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Blood Dec 2023Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. Although hemostatic dysfunction appears to be a major determinant of the...
Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. Although hemostatic dysfunction appears to be a major determinant of the severity of the disease, it is still unclear what pathogenic mechanisms lead to it. In clinical studies it is found that arenaviruses, such as Lassa, Machupo, and Guanarito viruses cause HF that vary in symptoms and biological alterations. In this study we aimed to characterize the hemostatic dysfunction induced by arenaviral HF to determine its implication in the severity of the disease and to elucidate the origin of this syndrome. We found that lethal infection with Machupo, Guanarito, and Lassa viruses is associated with cutaneomucosal, cerebral, digestive, and pulmonary hemorrhages. The affected animals developed a severe alteration of the coagulation system, which was concomitant with acute hepatitis, minor deficit of hepatic factor synthesis, presence of a plasmatic inhibitor of coagulation, and dysfunction of the fibrinolytic system. Despite signs of increased vascular permeability, endothelial cell infection was not a determinant factor of the hemorrhagic syndrome. There were also alterations of the primary hemostasis during lethal infection, with moderate to severe thrombocytopenia and platelet dysfunction. Finally, we show that lethal infection is accompanied by a reduced hematopoietic potential of the bone marrow. This study provides an unprecedented characterization of the hemostasis defects induced by several highly pathogenic arenaviruses.
Topics: Animals; Arenaviridae; Arenavirus; Hemorrhagic Fevers, Viral; Hemorrhage; Hemostasis; Hemostatics; Macaca
PubMed: 37699247
DOI: 10.1182/blood.2023020351 -
Biomolecules Jan 2024A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and, as such, provides a semi-selective barrier between the blood and the interstitial space.... (Review)
Review
A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and, as such, provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may result in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn. Members of this HDAC group are involved in epigenetic regulation primarily by modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extranuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases, and we will discuss the potential of their inhibitors for lung injury prevention.
Topics: Histone Deacetylases; Endothelial Cells; Epigenesis, Genetic; Zinc; Histone Deacetylase Inhibitors; Lung; Histones
PubMed: 38397377
DOI: 10.3390/biom14020140 -
JCI Insight Nov 2023Although SARS-CoV-2 evolution seeds a continuous stream of antibody-evasive viral variants, COVID-19 mRNA vaccines provide robust protection against severe disease and...
Although SARS-CoV-2 evolution seeds a continuous stream of antibody-evasive viral variants, COVID-19 mRNA vaccines provide robust protection against severe disease and hospitalization. Here, we asked whether mRNA vaccine-induced memory T cells limit lung SARS-CoV-2 replication and severe disease. We show that mice and humans receiving booster BioNTech mRNA vaccine developed potent CD8 T cell responses and showed similar kinetics of expansion and contraction of granzyme B/perforin-expressing effector CD8 T cells. Both monovalent and bivalent mRNA vaccines elicited strong expansion of a heterogeneous pool of terminal effectors and memory precursor effector CD8 T cells in spleen, inguinal and mediastinal lymph nodes, pulmonary vasculature, and most surprisingly in the airways, suggestive of systemic and regional surveillance. Furthermore, we document that: (a) CD8 T cell memory persists in multiple tissues for > 200 days; (b) following challenge with pathogenic SARS-CoV-2, circulating memory CD8 T cells rapidly extravasate to the lungs and promote expeditious viral clearance, by mechanisms that require CD4 T cell help; and (c) adoptively transferred splenic memory CD8 T cells traffic to the airways and promote lung SARS-CoV-2 clearance. These findings provide insights into the critical role of memory T cells in preventing severe lung disease following breakthrough infections with antibody-evasive SARS-CoV-2 variants.
Topics: Humans; Animals; Mice; COVID-19 Vaccines; Memory T Cells; COVID-19; SARS-CoV-2; Lung
PubMed: 37796612
DOI: 10.1172/jci.insight.172510 -
BMC Pulmonary Medicine Nov 2023Our aims were to describe respiratory sequelae up to 12 months after discharge in COVID-19 patients with severe pneumonia requiring non-invasive respiratory support...
