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In Vivo (Athens, Greece) 2023Gaucher disease (GD) is a rare lysosomal storage disorder that can involve the lungs and pulmonary vasculature. The long-term effects of GD on respiratory health remain...
BACKGROUND/AIM
Gaucher disease (GD) is a rare lysosomal storage disorder that can involve the lungs and pulmonary vasculature. The long-term effects of GD on respiratory health remain unclear due to limited data on the natural history of this disease. We analyzed electronic health records for 11,004 patients with GD over 10-20 years to determine the incidence of pulmonary hypertension (PH), lung disease, and other respiratory comorbidities and better understand disease course to guide management.
PATIENTS AND METHODS
We conducted a retrospective cohort study using the TriNetX research database of 130 million international patients. The incidence of primary/secondary PH, pulmonary heart disease, interstitial/obstructive/restrictive lung disease, pulmonary hemorrhage, and pulmonary embolism was assessed in patients with GD from 2000-2020.
RESULTS
Incidence rates of all conditions assessed increased from 10 to 20 years of follow-up. Excess risk of PH, lung disease, and pulmonary hemorrhage was significantly higher in GD patients after 20 versus 10 years.
CONCLUSION
Extended follow-up in GD is associated with substantially higher risks of PH, lung disease and other respiratory comorbidities, highlighting the need for close monitoring and early intervention to mitigate long-term pulmonary decline. Improved understanding of mechanisms driving respiratory deterioration can support the development of novel treatments to optimize outcomes in this population at high risk of pulmonary morbidity and mortality.
Topics: Humans; Gaucher Disease; Incidence; Retrospective Studies; Lung; Lung Diseases; Cohort Studies; Hemorrhage
PubMed: 37652520
DOI: 10.21873/invivo.13330 -
Blood Advances Aug 2023Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters the respiratory tract, where it infects the alveoli epithelial lining. However, patients have...
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters the respiratory tract, where it infects the alveoli epithelial lining. However, patients have sequelae that extend well beyond the alveoli into the pulmonary vasculature and, perhaps, beyond to the brain and other organs. Because of the dynamic events within blood vessels, histology does not report platelet and neutrophil behavior. Because of the rapid nontranscriptional response of these cells, neither single-cell RNA sequencing nor proteomics report robustly on their critical behaviors. We used intravital microscopy in level-3 containment to examine the pathogenesis of SARS-CoV-2 within 3 organs in mice expressing human angiotensin converting enzyme 2 (ACE-2) ubiquitously (CAG-AC-70) or on epithelium (K18-promoter). Using a neon-green SARS-CoV-2, we observed both the epithelium and endothelium infected in AC70 mice but only the epithelium in K18 mice. There were increased neutrophils in the microcirculation but not in the alveoli of the lungs of AC70 mice. Platelets formed large aggregates in the pulmonary capillaries. Despite only neurons being infected within the brain, profound neutrophil adhesion forming the nidus of large platelet aggregates were observed in the cerebral microcirculation, with many nonperfused microvessels. Neutrophils breached the brain endothelial layer associated with a significant disruption of the blood-brain-barrier. Despite ubiquitous ACE-2 expression, CAG-AC-70 mice had very small increases in blood cytokine, no increase in thrombin, no infected circulating cells, and no liver involvement suggesting limited systemic effects. In summary, our imaging of SARS-CoV-2-infected mice gave direct evidence that there is a significant perturbation locally in the lung and brain microcirculation induced by local viral infection leading to increased local inflammation and thrombosis in these organs.
Topics: Animals; Mice; COVID-19; Inflammation; Lung; SARS-CoV-2
PubMed: 37307197
DOI: 10.1182/bloodadvances.2022009430 -
Neurocritical Care Aug 2023Aneurysmal subarachnoid hemorrhage is a medical emergency that necessitates direct transfer to a tertiary referral center specialized in the diagnosis and treatment of...
Aneurysmal subarachnoid hemorrhage is a medical emergency that necessitates direct transfer to a tertiary referral center specialized in the diagnosis and treatment of this condition. The initial hours after aneurysmal rupture are critical for patients with aneurysmal subarachnoid hemorrhage, both in terms of rebleeding and combating the effect of early brain injury. No good treatment options are available to reduce the risk of rebleeding before aneurysm occlusion. Lowering the blood pressure may reduce the risk of rebleeding but carries a risk of inducing delayed cerebral ischemia or aggravating the consequences of early brain injury. Early brain injury after aneurysmal rupture has an important effect on final clinical outcome. Proper cerebral perfusion is pivotal in these initial hours after aneurysmal rupture but threatened by complications such as neurogenic pulmonary edema and cardiac stunning, or by acute hydrocephalus, which may necessitate early drainage of cerebrospinal fluid.
