ABSTRACT
A good safety and immunogenicity profile was reported in Phase I and II clinical trials of inactivated SARS-CoV-2 vaccines. Here, we report two cases associated with vaccine-associated adverse events, including one patient with fever and another with anaphylactic shock resulting from inactivated SARS-CoV-2 vaccination. Cell sub-types and the importance of genetic characteristics were assessed using single-cell mRNA sequencing and machine learning. Overall, the patient with fever showed a significant increase in the numbers of cytotoxic CD8 T cells and MKI67high CD8 T cells. A potential concurrent infection with the Epstein-Barr virus enhanced interferon type I responses to vaccination against the virus. STAT1, E2F1, YBX1, and E2F7 played a key role in the transcription regulation of MKI67high CD8 T cells. In contrast, the patient with allergic shock displayed predominant increases in the numbers of S100A9high monocytes, activated CD4 T cells, and PPBPhigh megakaryocytes. The decision tree showed that LYZ and S100A8 in S100A9high monocytes contributed to the degranulation of neutrophils and activation of neutrophils involved in allergic shock. PPBP and PF4 were major contributors to platelet degranulation. These findings highlight the diversity of adverse reactions following inactivated SARS-CoV-2 vaccination and show the emerging role of cellular subtypes and central genes in vaccine-associated adverse reactions.
The identification of cell sub-types may help in the diagnosis of COVID-19 vaccine-related adverse events.COVID-19 vaccination-related acute pulmonary edema may induce a higher risk of thrombosis.The long-term fever after vaccination may attribute to the excessive type I interferon responses.
Subject(s)
COVID-19 Vaccines , Humans , Male , Female , Adult , COVID-19 Vaccines/adverse effects , Fever/immunology , Fever/pathology , Pulmonary Edema/immunology , Pulmonary Edema/pathology , CD8-Positive T-Lymphocytes/cytology , Cell Proliferation , Megakaryocytes/pathology , Single-Cell Gene Expression Analysis , B-Lymphocytes/cytology , Monocytes/cytology , Anaphylaxis/immunology , Anaphylaxis/pathologyABSTRACT
Emerging evidence has demonstrated that several microvesicles (MVs) are secreted in bronchoalveolar lavage fluid (BALF) during the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the impact of alveolar macrophage (AM)-derived MVs on epithelial cells and their in vivo effects on ALI/ARDS require further exploration. In this study, MVs were isolated from BALF of mice or mouse alveolar macrophage (MHS) cells by sequential centrifugation and then delivered to epithelial cells or mice. Enzyme-linked immunosorbent assay revealed that BALF-derived MVs (BALF-MVs) and MHS-derived MVs (AM-MVs) were rich in tumor necrosis factor-α (TNF-α) at the early stage of lung injury. In vitro, both inflammatory BALF-MVs and AM-MVs decreased the expression of α subunit of epithelial sodium channel (α-ENaC), γ-ENaC, and Na+,K+-ATPase α1 and ß1 in lung epithelial cells. However, antibodies against TNF-α inhibited the effects of inflammatory AM-MVs in epithelial cells. In vivo, the inflammatory AM-MVs, delivered intratracheally to mice, impaired lung tissues and increased the injury score. They also resulted in decreased alveolar fluid clearance and increased lung wet weight/dry weight ratio. Furthermore, inflammatory AM-MVs downregulated the α-ENaC, γ-ENaC, and Na+,K+-ATPase α1 and ß1 levels in lung tissues. According to our results, inflammatory AM-derived MVs may potentially contribute to lung injury and pulmonary edema, thereby indicating a potential novel therapeutic approach against ALI/ARDS based on AM-MVs.
Subject(s)
Cell-Derived Microparticles/metabolism , Epithelial Cells/immunology , Inflammation/immunology , Lung/pathology , Macrophages, Alveolar/immunology , Pulmonary Edema/immunology , Respiratory Distress Syndrome/immunology , Animals , Cells, Cultured , Epithelial Sodium Channels/metabolism , Humans , Mice , Mice, Inbred C57BL , Sodium-Potassium-Exchanging ATPase/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Nearly 5% of patients suffering from COVID-19 develop acute respiratory distress syndrome (ARDS). Extravascular lung water index (EVLWI) is a marker of pulmonary oedema which is associated with mortality in ARDS. In this study, we evaluate whether EVLWI is higher in patients with COVID-19 associated ARDS as compared to COVID-19 negative, ventilated patients with ARDS and whether EVLWI has the potential to monitor disease progression. EVLWI and cardiac function were monitored by transpulmonary thermodilution in 25 patients with COVID-19 ARDS subsequent to intubation and compared to a control group of 49 non-COVID-19 ARDS patients. At intubation, EVLWI was noticeably elevated and significantly higher in COVID-19 patients than in the control group (17 (11-38) vs. 11 (6-26) mL/kg; p < 0.001). High pulmonary vascular permeability index values (2.9 (1.0-5.2) versus 1.9 (1.0-5.2); p = 0.003) suggested a non-cardiogenic pulmonary oedema. By contrast, the cardiac parameters SVI, GEF and GEDVI were comparable in both cohorts. High EVLWI values were associated with viral persistence, prolonged intensive care treatment and in-hospital mortality (23.2 ± 6.7% vs. 30.3 ± 6.0%, p = 0.025). Also, EVLWI showed a significant between-subjects (r = - 0.60; p = 0.001) and within-subjects correlation (r = - 0.27; p = 0.028) to Horowitz index. Compared to non COVID-19 ARDS, COVID-19 results in markedly elevated EVLWI-values in patients with ARDS. High EVLWI reflects a non-cardiogenic pulmonary oedema in COVID-19 ARDS and could serve as parameter to monitor ARDS progression on ICU.