BACKGROUND
Our aims were to describe respiratory sequelae up to 12 months after discharge in COVID-19 patients with severe pneumonia requiring non-invasive respiratory support therapies.
METHODS
This study was undertaken at University Hospital Doctor Josep Trueta (Girona, Spain) between March 2020 and June 2020. Three months after discharge, we evaluated their dyspnoea and performed Saint George's respiratory questionnaire, pulmonary function tests, blood test, 6-min walking test, and a high-resolution CT (HRCT). At the six and 12-month follow-up, we repeated all tests except for pulmonary function, 6-min walking test, and HRCT, which were performed only if abnormal findings had been previously detected.
RESULTS
Out of the 94 patients recruited, 73% were male, the median age was 62.9 years old, and most were non-smokers (58%). When comparing data three and 12 months after discharge, the percentage of patients presenting dyspnoea ≥ 2 decreased (19% vs 7%), the quality-of-life total score improved (22.8% vs 18.9%; p = 0.019), there were less abnormal results in the pulmonary function tests (47% vs 23%), the 6-min walking test distance was enhanced (368.3 m vs 390.7 m, p = 0.020), ground glass opacities findings waned (51.6% vs 11.5%), and traction bronchiectasis increased (5.6% vs 15.9%). Only age showed significant differences between patients with and without pulmonary fibrotic-like changes.
CONCLUSION
Most patients improved their clinical condition, pulmonary function, exercise capacity and quality of life one year after discharge. Nonetheless, pulmonary fibrotic-like changes were observed during the follow-ups.
Topics: Humans; Male; Middle Aged; Female; COVID-19; Cohort Studies; Quality of Life; Lung; Pulmonary Fibrosis; Dyspnea
PubMed: 37951891
DOI: 10.1186/s12890-023-02627-w -
American Journal of Respiratory and... May 2024Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. We hypothesized that structural change...
Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV decline, as was a higher CAT score. Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).
Topics: Adult; Female; Humans; Male; Middle Aged; Young Adult; Disease Progression; Forced Expiratory Volume; Lung; Pulmonary Disease, Chronic Obstructive; Smokers; Smoking; Spirometry; Tomography, X-Ray Computed; Case-Control Studies
PubMed: 38175920
DOI: 10.1164/rccm.202307-1203OC -
Respiratory Research Mar 2024The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven...
BACKGROUND
The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven inflammation. Recent studies have revealed that Dectin-1 is overexpressed in asthma, but the specific mechanism remains elusive. Additionally, Dectin-1 has been implicated in promoting pyroptosis, a hallmark of severe asthma airway inflammation. Nevertheless, the involvement of the non-classical pyroptosis signal caspase-11/4 and its upstream regulatory mechanisms in asthma has not been completely explored.
METHODS
House dust mite (HDM)-induced mice was treated with Dectin-1 agonist Curdlan, Dectin-1 inhibitor Laminarin, and caspase-11 inhibitor wedelolactone separately. Subsequently, inflammatory cells in bronchoalveolar lavage fluid (BALF) were analyzed. Western blotting was performed to measure the protein expression of caspase-11 and gasdermin D (GSDMD). Cell pyroptosis and the expression of chemokine were detected in vitro. The correlation between Dectin-1 expression, pyroptosis factors and neutrophils in the induced sputum of asthma patients was analyzed.
RESULTS
Curdlan appeared to exacerbate neutrophil airway inflammation in asthmatic mice, whereas wedelolactone effectively alleviated airway inflammation aggravated by Curdlan. Moreover, Curdlan enhanced the release of caspase-11 activation fragments and N-terminal fragments of gasdermin D (GSDMD-N) stimulated by HDM both in vivo or in vitro. In mouse alveolar macrophages (MH-S cells), Curdlan/HDM stimulation resulted in vacuolar degeneration and elevated lactate dehydrogenase (LDH) release. In addition, there was an upregulation of neutrophil chemokines CXCL1, CXCL3, CXCL5 and their receptor CXCR2, which was suppressed by wedelolactone. In asthma patients, a positive correlation was observed between the expression of Dectin-1 on macrophages and caspase-4 (the human homology of caspase-11), and the proportion of neutrophils in induced sputum.
