scholarly journals Genetic variability of T cell responses in hypersensitivity pneumonitis identified using the BXD genetic reference panel

2020 ◽  
Vol 318 (4) ◽  
pp. L631-L643 ◽  
Author(s):  
Jin Wang ◽  
Tae Won Yoon ◽  
Robert Read ◽  
Ae-Kyung Yi ◽  
Robert W. Williams ◽  
...  
Keyword(s):  
T Cells ◽  
Genetic Variability ◽  
Hypersensitivity Pneumonitis ◽  
Significant Risk ◽  
Wall Thickening ◽  
Alveolar Wall ◽  
Mesenchymal Transition ◽  
Risk Of Death ◽  
Exposed Population ◽  
Lymphoid Aggregates

Hypersensitivity pneumonitis (HP) is an interstitial lung disease that may progress to fibrosis and significant risk of death. HP develops following repeated exposures to inhaled environmental antigens; however, only a fraction of the exposed population develops the disease, suggesting that host genetics contribute to disease susceptibility. We used the BXD family of mice with the Saccharopolyspora rectivirgula (SR) model of HP to investigate the role of genetics in susceptibility to HP. The BXD family is derived from a B6 mother and a D2 father and has been used to map susceptibility loci to numerous diseases. B6, D2, and BXD progeny strains were exposed to SR for 3 wk, and the development of HP was monitored. The B6 and D2 strains developed alveolitis; however, the cellular composition was neutrophilic in the D2 strain and more lymphocytic in the B6 strain. Hematoxylin-eosin staining of lung sections revealed lymphoid aggregates in B6 lungs, whereas D2 lungs exhibited a neutrophilic infiltration. Twenty-eight BXD strains of mice were tested, and the results reveal significant heritable variation for numbers of CD4+ or CD8+ T cells in the air spaces. There was significant genetic variability for lymphoid aggregates and alveolar wall thickening. We mapped a significant quantitative trait locus (QTL) on chromosome 18 for CD8+CD69+ T cells that includes cadherin 2 ( Cdh2), an excellent candidate gene associated with epithelial-mesenchymal transition, which is upregulated in lungs of strains with HP. These results demonstrate that the BXD family is a valuable and translationally relevant model to identify genes contributing to HP and to devise early and effective interventions.

scholarly journals Overexpression of long non coding RNA OR3A4 is associated with altered p38 signalling, morphological and phenotypic changes, and reduced immunogenicity in Barretts Oesophagus

2021 ◽  
Author(s):  
Thomas Nieto ◽  
Yash Sinha ◽  
Qin Qin Zhuang ◽  
Mathew Coleman ◽  
Joanne D Stockton ◽  
...  
Keyword(s):  
T Cells ◽  
P38 Mapk ◽  
Significant Risk ◽  
Oesophageal Adenocarcinoma ◽  
Cellular Phenotype ◽  
Over Expression ◽  
Non Coding Rna ◽  
P38 Mapk Inhibitor ◽  
Long Non Coding Rna ◽  
Mapk Inhibitor

Background: Barretts Oesophagus (BO) presents a particular pathological dilemma, in that patients who have no dysplasia within their BO experience a small but significant risk of malignant progression each year. Screening programmes have attempted to reduce the mortality from BO associated oesophageal adenocarcinoma but cannot predict which BO patients will progress to invasive malignancy. We have previously identified the long non coding RNA, OR3A4, is differentially hypomethylated in progressive BO. We aimed to understand its role in BO pathogenicity Methods: The stable BO cell line CP-A, as well as the oesophageal adenocarcinoma cells line OE-33 was transfected with a lentiviral OR3A4 over-expression vector, and underwent high resolution microscopy, immunofluorescence, RT-qPCR, RNA sequencing, and targeted drug screening with the p38-MAPK inhibitor domipramod to understand the effects of OR3A4 expression on progression. We then compared progressive vs. non-progressive BO samples using quantitative multi-fluorophore (Vectra) immunohistochemistry. Results: Over-expression of OR3A4 in CP-A lines resulted in a hyperproliferative, dysplastic cellular phenotype, with strong over-expression of MAPK and anti-apoptotic pathways at the RNA and protein level, which was sensitive to the p38-MAPK inhibitor domipramod. Vectra immunohistochemistry demonstrated that progressive BO had reduced visibility associated with a reduction in CD8+ T-cells and CD68+ macrophages and reduced CD4+ T-cells in the stomal compartment. Conclusion: The overexpression of OR3A4, which we have previously shown is associated with progressive BO leads to a proliferative dysplastic cellular phenotype associated with increased, reversible MAPK signalling and loss of immune visibility.