Subject(s)
COVID-19/complications , Extravascular Lung Water/immunology , Pulmonary Edema/mortality , Respiratory Distress Syndrome/mortality , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/immunology , COVID-19/mortality , Capillary Permeability , Disease Progression , Extravascular Lung Water/virology , Female , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Length of Stay/statistics & numerical data , Lung/blood supply , Lung/physiopathology , Male , Middle Aged , Monitoring, Physiologic/methods , Monitoring, Physiologic/statistics & numerical data , Prognosis , Pulmonary Edema/diagnosis , Pulmonary Edema/immunology , Pulmonary Edema/virology , Respiration, Artificial , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , Risk Assessment/methods , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thermodilution/methods , Thermodilution/statistics & numerical data , Young AdultABSTRACT
Morbidity and mortality associated with neonatal sepsis remains a healthcare crisis. PD1-/- neonatal mice endured experimental sepsis, in the form of cecal slurry (CS), and showed improved rates of survival compared to wildtype (WT) counterparts. End-organ injury, particularly of the lung, contributes to the devastation set forth by neonatal sepsis. PDL1-/- neonatal mice, in contrast to PD1-/- neonatal mice did not have a significant improvement in survival after CS. Because of this, we focused subsequent studies on the impact of PD1 gene deficiency on lung injury. Here, we observed that at 24 h post-CS (but not at 4 or 12 h) there was a marked increase in pulmonary edema (PE), neutrophil influx, myeloperoxidase (MPO) levels, and cytokine expression sham (Sh) WT mice. Regarding pulmonary endothelial cell (EC) adhesion molecule expression, we observed that Zona occludens-1 (ZO-1) within the cell shifted from a membranous location to a peri-nuclear location after CS in WT murine cultured ECs at 24hrs, but remained membranous among PD1-/- lungs. To expand the scope of this inquiry, we investigated human neonatal lung tissue. We observed that the lungs of human newborns exposed to intrauterine infection had significantly higher numbers of PD1+ cells compared to specimens who died from non-infectious causes. Together, these data suggest that PD1/PDL1, a pathway typically thought to govern adaptive immune processes in adult animals, can modulate the largely innate neonatal pulmonary immune response to experimental septic insult. The potential future significance of this area of study includes that PD1/PDL1 checkpoint proteins may be viable therapeutic targets in the septic neonate.
Subject(s)
B7-H1 Antigen/metabolism , Lung Injury/etiology , Lung/metabolism , Neonatal Sepsis/complications , Programmed Cell Death 1 Receptor/metabolism , Animals , Animals, Newborn , B7-H1 Antigen/genetics , Case-Control Studies , Cells, Cultured , Disease Models, Animal , Endothelial Cells/immunology , Endothelial Cells/metabolism , Female , Humans , Immunity, Innate , Infant, Newborn , Lung/immunology , Lung/pathology , Lung Injury/immunology , Lung Injury/metabolism , Lung Injury/pathology , Male , Mice, Inbred C57BL , Mice, Knockout , Neonatal Sepsis/immunology , Neonatal Sepsis/metabolism , Neonatal Sepsis/microbiology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Programmed Cell Death 1 Receptor/genetics , Pulmonary Edema/etiology , Pulmonary Edema/immunology , Pulmonary Edema/metabolism , Pulmonary Edema/pathology , Zonula Occludens-1 Protein/metabolismABSTRACT
Pneumonia-induced lung injury and acute respiratory distress syndrome can develop because of an inappropriate inflammatory response to acute infections, leading to a compromised alveolar barrier. Recent work suggests that hospitalized patients with allergies/asthma are less likely to die of pulmonary infections and that there is a correlation between survival from acute respiratory distress syndrome and higher eosinophil counts; thus, we hypothesized that eosinophils associated with a type 2 immune response may protect against pneumonia-induced acute lung injury. To test this hypothesis, mice were treated with the type 2-initiating cytokine IL-33 intratracheally 3 days before induction of pneumonia with airway administration of a lethal dose of Staphylococcus aureus. Interestingly, IL-33 pretreatment promoted survival by inhibiting acute lung injury: amount of BAL fluid proinflammatory cytokines and pulmonary edema were both reduced, with an associated increase in oxygen saturation. Pulmonary neutrophilia was also reduced, whereas eosinophilia was strongly increased. This eosinophilia was key to protection; eosinophil reduction eliminated both IL-33-mediated protection against mortality and inhibition of neutrophilia and pulmonary edema. Together, these data reveal a novel role for eosinophils in protection against lung injury and suggest that modulation of pulmonary type 2 immunity may represent a novel therapeutic strategy.