Topics: Humans; Subarachnoid Hemorrhage; Intracranial Aneurysm; Hydrocephalus; Brain Ischemia
PubMed: 37344653
DOI: 10.1007/s12028-023-01757-7 -
Nature Immunology Dec 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection. Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ). IFN-γ production was strongest in BAL NKG2rCD8 T cells and NKG2A natural killer (NK) cells and was further increased in NKG2A NK cells after spike protein stimulation. However, IFN-γ production was impaired in NK cells from macaques with persisting virus. Moreover, IFN-γ also enhanced the expression of major histocompatibility complex (MHC)-E on BAL macrophages, possibly inhibiting NK cell-mediated killing. Macaques with less persisting virus mounted adaptive NK cells that escaped the MHC-E-dependent inhibition. Our findings reveal an interplay between NK cells and macrophages that regulated SARS-CoV-2 persistence in macrophages and was mediated by IFN-γ.
Topics: Animals; Interferon-gamma; SARS-CoV-2; CD8-Positive T-Lymphocytes; Macrophages, Alveolar; COVID-19; Killer Cells, Natural; Lung; Macaca
PubMed: 37919524
DOI: 10.1038/s41590-023-01661-4 -
Stem Cell Research & Therapy Aug 2023Mesenchymal stem cell (MSC) treatment plays a major role in the management of acute lung injury (ALI), and neutrophils are the initial line of defense against ALI....
BACKGROUND
Mesenchymal stem cell (MSC) treatment plays a major role in the management of acute lung injury (ALI), and neutrophils are the initial line of defense against ALI. However, the effect of MSCs on neutrophils in ALI remains mostly unknown.
METHODS
We investigated the characteristics of neutrophils in lung tissue of ALI mice induced by lipopolysaccharide after treatment with MSCs using single-cell RNA sequencing. Neutrophils separated from lung tissue in ALI were co-cultured with MSCs, and then samples were collected for reverse transcription-polymerase chain reaction and flow cytometry.
RESULTS
During inflammation, six clusters of neutrophils were identified, annotated as activated, aged, and circulatory neutrophils. Activated neutrophils had higher chemotaxis, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase scores than aged neutrophils. Circulatory neutrophils occurred mainly in healthy tissue and were characterized by higher expression of Cxcr2 and Sell. Activated neutrophils tended to exhibit higher expression of Cxcl10 and Cd47, and lower expression of Cd24a, while aged neutrophils expressed a lower level of Cd47 and higher level of Cd24a. MSC treatment shifted activated neutrophils toward an aged neutrophil phenotype by upregulating the expression of CD24, thereby inhibiting inflammation by reducing chemotaxis, ROS production, and NADPH oxidase.
CONCLUSION
We identified the immunosuppressive effects of MSCs on the subtype distribution of neutrophils and provided new insight into the therapeutic mechanism of MSC treatment in ALI.
Topics: Mice; Animals; Neutrophils; CD47 Antigen; Reactive Oxygen Species; Acute Lung Injury; Lung; Lipopolysaccharides; Inflammation; Mesenchymal Stem Cells; Mesenchymal Stem Cell Transplantation
PubMed: 37553691
DOI: 10.1186/s13287-023-03438-w -
Nature Communications Oct 2023Intravesical administration of Bacillus Calmette-Guérin (BCG) was one of the first FDA-approved immunotherapies and remains a standard treatment for bladder cancer....
Intravesical administration of Bacillus Calmette-Guérin (BCG) was one of the first FDA-approved immunotherapies and remains a standard treatment for bladder cancer. Previous studies have demonstrated that intravenous (IV) administration of BCG is well-tolerated and effective in preventing tuberculosis infection in animals. Here, we examine IV BCG in several preclinical lung tumor models. Our findings demonstrate that BCG inoculation reduced tumor growth and prolonged mouse survival in models of lung melanoma metastasis and orthotopic lung adenocarcinoma. Moreover, IV BCG treatment was well-tolerated with no apparent signs of acute toxicity. Mechanistically, IV BCG induced tumor-specific CD8 T cell responses, which were dependent on type 1 conventional dendritic cells, as well as NK cell-mediated immunity. Lastly, we also show that IV BCG has an additive effect on anti-PD-L1 checkpoint inhibitor treatment in mouse lung tumors that are otherwise resistant to anti-PD-L1 as monotherapy. Overall, our study demonstrates the potential of systemic IV BCG administration in the treatment of lung tumors, highlighting its ability to enhance immune responses and augment immune checkpoint blockade efficacy.