scholarly journals Cytotoxic CD8+ T Cells Promote Granzyme B-Dependent Adverse Post-Ischemic Cardiac Remodeling

2020 ◽  
Author(s):  
Icia Santos Zas ◽  
Jeremie Lemarie ◽  
Ivana Zlatanova ◽  
Marine Cachanado ◽  
Jean-Christophe Seghezzi ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Ventricular Remodeling ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Granzyme B ◽  
Acute Ischemia ◽  
Risk Of Death ◽  
Increased Risk ◽  
Acute Mi

Abstract Acute myocardial infarction (MI) is a common condition responsible for heart failure and sudden death. Here, we show that following acute MI in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue, and release Granzyme B leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function was confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of Granzyme B in patients with acute MI predict increased risk of death at 1-year follow-up. Our work unravels an unsuspected deleterious role of CD8+ T lymphocytes following acute ischemia, and identifies novel therapeutic strategy targeting pathogenic CD8+ T lymphocytes in the setting of acute MI.

scholarly journals Ethnicity and other COVID-19 death risk factors in Mexico

2020 ◽  
Author(s):  
Erwin Chiquete ◽  
Jesus Alegre-Díaz ◽  
Ana Ochoa-Guzmán ◽  
Liz Nicole Toapanta-Yanchapaxi ◽  
Carlos González-Carballo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Proportional Hazards Model ◽  
Invasive Mechanical Ventilation ◽  
Significant Risk ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Chronic Obstructive ◽  
Death Risk ◽  
Factors Associated ◽  
Risk Of Death

IntroductionPatients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may develop coronavirus disease 2019 (COVID-19). Risk factors associated with death vary among countries with different ethnic backgrounds. We aimed to describe the factors associated with death in Mexicans with confirmed COVID-19.Material and methodsWe analysed the Mexican Ministry of Health’s official database on people tested for SARS-CoV-2 infection by real-time reverse transcriptase–polymerase chain reaction (rtRT-PCR) of nasopharyngeal fluids. Bivariate analyses were performed to select characteristics potentially associated with death, to integrate a Cox-proportional hazards model.ResultsAs of May 18, 2020, a total of 177,133 persons (90,586 men and 86,551 women) in Mexico received rtRT-PCR testing for SARS-CoV-2. There were 5332 deaths among the 51,633 rtRT-PCR-confirmed cases (10.33%, 95% CI: 10.07–10.59%). The median time (interquartile range, IQR) from symptoms onset to death was nine days (5–13 days), and from hospital admission to death 4 days (2–8 days). The analysis by age groups revealed that the significant risk of death started gradually at the age of 40 years. Independent death risk factors were obesity, hypertension, male sex, indigenous ethnicity, diabetes, chronic kidney disease, immunosuppression, chronic obstructive pulmonary disease, age > 40 years, and the need for invasive mechanical ventilation (IMV). Only 1959 (3.8%) cases received IVM, of whom 1893 were admitted to the intensive care unit (96.6% of those who received IMV).ConclusionsIn Mexico, highly prevalent chronic diseases are risk factors for death among persons with COVID-19. Indigenous ethnicity is a poorly studied factor that needs more investigation.

scholarly journals Endogenous Hydrogen Sulfide Is an Important Factor in Maintaining Arterial Oxygen Saturation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Huang ◽  
Gang Wang ◽  
Zhan Zhou ◽  
Zhengshan Tang ◽  
Ningning Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Injury ◽  
Arterial Oxygen Saturation ◽  
Arterial Oxygen ◽  
Wall Thickening ◽  
Alveolar Wall ◽  
Leukocyte Infiltration ◽  
Wild Type ◽  
Interstitial Edema ◽  
And Oxidative Stress