CONCLUSION
Dectin-1 activation in asthma induced caspase-11/4 mediated macrophage pyroptosis, which subsequently stimulated the secretion of chemokines, leading to the exacerbation of airway neutrophil inflammation.
Topics: Animals; Humans; Mice; Asthma; Caspases; Chemokines; Gasdermins; Inflammation; Lectins, C-Type; Lung; Macrophages; Neutrophils; Pyroglyphidae; Pyroptosis
PubMed: 38459541
DOI: 10.1186/s12931-024-02743-z -
Respiratory Research Dec 2023Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a poor prognosis. Current/available clinical prediction tools have limited sensitivity...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a poor prognosis. Current/available clinical prediction tools have limited sensitivity and accuracy when evaluating clinical outcomes of IPF. Research has shown that focal adhesion kinase (FAK), produced by the protein tyrosine kinase 2 (PTK2) gene, is crucial in IPF development. FAK activation is a characteristic of lesional fibroblasts; Thus, FAK may be a valuable therapeutic target or prognostic biomarker for IPF. This study aimed to create a gene signature based on PTK2-associated genes and microarray data from blood cells to predict disease prognosis in patients with IPF. PTK2 levels were found to be higher in lung tissues of IPF patients compared to healthy controls, and PTK2 inhibitor Defactinib was found to reduce TGFβ-induced FAK activation and increase α-smooth muscle actin. Although the blood PTK2 levels were higher in IPF patients, blood PTK level alone could not predict IPF prognosis. From 196 PTK2-associated genes, 11 genes were prioritized to create a gene signature (PTK2 molecular signature) and a risk score system using univariate and multivariate Cox regression analysis. Patients were divided into high-risk and low-risk groups using PTK2 molecular signature. Patients in the high-risk group experienced decreased survival rates compared to patients in the low-risk group across all discovery and validation cohorts. Further functional enrichment and immune cell proportion analyses revealed that the PTK2 molecular signature strongly reflected the activation levels of immune pathways and immune cells. These findings suggested that PTK2 is a molecular target of IPF and the PTK2 molecular signature is an effective IPF prognostic biomarker.
Topics: Humans; Focal Adhesion Kinase 1; Idiopathic Pulmonary Fibrosis; Lung; Prognosis; Biomarkers
PubMed: 38053045
DOI: 10.1186/s12931-023-02582-4 -
Nature Communications Jan 2024Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental...
Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease.
Topics: Animals; Mice; Acute Lung Injury; Extracellular Traps; Lung; Malaria; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Protein Tyrosine Phosphatases; Immediate-Early Proteins
PubMed: 38286811
DOI: 10.1038/s41467-024-45210-5 -
American Journal of Physiology. Lung... Oct 2023Studies of pulmonary inflammation require unique considerations due to the complex structure and composition of the lungs. The lungs have multiple compartments and...
Studies of pulmonary inflammation require unique considerations due to the complex structure and composition of the lungs. The lungs have multiple compartments and diverse immune cell populations, with inherently high autofluorescence, and are involved in the host response to pulmonary pathogens. We describe a protocol that accounts for these factors through a novel combination of methodologies-in vivo compartmental analysis and spectral flow cytometry with a broad panel of antibodies. In vivo compartmental analysis enables the precise localization of immune cells within the marginated vasculature, lung interstitium, nonlavageable airways, and lavageable airways of the lungs, as well as the pulmonary lymph nodes. Spectral flow cytometry with a broad panel of antibodies supports an unbiased exploratory approach to investigating diverse immune cell populations during pulmonary inflammation. Most importantly, spectral flow uses cellular autofluorescence to aid in the resolution and identification of immune cell populations. This methodology enables the acquisition of high-quality data compatible with informed gating and dimensionality reduction algorithms. In addition, our protocol emphasizes considerations for compartmentalization of the inflammatory response, spectral flow panel design, and autofluorescence spectra analysis. These methodologies are critical for increasing the rigor of pulmonary research. We apply this protocol for the precise characterization and localization of leukocytes in the pulmonary host response to influenza A virus in C57BL/6J mice. In particular, we demonstrate that this protocol improves the quantification and localization of alveolar macrophages within the airways. The methodology is modifiable and expandable to allow for further characterization of leukocyte populations of special interest. We describe a novel combination of methodologies that incorporates dual in vivo compartmental analysis using intravascular and intratracheal CD45 labeling, a broad panel of antibodies for identifying lymphoid and nonlymphoid cells, and spectral flow cytometry that uses cellular autofluorescence to aid in resolving and identifying immune cell populations. This methodology allows precise localization of immune cells in the lavageable airways, nonlavageable airways, interstitial lung tissue, and marginated in the lung vasculature.