Topics: Mice; Animals; BCG Vaccine; Urinary Bladder Neoplasms; CD8-Positive T-Lymphocytes; Administration, Intravenous; Immunity, Cellular; Killer Cells, Natural; Lung; Lung Neoplasms
PubMed: 37794033
DOI: 10.1038/s41467-023-41768-8 -
Mucosal Immunology Aug 2023Short-chain fatty acids (SCFAs) are metabolites that are produced after microbial fermentation of dietary fiber and impact cell metabolism and anti-inflammatory pathways...
Short-chain fatty acids (SCFAs) are metabolites that are produced after microbial fermentation of dietary fiber and impact cell metabolism and anti-inflammatory pathways both locally in the gut and systemically. In preclinical models, administration of SCFAs, such as butyrate, ameliorates a range of inflammatory disease models including allergic airway inflammation, atopic dermatitis, and influenza infection. Here we report the effect of butyrate on a bacteria-induced acute neutrophil-driven immune response in the airways. Butyrate impacted discrete aspects of hematopoiesis in the bone marrow resulting in the accumulation of immature neutrophils. During Pseudomonas aeruginosa infection, butyrate treatment led to the enhanced mobilization of neutrophils to the lungs as a result of increased CXCL2 expression by lung macrophages. Despite this increase in granulocyte numbers and their enhanced phagocytic capacity, neutrophils failed to control early bacterial growth. Butyrate reduced the expression of nicotinamide adenine dinucleotide phosphate, oxidase complex components required for reactive oxygen species production, and reduced secondary granule enzymes, culminating in impaired bactericidal activity. These data reveal that SCFAs tune neutrophil maturation and effector function in the bone marrow under homeostatic conditions, potentially to mitigate against excessive granulocyte-driven immunopathology, but their consequently restricted bactericidal capacity impairs early control of Pseudomonas infection.
Topics: Humans; Butyrates; Neutrophils; Fatty Acids, Volatile; Lung; Inflammation; Homeostasis; Anti-Infective Agents
PubMed: 37178819
DOI: 10.1016/j.mucimm.2023.05.005 -
Neurosurgical Review Jul 2023Neurogenic pulmonary edema (NPE) is a life-threatening and severe complication in patients with spontaneous subarachnoid hemorrhage (SAH). The prevalence of NPE varies... (Meta-Analysis)
Meta-Analysis Review
Neurogenic pulmonary edema (NPE) is a life-threatening and severe complication in patients with spontaneous subarachnoid hemorrhage (SAH). The prevalence of NPE varies significantly across studies due to differences in case definitions, study populations, and methodologies. Therefore, a precise estimation of the prevalence and risk factors related to NPE in patients with spontaneous SAH is important for clinical decision-makers, policy providers, and researchers. We conducted a systematic search of the PubMed/Medline, Embase, Web of Science, Scopus, and Cochrane Library databases from their inception to January 2023. Thirteen studies were included in the meta-analysis, with a total of 3,429 SAH patients. The pooled global prevalence of NPE was estimated to be 13%. Out of the eight studies (n = 1095, 56%) that reported the number of in-hospital mortalities of NPE among patients with SAH, the pooled proportion of in-hospital deaths was 47%. Risk factors associated with NPE after spontaneous SAH included female gender, WFNS class, APACHE II score ≥ 20, IL-6 > 40 pg/mL, Hunt and Hess grade ≥ 3, elevated troponin I, elevated white blood cell count, and electrocardiographic abnormalities. Multiple studies showed a strong positive correlation between the WFNS class and NPE. In conclusion, NPE has a moderate prevalence but a high in-hospital mortality rate in patients with SAH. We identified multiple risk factors that can help identify high-risk groups of NPE in individuals with SAH. Early prediction of the onset of NPE is crucial for timely prevention and early intervention.
Topics: Humans; Female; Pulmonary Edema; Subarachnoid Hemorrhage; Hospital Mortality; Prevalence; Databases, Factual
PubMed: 37432487
DOI: 10.1007/s10143-023-02081-6 -
American Journal of Respiratory Cell... Jul 2023VISTA (V domain immunoglobulin suppressor of T cell activation, also called PD-1H [programmed death-1 homolog]), a novel immune regulator expressed on myeloid and T...