The gasotransmitter H2S is involved in various physiological and pathophysiological processes. The aim of this study was to investigate the physiological functions of H2S in the lungs. In the model of mouse with genetic deficiency in a H2S natural synthesis enzyme cystathionine-γ-lyase (CSE), we found that arterial oxygen saturation (SaO2) was decreased compared with wild type mice. Hypoxyprobe test showed that mild hypoxia occurred in the tissues of heart, lungs and kidneys in Cse-/- mice. H2S donor GYY4137 treatment increased SaO2 and ameliorated hypoxia state in cardiac and renal tissues. Further, we revealed that lung blood perfusion and airway responsiveness were not linked to reduced SaO2 level. Lung injury was found in Cse-/- mice as evidenced by alveolar wall thickening, diffuse interstitial edema and leukocyte infiltration in pulmonary tissues. IL-8, IL-1β, and TNF-α levels were markedly increased and oxidative stress levels were also significantly higher with increased levels of the pro-oxidative biomarker, MDA, decreased levels of the anti-oxidative biomarkers, T-AOC and GSH/GSSG, and reduced superoxide dismutase (SOD) activity in lung tissues of Cse-/- mice compared with those of wild type mice. GYY4137 treatment ameliorated lung injury and suppressed inflammatory state and oxidative stress in lung tissues of Cse-/- mice. A decrease in SaO2 was found in normal mice under hypoxia. These mice displayed lung injury as evidenced by alveolar wall thickening, interstitial edema and leukocyte infiltration. Increased levels of inflammatory cytokines and oxidative stress were also found in lung tissues of the mice with hypoxia insult. GYY4137 treatment increased SaO2 and ameliorated lung injury, inflammation and oxidative stress. Our data indicate that endogenous H2S is an important factor in maintaining normal SaO2 by preventing oxidative stress and inflammation in the lungs.

scholarly journals Exposure to Atmospheric Ultrafine Particles Induces Severe Lung Inflammatory Response and Tissue Remodeling in Mice

2019 ◽  
Vol 16 (7) ◽  
pp. 1210 ◽  
Author(s):  
Yara Saleh ◽  
Sébastien Antherieu ◽  
Romain Dusautoir ◽  
Laurent Y. Alleman ◽  
Jules Sotty ◽  
...  
Keyword(s):  
Ultrafine Particles ◽  
Chronic Exposure ◽  
Time Course ◽  
Fine Particles ◽  
Respiratory Health ◽  
Wall Thickening ◽  
Alveolar Wall ◽  
Similar Chemical ◽  
Time Course Experiment ◽  
Severe Lung

Exposure to particulate matter (PM) is leading to various respiratory health outcomes. Compared to coarse and fine particles, less is known about the effects of chronic exposure to ultrafine particles, despite their higher number and reactivity. In the present study, we performed a time-course experiment in mice to better analyze the lung impact of atmospheric ultrafine particles, with regard to the effects induced by fine particles collected on the same site. Trace element and PAH analysis demonstrated the almost similar chemical composition of both particle fractions. Mice were exposed intranasally to FF or UFP according to acute (10, 50 or 100 µg of PM) and repeated (10 µg of PM 3 times a week during 1 or 3 months) exposure protocols. More particle-laden macrophages and even greater chronic inflammation were observed in the UFP-exposed mice lungs. Histological analyses revealed that about 50% of lung tissues were damaged in mice exposed to UFP for three months versus only 35% in FF-exposed mice. These injuries were characterized by alveolar wall thickening, macrophage infiltrations, and cystic lesions. Taken together, these results strongly motivate the update of current regulations regarding ambient PM concentrations to include UFP and limit their emission.

On Small Solute Clearance and Patient Outcomes: Evidential Practice or Observational Trepidation?

2009 ◽  
Vol 29 (6) ◽  
pp. 623-629 ◽  
Author(s):  
Edward Vonesh
Keyword(s):  
Patient Outcomes ◽  
Observational Studies ◽  
Significant Risk ◽  
Level Of Evidence ◽  
Dialysis Adequacy ◽  
Risk Of Death ◽  
Randomized Controlled ◽  
Anzdata Registry ◽  
Small Solute ◽  
Solute Clearance

Recent guidelines on peritoneal dialysis adequacy set a minimum target for small solute clearance at Kt/V urea 1.70. While evidence from both observational studies and randomized controlled trials (RCTs) supports such a minimum target, there continues to be debate over what role small solute clearance plays in determining patient outcome. Current ANZDATA Registry results from Australia and New Zealand add fuel to this debate by demonstrating a significant nonlinear U-shaped relationship between peritoneal small solute clearance and patient survival. The ANZDATA results indicate that patients with too low or too high peritoneal Kt/V urea may be at significant risk of death compared to those with a peritoneal Kt/V urea between 1.70 and 2.00. As these results are somewhat at odds with results from published RCTs, we will examine the level of evidence from the observational setting that is the ANZDATA Registry and contrast it against the level of evidence from RCTs, particularly the ADEMEX trial. New results from the ADEMEX study are presented as a possible explanation for the paradoxical U-shaped results seen in the ANZDATA study.