Subject(s)
Acute Lung Injury/immunology , Eosinophils/immunology , Interleukin-33/immunology , Pneumonia, Staphylococcal/immunology , Pulmonary Edema/immunology , Respiratory Distress Syndrome/immunology , Staphylococcus aureus/pathogenicity , Acute Lung Injury/etiology , Acute Lung Injury/microbiology , Acute Lung Injury/prevention & control , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Diphtheria Toxin/pharmacology , Disease Models, Animal , Eosinophils/drug effects , Female , Gene Expression , Humans , Interleukin-33/genetics , Interleukin-33/pharmacology , Interleukin-5/deficiency , Interleukin-5/genetics , Interleukin-5/immunology , Leukocyte Count , Leukocyte Reduction Procedures , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/drug effects , Neutrophils/immunology , Pneumonia, Staphylococcal/complications , Pneumonia, Staphylococcal/microbiology , Pneumonia, Staphylococcal/mortality , Pulmonary Edema/complications , Pulmonary Edema/microbiology , Pulmonary Edema/mortality , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/microbiology , Respiratory Distress Syndrome/prevention & control , Staphylococcus aureus/immunology , Survival AnalysisABSTRACT
BACKGROUND: Brain death (BD) affects the viability of lungs for transplantation. A correlation exists between high-lung inflammation after BD and the decrease in female sex hormones, especially estradiol. Therefore, we investigated the effects of 17ß-estradiol (E2) treatment on the lungs of female brain dead rats. METHODS: Female Wistar rats were divided into 4 groups: BD (submitted to BD for 6 h), sham (false operated), E2-T0 (treated with E2 immediately after BD; 50 µg/mL, 2 mL/h), and E2-T3 (treated with E2 after 3 h of BD; 50 µg/mL, 2 mL/h). Lung edema, hemorrhage, and leukocyte infiltration were analyzed. Adhesion molecules were evaluated, and analysis of NO synthase gene and protein expression was performed using real-time PCR and immunohistochemistry, respectively. Release of chemokines and matrix degradation in the lungs was analyzed. RESULTS: BD increased leukocyte infiltration, as shown by intravital microscopy (P = 0.017), bronchoalveolar lavage cell count (P = 0.016), the release of inflammatory mediators (P = 0.02), and expression of adhesion molecules. BD also increased microvascular permeability and the expression and activity of matrix metalloproteinase-9 in the lungs. E2 treatment reduced leukocyte infiltration, especially in the E2-T3 group, release of inflammatory mediators, adhesion molecules, and matrix metalloproteinase activity in the lungs. CONCLUSIONS: E2 treatment was successful in controlling the lung inflammatory response in females submitted to BD. Our results suggest that E2 directly decreases the release of chemokines, restraining cell traffic into the lungs. Thus, E2 has a therapeutic potential, and its role in improving donor lung quality should be explored further.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Brain Death , Estradiol/pharmacology , Lung/drug effects , Pneumonia/prevention & control , Animals , Capillary Permeability/drug effects , Cell Adhesion Molecules/metabolism , Chemotaxis, Leukocyte/drug effects , Cytoprotection , Disease Models, Animal , Female , Inflammation Mediators/metabolism , Leukocytes/drug effects , Leukocytes/immunology , Leukocytes/metabolism , Lung/immunology , Lung/metabolism , Lung/pathology , Matrix Metalloproteinase 9/metabolism , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia/pathology , Pulmonary Edema/immunology , Pulmonary Edema/metabolism , Pulmonary Edema/pathology , Pulmonary Edema/prevention & control , Rats, Wistar , Tissue Culture TechniquesABSTRACT
Pulmonary macrophages play a critical role in the recognition of pathogens, initiation of host defense via inflammation, clearance of pathogens from the airways, and resolution of inflammation. Recently, we have shown a pivotal role for the nuclear factor of activated T-cell cytoplasmic member 3 (NFATc3) transcription factor in modulating pulmonary macrophage function in LPS-induced acute lung injury (ALI) pathogenesis. Although the NFATc proteins are activated primarily by calcineurin-dependent dephosphorylation, here we show that LPS induces posttranslational modification of NFATc3 by polyADP-ribose polymerase 1 (PARP-1)-mediated polyADP-ribosylation. ADP-ribosylated NFATc3 showed increased binding to iNOS and TNFα promoter DNA, thereby increasing downstream gene expression. Inhibitors of PARP-1 decreased LPS-induced NFATc3 ribosylation, target gene promoter binding, and gene expression. LPS increased NFAT luciferase reporter activity in lung macrophages and lung tissue that was inhibited by pretreatment with PARP-1 inhibitors. More importantly, pretreatment of mice with the PARP-1 inhibitor olaparib markedly decreased LPS-induced cytokines, protein extravasation in bronchoalveolar fluid, lung wet-to-dry ratios, and myeloperoxidase activity. Furthermore, PARP-1 inhibitors decreased NF-кB luciferase reporter activity and LPS-induced ALI in NF-кB reporter mice. Thus, our study demonstrates that inhibiting NFATc3 and NF-кB polyADP-ribosylation with PARP-1 inhibitors prevented LPS-induced ALI pathogenesis.