Topics: Mice; Animals; Flow Cytometry; Mice, Inbred C57BL; Lung; Leukocytes; Pneumonia; Antibodies
PubMed: 37581225
DOI: 10.1152/ajplung.00317.2022 -
Annals of Internal Medicine Oct 2023Bronchiectasis in adults with chronic obstructive pulmonary disease (COPD) is associated with greater mortality. However, whether suspected bronchiectasis-defined as...
BACKGROUND
Bronchiectasis in adults with chronic obstructive pulmonary disease (COPD) is associated with greater mortality. However, whether suspected bronchiectasis-defined as incidental bronchiectasis on computed tomography (CT) images plus clinical manifestation-is associated with increased mortality in adults with a history of smoking with normal spirometry and preserved ratio impaired spirometry (PRISm) is unknown.
OBJECTIVE
To determine the association between suspected bronchiectasis and mortality in adults with normal spirometry, PRISm, and obstructive spirometry.
DESIGN
Prospective, observational cohort.
SETTING
The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study.
PARTICIPANTS
7662 non-Hispanic Black or White adults, aged 45 to 80 years, with 10 or more pack-years of smoking history. Participants who were former and current smokers were stratified into normal spirometry ( = 3277), PRISm ( = 986), and obstructive spirometry ( = 3399).
MEASUREMENTS
Bronchiectasis identified by CT was ascertained using artificial intelligence-based measurements of an airway-to-artery ratio (AAR) greater than 1 (AAR >1), a measure of bronchial dilatation. The primary outcome of "suspected bronchiectasis" was defined as an AAR >1 of greater than 1% plus 2 of the following: cough, phlegm, dyspnea, and history of 2 or more exacerbations.
RESULTS
Among the 7662 participants (mean age, 60 years; 52% women), 1352 (17.6%) had suspected bronchiectasis. During a median follow-up of 11 years, 2095 (27.3%) died. Ten-year mortality risk was higher in participants with suspected bronchiectasis, compared with those without suspected bronchiectasis (normal spirometry: difference in mortality probability [Pr], 0.15 [95% CI, 0.09 to 0.21]; PRISm: Pr, 0.07 [CI, -0.003 to 0.15]; obstructive spirometry: Pr, 0.06 [CI, 0.03 to 0.09]). When only CT was used to identify bronchiectasis, the differences were attenuated in the normal spirometry (Pr, 0.04 [CI, -0.001 to 0.08]).
LIMITATIONS
Only 2 racial groups were studied. Only 1 measurement was used to define bronchiectasis on CT. Symptoms of suspected bronchiectasis were nonspecific.
CONCLUSION
Suspected bronchiectasis was associated with a heightened risk for mortality in adults with normal and obstructive spirometry.
PRIMARY FUNDING SOURCE
National Heart, Lung, and Blood Institute.
Topics: Humans; Adult; Female; Middle Aged; Male; Cohort Studies; Prospective Studies; Artificial Intelligence; Pulmonary Disease, Chronic Obstructive; Lung; Smoking; Bronchiectasis; Spirometry; Forced Expiratory Volume
PubMed: 37782931
DOI: 10.7326/M23-1125