were obtained from 17 patients with COVID-19 related persistent acute respiratory distress syndrome (mechanical ventilation > 7 days) 1 and 2 weeks after start mechanical ventilation and compared with 8 healthy controls. Thirty-four host response biomarkers stratified into five functional domains (coagulation, complement system, cytokines, chemokines and growth factors) were measured.

In all patients, all functional domains were activated, especially in the bronchoalveolar compartment, with significantly increased levels of D-dimers, thrombin-antithrombin complexes, soluble tissue factor, C1-inhibitor antigen and activity levels, tissue type plasminogen activator, plasminogen activator inhibitor type I, soluble CD40 ligand and soluble P-selectin (coagulation), next to activation of C3bc and C4bc (complement) and multiple interrelated cytokines, chemokines and growth factors. In 10 patients in whom follow-up samples were obtained between 3 and 4 weeks after start mechanical ventilation many bronchoalveolar and plasma host response biomarkers had declined.

Critically ill, ventilated patients with COVID-19 show strong responses relating to coagulation, the complement system, cytokines, chemokines and growth factors in the bronchoalveolar compartment. These results suggest a local pulmonary rather than a systemic procoagulant and inflammatory “storm” in severe COVID-19.

• COVID-19
• bronchoalveolar space
• coagulation
• innate immune response
• persistent ARDS

The mortality rate of critically ill patients with acute respiratory distress syndrome (ARDS) is 30.9% to 46.1%. The emergence of the coronavirus disease 2019 (Covid-19) has become a global issue with raising dire concerns. Patients with severe Covid-19 may progress toward ARDS. Mesenchymal stem cells (MSCs) can be derived from bone marrow, umbilical cord, adipose tissue and so on. The easy accessibility and low immunogenicity enable MSCs for allogeneic administration, and thus they were widely used in animal and clinical studies. Accumulating evidence suggests that mesenchymal stem cell infusion can ameliorate ARDS. However, the underlying mechanisms of MSCs need to be discussed. Recent studies showed MSCs can modulate immune/inflammatory cells, attenuate endoplasmic reticulum stress, and inhibit pulmonary fibrosis. The paracrine cytokines and exosomes may account for these beneficial effects. In this review, we summarize the therapeutic mechanisms of MSCs in ARDS, analyzed the most recent animal experiments and Covid-19 clinical trial results, discussed the adverse effects and prospects in the recent studies, and highlight the potential roles of MSC therapy for Covid-19 patients with ARDS.

• Acute respiratory distress syndrome
• Covid-19
• Mesenchymal stem cells

Osteoarthritis (OA) is thought to be the most prevalent chronic joint disease, especially in Tibet of China. Here, we aimed to explore the integrative lncRNA and mRNA landscape between the OA patients of Tibet and Han.

The lncRNA and mRNA expression microarray profiling was performed by SurePrint G3 Human Gene Expression 8x60K v2 Microarray in articular cartilage samples from OA patients of Han nationality and Tibetans, followed by GO, KEGG, and trans-regulation and cis-regulation analysis of lncRNA and mRNA.

We found a total of 117 lncRNAs and 297 mRNAs differently expressed in the cartilage tissues of Tibetans (n = 5) comparing with those of Chinese Han (n = 3), in which 49 lncRNAs and 158 mRNAs were upregulated, and 68 lncRNAs and 139 mRNAs were downregulated. GO and KEGG analysis showed that several unreported biological processes and signaling pathways were particularly identified. LncRNA-mRNA co-expression analysis revealed a remarkable lncRNA-mRNA relationship, in which OTOA may play a critical role in the different mechanisms of the OA progression between Tibetans and Chinese Han.

This study identified different lncRNA/mRNA expression profiling between OA patients of Tibetans and Han, which were involved in many characteristic biological processes and signaling pathways.

The online version contains supplementary material available at 10.1186/s13018-021-02213-y.