Subject(s)
Acute Lung Injury/metabolism , Inflammation/genetics , Lung/immunology , Macrophages/immunology , NF-kappa B/metabolism , NFATC Transcription Factors/metabolism , Pulmonary Edema/immunology , Acute Lung Injury/immunology , Animals , Cells, Cultured , Disease Models, Animal , Gene Expression Regulation , Humans , Lipopolysaccharides/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly ADP RibosylationABSTRACT
BACKGROUND: COVID-19, as a newly-emerged viral infection has now spread all over the world after originating in Wuhan, China. Pneumonia is the hallmark of the disease, with dyspnea in half of the patients and acute respiratory distress syndrome (ARDS) in up to one -third of the cases. Pulmonary edema, neutrophilic infiltration, and inflammatory cytokine release are the pathologic signs of this disease. The anti-inflammatory effect of the photobiomodulation (PBM) has been confirmed in many previous studies. Therefore, this review study was conducted to evaluate the direct effect of PBM on the acute lung inflammation or ARDS and also accelerating the regeneration of the damaged tissues. The indirect effects of PBM on modulation of the immune system, increasing the blood flow and oxygenation in other tissues were also considered. METHODOLOGY: The databases of PubMed, Cochrane library, and Google Scholar were searched to find the relevant studies. Keywords included the PBM and related terms, lung inflammation, and COVID-19 -related signs. Studies were categorized with respect to the target tissue, laser parameters, and their results. RESULTS: Seventeen related papers were included in this review. All of them were in animal models. They showed that the PBM could significantly decrease the pulmonary edema, neutrophil influx, and generation of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), intracellular adhesion molecule (ICAM), reactive oxygen species (ROS), isoform of nitric oxide synthase (iNOS), and macrophage inflammatory protein 2 (MIP-2)). CONCLUSION: Our findings revealed that the PBM could be helpful in reducing the lung inflammation and promoting the regeneration of the damaged tissue. PBM can increase the oxygenation indirectly in order to rehabilitate the affected organs. Thus, the infra-red lasers or light-emitting diodes (LEDs) are recommended in this regard.
Subject(s)
COVID-19/radiotherapy , Low-Level Light Therapy , Lung/radiation effects , Pneumonia/radiotherapy , COVID-19/blood , COVID-19/immunology , Cytokines/metabolism , Humans , Lung/physiopathology , Macrophages/drug effects , Macrophages/immunology , Neutrophils/drug effects , Neutrophils/immunology , Pneumonia/immunology , Pneumonia/physiopathology , PubMed , Pulmonary Edema/immunology , Pulmonary Edema/physiopathology , Pulmonary Edema/radiotherapy , Reactive Oxygen Species/metabolism , Respiratory Distress Syndrome/radiotherapyABSTRACT
Current study investigates the immunomodulatory effects of T. stocksianum using mouse model of ovalbumin (OVA)-induced allergic asthma. The mice were treated with methanolic extract, n-hexane, and ethyl acetate fractions for consecutive 7 days along with intranasal challenge. The mRNA expression levels of interleukin-4 (IL-4), IL-5, Aquaporin-1 (AQP1) and Aquaporin-5 (AQP5) were evaluated using reverse transcription polymerase chain reaction. The data showed that T. stocksianum significantly reduced airway inflammation as indicated by reduced inflammatory cell infiltration in lungs, and attenuated total and differential leukocyte counts both in blood and BALF. Expression levels of pro-inflammatory IL-4 and IL-5 in lungs were also found significantly reduced. T. stocksianum significantly reduced pulmonary edema as indicated by reduced lung wet/dry ratio and goblet cell hyperplasia. AQP1 and AQP5 expression levels were also found elevated in treatment groups. In conclusion, T. stocksianum possesses anti-asthmatic activity which may be attributed to reduction in IL-4 and IL-5 expression levels, and elevation in AQP1 and AQP5 expression levels.