VISTA (V domain immunoglobulin suppressor of T cell activation, also called PD-1H [programmed death-1 homolog]), a novel immune regulator expressed on myeloid and T lymphocyte lineages, is upregulated in mouse and human idiopathic pulmonary fibrosis (IPF). However, the significance of VISTA and its therapeutic potential in regulating IPF has yet to be defined. To determine the role of VISTA and its therapeutic potential in IPF, the expression profile of VISTA was evaluated from human single-cell RNA sequencing data (IPF Cell Atlas). Inflammatory response and lung fibrosis were assessed in bleomycin-induced experimental pulmonary fibrosis models in VISTA-deficient mice compared with wild-type littermates. In addition, these outcomes were evaluated after VISTA agonistic antibody treatment in the wild-type pulmonary fibrosis mice. VISTA expression was increased in lung tissue-infiltrating monocytes of patients with IPF. VISTA was induced in the myeloid population, mainly circulating monocyte-derived macrophages, during bleomycin-induced pulmonary fibrosis. Genetic ablation of VISTA drastically promoted pulmonary fibrosis, and bleomycin-induced fibroblast activation was dependent on the interaction between VISTA-expressing myeloid cells and fibroblasts. Treatment with VISTA agonistic antibody reduced fibrotic phenotypes accompanied by the suppression of lung innate immune and fibrotic mediators. In conclusion, these results suggest that VISTA upregulation in pulmonary fibrosis may be a compensatory mechanism to limit inflammation and fibrosis, and stimulation of VISTA signaling using VISTA agonists effectively limits the fibrotic innate immune landscape and consequent tissue fibrosis. Further studies are warranted to test VISTA as a novel therapeutic target for the IPF treatment.
Topics: Humans; Mice; Animals; Idiopathic Pulmonary Fibrosis; Lung; Fibrosis; Bleomycin; Inflammation; Fibroblasts
PubMed: 36450109
DOI: 10.1165/rcmb.2022-0219OC -
JCI Insight Apr 2024BACKGROUNDPersistent cough and dyspnea are prominent features of postacute sequelae of SARS-CoV-2 (also termed "long COVID"); however, physiologic measures and clinical...
BACKGROUNDPersistent cough and dyspnea are prominent features of postacute sequelae of SARS-CoV-2 (also termed "long COVID"); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. Using longitudinal pulmonary function testing (PFT) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary long COVID.METHODSThis single-center retrospective study included 1,097 patients with clinically defined long COVID characterized by persistent pulmonary symptoms (dyspnea, cough, and chest discomfort) lasting for 1 or more months after resolution of primary COVID infection.RESULTSAfter exclusion, a total of 929 patients with post-COVID pulmonary symptoms and PFTs were stratified as diffusion impairment and pulmonary restriction, as measured by percentage predicted diffusion capacity for carbon monoxide (DLCO) and total lung capacity (TLC). Longitudinal evaluation revealed diffusion impairment (DLCO ≤ 80%) and pulmonary restriction (TLC ≤ 80%) in 51% of the cohort overall (n = 479). In multivariable modeling regression analysis, invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary long COVID with diffusion impairment and restriction (adjusted odds ratio [aOR] = 9.89, 95% CI 3.62-26.9]). Finally, a subanalysis of CT imaging identified radiographic evidence of fibrosis in this patient population.CONCLUSIONLongitudinal PFTs revealed persistent diffusion-impaired restriction as a key feature of pulmonary long COVID. These results emphasize the importance of incorporating PFTs into routine clinical practice for evaluation of long COVID patients with prolonged pulmonary symptoms. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary long COVID patients.FUNDINGNational Institute of Allergy and Infectious Diseases (AI156898, K08AI129705), National Heart, Lung, and Blood Institute (HL153113, OTA21-015E, HL149944), and the COVID-19 Urgent Research Response Fund at the University of Alabama at Birmingham.
Topics: Humans; COVID-19; Male; Female; Middle Aged; Retrospective Studies; SARS-CoV-2; Aged; Post-Acute COVID-19 Syndrome; Lung; Respiratory Function Tests; Tomography, X-Ray Computed; Dyspnea; Cough
PubMed: 38652535
DOI: 10.1172/jci.insight.177518