Ketogenic Diet in Status Epilepticus

2016 ◽  
Author(s):  
Rima Nabbout
Keyword(s):  
Intensive Care ◽  
Status Epilepticus ◽  
Intensive Care Units ◽  
Ketogenic Diet ◽  
Significant Risk ◽  
Refractory Status Epilepticus ◽  
Dietary Therapy ◽  
Risk Of Death ◽  
Refractory Status ◽  
Neurological Morbidity

Refractory status epilepticus (RSE) is associated with a significant risk of death or neurological morbidity. The ketogenic diet (KD) is a dietary therapy that succeeds in controlling seizures in otherwise RSE in children and adult patients. Inflammatory etiologies might be a particular target, but KD has reported efficacy in other etiologies. KD is well tolerated, and the effect is seen within days. Randomized and controlled studies are lacking in this area, and studies are needed to prove the efficacy of KD in RSE and to identify specific indications. This would help to increase its use and to implement it in intensive care units to resolve severe epileptic conditions quickly.

scholarly journals Maintenance Negative Pressure Ventilation Improves Survival in COPD Patients with Exercise Desaturation

2019 ◽  
Vol 8 (4) ◽  
pp. 562
Author(s):  
Hung-Yu Huang ◽  
Chun-Yu Lo ◽  
Lan-Yan Yang ◽  
Fu-Tsai Chung ◽  
Te-Fang Sheng ◽  
...  
Keyword(s):  
Lung Function ◽  
Negative Pressure ◽  
Significant Risk ◽  
Forced Expiratory Volume ◽  
Walking Distance ◽  
Chronic Obstructive ◽  
Negative Pressure Ventilation ◽  
Risk Of Death ◽  
Copd Patients

Negative pressure ventilation (NPV), when used as an adjuvant to pulmonary rehabilitation, improves lung function, increases exercise capacity, and reduces exacerbations. The aim of this study was to determine whether maintenance NPV improves long-term clinical outcomes and reduces mortality in patients with chronic obstructive pulmonary disease (COPD). Between 2003 and 2009, 341 patients were treated for COPD either with or without hospital-based NPV. We measured forced expiratory volume in one second (FEV1), 6-min walking distance (6MWD), and oxygen saturation by pulse oximetry (SpO2) during a 6-min walk test (6MWT) every 3–6 months. Desaturation (D) during the 6MWT was defined as a reduction in SpO2 of ≥10% from baseline. The NPV group had a better survival outcome than the Non-NPV group. The 8-year survival probabilities for the NPV and Non-NPV groups were 60% and 20%, respectively (p < 0.01). Baseline desaturation was a significant risk factor for death, and the risk of death increased with desaturation severity (SpO2 80~89: hazard ratios (HR) 2.7, 95% confidence interval (CI) 1.4–5.3; SpO2 < 80: HR 3.1, 95% CI 1.3–7.4). The NPV group had a slower decline in lung function and 6MWD. The NPV + D and Non-NPV+D had a threefold and fourfold increase in the risks of all-cause mortality compared with the NPV-ND, respectively. Maintenance non-invasive NPV reduced long-term mortality in COPD patients. The desaturating COPD patients had an increased mortality risk compared with non-desaturating COPD patients.

scholarly journals Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 428 ◽  
Author(s):  
József Dudás ◽  
Andrea Ladányi ◽  
Julia Ingruber ◽  
Teresa Bernadette Steinbichler ◽  
Herbert Riechelmann
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Protein Translation ◽  
Therapy Resistance ◽  
Mesenchymal Transition ◽  
Rna Molecules ◽  
Tumor Microenvironments ◽  
Micro Rnas

Epithelial to mesenchymal transition (EMT) contributes to tumor progression, cancer cell invasion, and therapy resistance. EMT is regulated by transcription factors such as the protein products of the SNAI gene family, which inhibits the expression of epithelial genes. Several signaling pathways, such as TGF-beta1, IL-6, Akt, and Erk1/2, trigger EMT responses. Besides regulatory transcription factors, RNA molecules without protein translation, micro RNAs, and long non-coding RNAs also assist in the initialization of the EMT gene cluster. A challenging novel aspect of EMT research is the investigation of the interplay between tumor microenvironments and EMT. Several microenvironmental factors, including fibroblasts and myofibroblasts, as well as inflammatory, immune, and endothelial cells, induce EMT in tumor cells. EMT tumor cells change their adverse microenvironment into a tumor friendly neighborhood, loaded with stromal regulatory T cells, exhausted CD8+ T cells, and M2 (protumor) macrophages. Several EMT inhibitory mechanisms are instrumental in reversing EMT or targeting EMT cells. Currently, these mechanisms are also significant for clinical use.

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