Subject(s)
Aquaporin 1/drug effects , Aquaporin 5/drug effects , Asthma/drug therapy , Hypersensitivity/drug therapy , Immunologic Factors/pharmacology , Inflammation/drug therapy , Interleukin-4 , Interleukin-5 , Pulmonary Edema/drug therapy , Respiratory Tract Diseases/drug therapy , Teucrium , Animals , Asthma/immunology , Disease Models, Animal , Female , Hypersensitivity/immunology , Immunologic Factors/administration & dosage , Inflammation/immunology , Male , Mice , Mice, Inbred BALB C , Plant Extracts/administration & dosage , Pulmonary Edema/immunology , Respiratory Tract Diseases/immunologyABSTRACT
A hypothesis concerning the potential utility of surfactant supplementation for the treatment of critically ill patients with COVID-19 is proposed, along with a brief summary of the data in the literature supporting this idea. It is thought that surfactant, which is already approved by the Food and Drug Administration for intratracheal administration to treat neonatal respiratory distress syndrome in pre-term infants, could benefit COVID-19-infected individuals by: (1) restoring surfactant damaged by lung infection and/or decreased due to the virus-induced death of the type II pneumocytes that produce it and (2) reducing surface tension to decrease the work of breathing and limit pulmonary edema. In addition, a constituent of surfactant, phosphatidylglycerol, could mitigate COVID-19-induced lung pathology by: (3) decreasing excessive innate immune system stimulation via its inhibition of toll-like receptor-2 and -4 activation by microbial components and cellular proteins released by damaged cells, thereby limiting inflammation and the resultant pulmonary edema, and (4) possibly blocking spread of the viral infection to non-infected cells in the lung. Therefore, it is suggested that surfactant preparations containing phosphatidylglycerol be tested for their ability to improve lung function in critically ill patients with COVID-19.
Subject(s)
COVID-19 Drug Treatment , COVID-19/therapy , Phosphatidylglycerols/therapeutic use , Pulmonary Surfactants/therapeutic use , Adult , Alveolar Epithelial Cells/drug effects , Animals , COVID-19/physiopathology , Cattle , Critical Illness , Humans , Immunity, Innate , Inflammation , Lung/pathology , Models, Theoretical , Pulmonary Edema/immunology , SwineABSTRACT
It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117+ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.
Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Mast Cells/immunology , Pneumonia, Viral/immunology , Pulmonary Alveoli/immunology , Pulmonary Edema/immunology , Thrombosis/immunology , Adult , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Influenza A Virus, H1N1 Subtype/immunology , Influenza, Human/immunology , Influenza, Human/pathology , Influenza, Human/virology , Interleukin-4/immunology , Male , Mast Cells/pathology , Middle Aged , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Proto-Oncogene Proteins c-kit/immunology , Pulmonary Alveoli/pathology , Pulmonary Alveoli/virology , Pulmonary Edema/pathology , Pulmonary Edema/virology , SARS-CoV-2 , Thrombosis/pathology , Thrombosis/virologyABSTRACT
In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. We are proposing a new hypothesis that neurogenic insult may also play a major role in the pathogenesis of these manifestations. SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius (NTS) may play a role in the acute exacerbation of pulmonary edema and microvascular clotting in COVID-19 patients.
Subject(s)
Coronavirus Infections/physiopathology , Hypotension/physiopathology , Lung/blood supply , Microvessels/physiopathology , Pneumonia, Viral/physiopathology , Pulmonary Edema/physiopathology , Solitary Nucleus/physiopathology , Thrombosis/physiopathology , Betacoronavirus , COVID-19 , Capillary Permeability/physiology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/physiopathology , Facial Nerve , Glossopharyngeal Nerve , Humans , Inflammation , Lung/immunology , Microvessels/immunology , Pandemics , Parasympathetic Nervous System/physiopathology , Pneumonia, Viral/immunology , Pulmonary Edema/immunology , SARS-CoV-2 , Solitary Nucleus/immunology , Vagus Nerve , VasoconstrictionABSTRACT
BACKGROUND: National health-system hospitals of Lombardy faced a heavy burden of admissions for acute respiratory distress syndromes associated with coronavirus disease (COVID-19). Data on patients of European origin affected by COVID-19 are limited. METHODS: All consecutive patients aged ≥18 years, coming from North-East of Milan's province and admitted at San Raffaele Hospital with COVID-19, between February 25th and March 24th, were reported, all patients were followed for at least one month. Clinical and radiological features at admission and predictors of clinical outcomes were evaluated. RESULTS: Of the 500 patients admitted to the Emergency Unit, 410 patients were hospitalized and analyzed: median age was 65 (IQR 56-75) years, and the majority of patients were males (72.9%). Median (IQR) days from COVID-19 symptoms onset was 8 (5-11) days. At hospital admission, fever (≥ 37.5 °C) was present in 67.5% of patients. Median oxygen saturation (SpO2) was 93% (range 60-99), with median PaO2/FiO2 ratio, 267 (IQR 184-314). Median Radiographic Assessment of Lung Edema (RALE) score was 9 (IQR 4-16). More than half of the patients (56.3%) had comorbidities, with hypertension, coronary heart disease, diabetes and chronic kidney failure being the most common. The probability of overall survival at day 28 was 66%. Multivariable analysis showed older age, coronary artery disease, cancer, low lymphocyte count and high RALE score as factors independently associated with an increased risk of mortality. CONCLUSION: In a large cohort of COVID-19 patients of European origin, main risk factors for mortality were older age, comorbidities, low lymphocyte count and high RALE.