• Microarray profiling
• OTOA
• Osteoarthritis
• Tibetan
• lncRNA-mRNA

• Animals
• Dendritic Cells/immunology
• Humans
• Immunity, Innate/physiology
• Infections/immunology
• Infections/pathology
• Inflammasomes/immunology
• Inflammasomes/metabolism
• Killer Cells, Natural/immunology
• Lung Diseases/immunology
• Lung Diseases/pathology
• Macrophages, Alveolar/immunology
• Macrophages, Alveolar/pathology
• Neutrophils/immunology
• Neutrophils/pathology
• Toll-Like Receptors/immunology
• Toll-Like Receptors/metabolism

• Acute lung injury
• Mass cytometry
• Mesenchymal stem cells
• Recruited mononuclear phagocytes
• Single-cell RNA sequencing

• Acute Lung Injury/chemically induced
• Acute Lung Injury/immunology
• Acute Lung Injury/pathology
• Acute Lung Injury/therapy
• Animals
• Cell Differentiation
• Cytokines/metabolism
• Disease Models, Animal
• Immunomodulation
• Lipopolysaccharides/toxicity
• Macrophages/drug effects
• Macrophages/immunology
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/cytology
• Mice
• Mice, Inbred C57BL
• Neutrophils/drug effects
• Neutrophils/immunology
• Phagocytes/drug effects
• Phagocytes/immunology

• Covid-19
• DC-SIGN
• SARS-CoV-2
• dendritic cells
• spike protein

• Betacoronavirus/pathogenicity
• Betacoronavirus/physiology
• COVID-19
• Coronavirus Infections/immunology
• Coronavirus Infections/metabolism
• Coronavirus Infections/virology
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Dendritic Cells/virology
• Humans
• Pandemics
• Pneumonia, Viral/immunology
• Pneumonia, Viral/metabolism
• Pneumonia, Viral/virology
• Pyroptosis
• Renin-Angiotensin System
• SARS-CoV-2
• Virus Internalization

• 11653 Associazione Italiana per la Ricerca sul Cancro

Background: High-mobility group box 1 protein (HMGB1) was identified as a highly conserved DNA binding nuclear protein, which participates in the processes of acute lung injury (ALI). HMGB1 binds to its specific receptors not only to activate the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways but also to regulate the activation of the phosphatidylinositol 3′-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway. Mature dendritic cells (DCs) regulate acute lung inflammation and pathological injury in ALI. In addition, studies have shown that the activation of the PI3K/AKT/mTOR signaling pathway may regulate the function and maturation of DCs.

Objective: Therefore, we speculate that HMGB1/PI3K/Akt/mTOR signaling participates in regulating the pathological process of ALI by regulating the maturation and function of DCs.

Methods: Anti-HMGB1 antibody, rHMGB1, or LY294002 (PI3K inhibitor) was administered in a murine model of lipopolysaccharide (LPS)-induced ALI. For in vitro studies, generated bone marrow-derived dendritic cells (BMDCs) primed by LPS were stimulated with the same reagents. The effects of these different treatments were observed on the expression of PI3K, AKT, and mTOR and on the function of DCs.

Results: HMGB1 upregulated the expression of PI3K, Akt, and mTOR mRNA and phosphorylated proteins in BMDCs. The HMGB1/PI3K/Akt/mTOR signaling pathway induced the maturation and antigen-presenting ability of lung DCs, mediated the percentage of myeloid DCs (mDCs), and enhanced the adhesion and chemotactic ability of lung DCs.

Conclusions: HMGB1/PI3K/Akt/mTOR signaling participates in the pathological process of ALI by regulating the maturation and functions of DCs.

• HMGB1
• PI3K/Akt/mTOR signaling
• acute lung injury
• dendritic cell
• lipopolysaccharide

• acute lung injury
• cytokine
• fluoroquinolone
• immunomodulatory
• lipopolysaccharide
• myeloperoxidase

• Acute Lung Injury/drug therapy
• Acute Lung Injury/microbiology
• Animals
• Anti-Bacterial Agents/pharmacology
• Anti-Inflammatory Agents/pharmacology
• Bacteria/drug effects
• Cytokines/blood
• Disease Models, Animal
• Humans
• Immunologic Factors/pharmacology
• Immunomodulation/drug effects
• Inflammation/drug therapy
• Leukocyte Count
• Lipopolysaccharides/toxicity
• Mice
• Microbial Sensitivity Tests
• Peroxidase/blood
• Quinolizines/pharmacology
• Quinolones/pharmacology

Acute respiratory distress syndrome (ARDS) is a sudden and serious disease with increasing morbidity and mortality rates. Phosphodiesterase 4 (PDE4) is a novel target for inflammatory disease, and ibudilast (IBU), a PDE4 inhibitor, inhibits inflammatory response. Our study investigated the effect of IBU on the pathogenesis of neonatal ARDS and the underlying mechanism related to it.

Western blotting was performed to analyze the expression levels of PDE4, CXCR4, SDF-1, CXCR5, CXCL1, inflammatory cytokines, and proteins related to cell apoptosis. Hematoxylin-eosin staining was performed to observe the pathological morphology of lung tissue. Pulmonary edema score was used to assess the degree of lung water accumulation after pulmonary injury. Enzyme-linked immunosorbent assay (ELISA) was used to assess levels of inflammatory factors (TNF-α, IL-1β, IL-6, and MCP-1) in serum. TUNEL assay was used to detect apoptotic cells.

Increased expression of PDE4 was observed in an LPS-induced neonatal ARDS mouse model, and IBU ameliorated LPS-induced pathological manifestations and pulmonary edema in lung tissue. In addition, IBU attenuated the secretion of inflammatory cytokines by inactivating the chemokine axis in the LPS-induced neonatal ARDS mouse model. Finally, IBU significantly reduced LPS-induced cell apoptosis in lung tissue.

IBU, a PDE4 inhibitor, protected against ARDS by interfering with pulmonary inflammation and apoptosis. Our findings provide a novel and promising strategy to regulate pulmonary inflammation in ARDS.

Neonatal acute respiratory distress syndrome (ARDS) is a common clinical syndrome caused by lung immaturity and the abnormal synthesis of pulmonary surfactant in preterm newborns, and it has high morbidity and mortality rates. The present study investigated the roles of interleukin-37 (IL-37) in the pathogenesis of neonatal ARDS and the underlying biochemical mechanism.

We used 6-day-old neonatal C57BL/6 mice to establish the ARDS model. Inflammatory cytokines levels were measured with enzyme-linked immunosorbent assay (ELISA) Kits. The pathological morphology of lung tissues was observed by hematoxylin-eosin (HE) staining. The expression levels of proteins were assessed by Western blotting and apoptotic cells were detected via TUNEL assay. Further, the expression of nucleotide-bound oligomerization domain (Nod)-like receptor P3 (NLRP3) was detected with immunohistochemistry and Western blotting.

IL-37 attenuated lipopolysaccharide (LPS)-induced cell apoptosis and excessive inflammatory cytokines levels, including IL-1β, IL-8, TNF-α, and MCP-1, and ameliorated lung pathological manifestations in an LPS-induced neonatal ARDS model. Moreover, IL-37 suppressed the abnormal expression of proteins related to the CXCR4/SDF-1 chemokine axis and NLRP3 inflammasome pathway.

The present results suggest that IL-37 protect against LPS-induced lung injury through inhibition of inflammation and apoptosis in lung tissue in an LPS-induced neonatal ARDS model. Hence, IL-37 may be considered as a potential therapeutic agent for neonatal ARDS.

Glycine supplementation has been reported to alleviate lipopolysaccharide (LPS)-induced lung injury in mice. However, the underlying mechanisms responsible for this beneficial effect remain unknown. In the present study, male C57BL/6 mice were treated with aerosolized glycine (1000 mg in 5 mL of 0.9% saline) or vehicle (0.9% saline) once daily for 7 continuous days, and then were exposed to aerosolized LPS (5 mg in 5 mL of 0.9% saline) for 30 min to induce lung injury. Sera and lung tissues were collected 24 h post LPS challenge. Results showed that glycine pretreatment attenuated LPS-induced decreases of mucin at both protein and mRNA levels, reduced LPS-triggered upregulation of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferons, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukins. Further study showed that glycine-reduced LPS challenge resulted in the upregulation of nuclear factor κB (NF-κB), nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. In addition, LPS exposure led to the downregulation of NRF2 and downstream targets, which were significantly improved by glycine administration in the lung tissues. Our findings indicated that glycine pretreatment prevented LPS-induced lung injury by regulating both NLRP3 inflammasome and NRF2 signaling.

• HSP70
• NF-κB
• NLRP3
• NRF2
• acute lung injury
• glycine
• lipopolysaccharide

• Acute Lung Injury/blood
• Acute Lung Injury/chemically induced
• Acute Lung Injury/drug therapy
• Acute Lung Injury/metabolism
• Animals
• Autophagy/drug effects
• Cytokines/blood
• Down-Regulation/drug effects
• Glycine/administration & dosage
• Glycine/pharmacology
• Glycine/therapeutic use
• HSP40 Heat-Shock Proteins/metabolism
• HSP70 Heat-Shock Proteins/metabolism
• Inflammation Mediators/blood
• Lipopolysaccharides
• Lung/pathology
• Male
• Mice, Inbred C57BL
• Mucins/metabolism
• NF-E2-Related Factor 2/metabolism
• NF-kappa B/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Signal Transduction