Subject(s)
Coronary Disease/diagnosis , Coronavirus Infections/diagnosis , Diabetes Mellitus/diagnosis , Hypertension/diagnosis , Kidney Failure, Chronic/diagnosis , Pneumonia, Viral/diagnosis , Pulmonary Edema/diagnosis , Severe Acute Respiratory Syndrome/diagnosis , Age Factors , Aged , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Comorbidity , Coronary Disease/epidemiology , Coronary Disease/immunology , Coronary Disease/mortality , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Diabetes Mellitus/mortality , Female , Hospitalization , Humans , Hypertension/epidemiology , Hypertension/immunology , Hypertension/mortality , Infectious Disease Incubation Period , Italy/epidemiology , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/immunology , Kidney Failure, Chronic/mortality , Lymphocyte Count , Lymphocytes/immunology , Lymphocytes/pathology , Lymphocytes/virology , Male , Middle Aged , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pulmonary Edema/epidemiology , Pulmonary Edema/immunology , Pulmonary Edema/mortality , Risk Factors , SARS-CoV-2 , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/mortality , Severity of Illness Index , Survival AnalysisABSTRACT
Interleukin-11 (IL-11) is an interleukin-6 (IL-6) family cytokine shown to play a protective role in acute inflammatory settings including systemic infection. In this study we addressed the role of IL-11 in acute bacterial pneumonia using a mouse model of E. coli pneumonia. Compared with other related cytokines, IL-11 protein was maintained at high levels in the lung at baseline, with only mild alterations in whole lung and BALF levels during acute infection. The primary source of IL-11 in the lung was the epithelium, but steady state production was not dependent on the inflammatory transcription factor nuclear factor kappa B in cells of either myeloid or epithelial lineage. Blockade of IL-11 with neutralizing antibodies resulted in a mild but significant decrease in neutrophil recruitment and increase in pulmonary edema during pneumonia, without detectable alterations in bacterial clearance. Exogenous IL-11 administration, however, had no effect at baseline or during infection. Overall, we conclude that maintenance of lung IL-11 concentrations may influence acute pulmonary inflammation during infection, albeit modestly.
Subject(s)
Interleukin-11/immunology , Neutrophil Infiltration/immunology , Neutrophils/immunology , Pneumonia, Bacterial/immunology , Pulmonary Edema/immunology , Acute Disease , Animals , Antibodies, Neutralizing/pharmacology , Interleukin-11/antagonists & inhibitors , Interleukin-11/genetics , Mice , Mice, Knockout , Neutrophil Infiltration/drug effects , Neutrophils/pathology , Pneumonia, Bacterial/drug therapy , Pneumonia, Bacterial/genetics , Pneumonia, Bacterial/pathology , Pulmonary Edema/drug therapy , Pulmonary Edema/genetics , Pulmonary Edema/pathologyABSTRACT
Staphylococcus aureus is frequently isolated from patients with community-acquired pneumonia and acute respiratory distress syndrome (ARDS). ARDS is associated with staphylococcal phosphatidylinositol-specific phospholipase C (PI-PLC); however, the role of PI-PLC in the pathogenesis and progression of ARDS remains unknown. Here, we showed that recombinant staphylococcal PI-PLC possesses enzyme activity that causes shedding of glycosylphosphatidylinositol-anchored CD55 and CD59 from human umbilical vein endothelial cell surfaces and triggers cell lysis via complement activity. Intranasal infection with PI-PLC-positive S. aureus resulted in greater neutrophil infiltration and increased pulmonary oedema compared with a plc-isogenic mutant. Although indistinguishable proinflammatory genes were induced, the wild-type strain activated higher levels of C5a in lung tissue accompanied by elevated albumin instillation and increased lactate dehydrogenase release in bronchoalveolar lavage fluid compared with the plc- mutant. Following treatment with cobra venom factor to deplete complement, the wild-type strain with PI-PLC showed a reduced ability to trigger pulmonary permeability and tissue damage. PI-PLC-positive S. aureus induced the formation of membrane attack complex, mainly on type II pneumocytes, and reduced the level of CD55/CD59, indicating the importance of complement regulation in pulmonary injury. In conclusion, S. aureus PI-PLC sensitised tissue to complement activation leading to more severe tissue damage, increased pulmonary oedema, and ARDS progression.
Subject(s)
Bacterial Proteins/metabolism , Complement System Proteins/metabolism , Phosphoinositide Phospholipase C/metabolism , Pulmonary Edema/immunology , Pulmonary Edema/microbiology , Respiratory Distress Syndrome/microbiology , Staphylococcal Infections/immunology , Staphylococcus aureus/enzymology , Alveolar Epithelial Cells/enzymology , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/microbiology , Animals , Bacterial Proteins/genetics , CD55 Antigens/immunology , CD59 Antigens/immunology , Cytokines/metabolism , Glycosylphosphatidylinositols/immunology , Glycosylphosphatidylinositols/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Mice , Mice, Inbred BALB C , Phosphoinositide Phospholipase C/genetics , Pulmonary Edema/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Staphylococcal Infections/metabolism , Staphylococcal Infections/microbiology , Staphylococcus aureus/genetics , Staphylococcus aureus/metabolismABSTRACT
The acute respiratory distress syndrome (ARDS), a devastating clinical syndrome, is one of the most severe complications of acute lung injury (ALI). Despite of decades of clinical trials and supportive ventilation strategies, the incidence and mortality of ALI/ARDS remain high. DL-3-n-butylphthalide (NBP) is a synthesized raceme of L-3-n-butylphthalide which has been approved to possess various activities. In the current study, we aimed to investigate the effect of NBP on ALI in lipopolysaccharide (LPS)-treated mice. We found that 10â¯mg/kg and 50â¯mg/kg NBP significantly prevented LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. Sirtuin 1 (SIRT1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was increased by NBP in lung of LPS-treated mice. Knockout of SIRT1 significantly aggravated LPS-induced ALI. Moreover, the absence of SIRT1 notably inhibited NBP-induced protective effects against LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. However, knockout of SIRT1 did not completely inhibit NBP-induced upregulation of Nrf2 and attenuation of ALI. The results demonstrated that NBP could activate Nrf2 antioxidant signaling in a SIRT1-dependent and SIRT1-independent manner, resulting in the amelioration of oxidative stress, inflammation and pulmonary edema. The data highlights the importance of SIRT1/Nrf2 signaling in the protective effects of NBP.
Subject(s)
Acute Lung Injury/immunology , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Benzofurans/pharmacology , NF-E2-Related Factor 2/immunology , Sirtuin 1/immunology , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Animals , Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Benzofurans/therapeutic use , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cytokines/immunology , Lipopolysaccharides , Lung/drug effects , Lung/immunology , Lung/pathology , Male , Mice, Inbred C57BL , Mice, Knockout , Pulmonary Edema/chemically induced , Pulmonary Edema/drug therapy , Pulmonary Edema/immunology , Pulmonary Edema/pathology , Sirtuin 1/geneticsABSTRACT
Secondary bacterial lung infection by Streptococcus pneumoniae (S. pneumoniae) poses a serious health concern, especially in developing countries. We posit that the emergence of multiantibiotic-resistant strains will jeopardize current treatments in these regions. Deaths arising from secondary infections are more often associated with acute lung injury, a common consequence of hypercytokinemia, than with the infection per se Given that secondary bacterial pneumonia often has a poor prognosis, newer approaches to improve treatment outcomes are urgently needed to reduce the high levels of morbidity and mortality. Using a sequential dual-infection mouse model of secondary bacterial lung infection, we show that host-directed therapy via immunoneutralization of the angiopoietin-like 4 c-isoform (cANGPTL4) reduced pulmonary edema and damage in infected mice. RNA sequencing analysis revealed that anti-cANGPTL4 treatment improved immune and coagulation functions and reduced internal bleeding and edema. Importantly, anti-cANGPTL4 antibody, when used concurrently with either conventional antibiotics or antipneumolysin antibody, prolonged the median survival of mice compared to monotherapy. Anti-cANGPTL4 treatment enhanced immune cell phagocytosis of bacteria while restricting excessive inflammation. This modification of immune responses improved the disease outcomes of secondary pneumococcal pneumonia. Taken together, our study emphasizes that host-directed therapeutic strategies are viable adjuncts to standard antimicrobial treatments.IMPORTANCE Despite extensive global efforts, secondary bacterial pneumonia still represents a major cause of death in developing countries and is an important cause of long-term functional disability arising from lung tissue damage. Newer approaches to improving treatment outcomes are needed to reduce the significant morbidity and mortality caused by infectious diseases. Our study, using an experimental mouse model of secondary S. pneumoniae infection, shows that a multimodal treatment that concurrently targets host and pathogen factors improved lung tissue integrity and extended the median survival time of infected mice. The immunoneutralization of host protein cANGPTL4 reduced the severity of pulmonary edema and damage. We show that host-directed therapeutic strategies as well as neutralizing antibodies against pathogen virulence factors are viable adjuncts to standard antimicrobial treatments such as antibiotics. In view of their different modes of action compared to antibiotics, concurrent immunotherapies using antibodies are potentially efficacious against secondary pneumococcal pneumonia caused by antibiotic-resistant pathogens.
Subject(s)
Angiopoietin-Like Protein 4/antagonists & inhibitors , Antibodies/therapeutic use , Coinfection/therapy , Pneumonia, Pneumococcal/immunology , Pneumonia, Pneumococcal/therapy , Pulmonary Edema/therapy , Angiopoietin-Like Protein 4/immunology , Animals , Anti-Bacterial Agents/therapeutic use , Coinfection/immunology , Coinfection/microbiology , Disease Models, Animal , Female , Inflammation , Lung/microbiology , Mice , Mice, Inbred BALB C , Pneumonia, Pneumococcal/drug therapy , Pulmonary Edema/immunology , Streptococcus pneumoniae/immunologyABSTRACT
The dysregulated, unbalanced immune response of sepsis results in a mortality exceeding 20%, yet recent findings by our group indicate that patients with allergic, type 2-mediated immune diseases are protected from developing sepsis. We evaluated CD4+ Th cell polarization among patients with Staphylococcus aureus bacteremia and confirmed that survivors had a higher percentage of circulating Th2 cells but lower frequencies of Th17 cells and neutrophils early in the course of infection. To establish the mechanism of this protection, we used a mouse model of lethal S. aureus bacteremia and found that intratracheal pretreatment with the type 2-initiating cytokine IL-33 activated pulmonary type 2 innate lymphoid cells (ILC2s) and promoted eosinophilia. In addition, stimulation of type 2 immunity before lethal infection suppressed the pulmonary neutrophilic response to S. aureus. Mice lacking functional ILC2s did not respond to IL-33 and were not protected from lethal bacteremia, but treatment of these mice with the type 2 cytokines IL-5 and IL-13 rescued them from death. Depletion of eosinophils abrogated IL-33-mediated protection, indicating that eosinophilia is also necessary for the survival benefit. Thus, we have identified a potentially novel mechanism by which type 2 immunity can balance dysregulated septic inflammatory responses, thereby clarifying the protective benefit of type 2 immune diseases on sepsis mortality.
Subject(s)
Bacteremia/prevention & control , Cytokines/metabolism , Eosinophils/immunology , Eosinophils/metabolism , Immunity, Innate , Staphylococcal Infections/immunology , Staphylococcus aureus/immunology , Animals , Antigens, CD1d/genetics , Asthma/immunology , Bacteremia/mortality , Disease Models, Animal , Humans , Hypersensitivity , Interleukin-13 , Interleukin-33/immunology , Interleukin-5 , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/immunology , Promyelocytic Leukemia Zinc Finger Protein/genetics , Pulmonary Edema/immunology , Pulmonary Edema/pathology , Th17 Cells/immunology , Th2 Cells/immunologyABSTRACT
Intrauterine inflammation generates inflammatory mediators that damage the developing bronchoalveolar epithelium, resulting in neonatal lung injury. Lung fluid transport disorders are the main reasons for the development of pulmonary edema, an important pathology of lung injury. Previous studies suggested that epithelial sodium channels (ENaCs) play an important role in lung fluid transport. Here, we investigated whether changes in the expression of ENaCs were observed when neonatal rat lung injury was induced by maternal exposure to endotoxin. We also examined the therapeutic effect of terbutaline nebulizer inhalation on this injury. The results showed that maternal exposure to endotoxin increased the levels of TNF-α and IL-1ß in bronchoalveolar lavage fluid, suppressed α-, ß-, γ-ENaC in the neonatal rat lung, and resulted in the formation of pulmonary edema on postnatal days 1 and 7. Terbutaline up-regulated the expression of ß- and γ-ENaC in the distal lung after 7 days of treatment. The potential signal molecules cAMP, PKA, and CREB expressions were increased after terbutaline treatment. In summary, maternal exposure to endotoxin decreased the expression of ENaCs in neonatal rats which, in turn, may exacerbate pulmonary edema. Inhalation of the ß2-adrenergic receptor agonist terbutaline improved lung liquid clearance. By increasing the expression of sodium ion channels, the effective removal of alveolar fluid provides a new way for the prevention and treatment of neonatal lung injury.
Subject(s)
Adrenergic beta-Agonists/therapeutic use , Endotoxins/toxicity , Epithelial Sodium Channels/metabolism , Lung Injury/drug therapy , Pulmonary Edema/drug therapy , Terbutaline/therapeutic use , Adrenergic beta-Agonists/pharmacology , Animals , Animals, Newborn , Biological Transport/drug effects , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , Female , Lung/drug effects , Lung/metabolism , Lung Injury/chemically induced , Lung Injury/immunology , Lung Injury/metabolism , Male , Maternal-Fetal Exchange , Pregnancy , Pulmonary Edema/chemically induced , Pulmonary Edema/immunology , Pulmonary Edema/metabolism , Rats, Sprague-Dawley , Terbutaline/pharmacologyABSTRACT
Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage-associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)-induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage.