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At least 91 records · Page 5
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Immune checkpoint analysis of T‐cell responses to pp65 and IE‐1 antigens in end‐stage lung diseases

Abstract Lung transplant (LTX) patients are at high risk of cytomegalovirus (CMV) infection, which is often associated with high mortality and morbidity. Reactivation of CMV causes cell injury due to the cytopathic effect of viral replication and triggering of T cell immunity. The aim of this study was to compare expression of immune checkpoints (ICs) (PD‐1, CTLA‐4, LAG‐3 and TIGIT) in CD4, CD8 and CD56 and activation markers CD137, CD154 and CD69 of end‐stage patients awaiting lung transplant. Eighteen pre‐LTX positive for anti‐CMV IgG titres and 18 healthy subjects were enrolled. IC and activation markers have been evaluated through flow cytometric analysis in HC and pre‐LTX patients. Reactive (QF+) and unreactive (QF−) patients were stratified according to QuantiFERON‐CMV assays. ICs' and activation markers' expression were determined before and after in vitro stimulation with pp‐65 and IE‐1 antigens. Lower expression of PD‐1 was observed in CD4 and CD8 cells of pre‐LTX patients than controls, whereas CTLA4 appeared upregulated in CD56 and CD8 cells. TIGIT is increased on the surface of CD4, CD8 and NK cells after peptide stimulation in QF‐negative patients and PD‐1 is only downregulated after stimulation in the QF‐positive patients. This study provides new evidence of immune dysregulation in patients with end‐stage lung disorders, particularly in relation to immune checkpoint cell biology. The change in QF+ mostly happens on cytotoxic cells NK and CD8, while the changes in QF− were observed in adaptive immune cells, including CD4 and CD8.

Bergantini, Laura↗
DOE OSTI2024

EMC3 regulates trafficking and pulmonary toxicity of the SFTPC I73T mutation associated with interstitial lung disease

The most common mutation in surfactant protein C gene (SFTPC), SFTPC I73T , causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPC I73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including Valosin Containing Protein (VCP) and its interactors. Treatment of Sftpc I73T knock-in mice and SFTPC I73T expressing iAT2 cells derived from SFTPC I73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPC I73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPC I73T mutant, providing novel therapeutical targets for SFTPC I73T -associated interstitial lung disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

A Murine Model of Radionuclide Lung Contamination for the Evaluation of Americium Decorporation Treatments

The hydroxypyridinone ligand 3,4,3-LI(1,2-HOPO) (HOPO), has been previously characterized as a promising chelating agent for in vivo decorporation of actinides, with decorporation being the removal of internally deposited contaminants from the body after exposure. The large majority of relevant literature reports have detailed the efficacy profile of HOPO as a decorporation agent in rodent models, where controlled radionuclide contamination is conducted via intravenous injection. However, this method of contamination does not necessarily reflect an accurate predictive model of the most probable biodistribution of free metal in the body. In the event of a radiological dispersal device or nuclear power plant accident scenario, it is most likely that first responders, military personnel, and victims of the event will be contaminated via air and water transmission. Therefore, research into the efficacy of chelating agents to treat lung-contaminated in vivo models needs to be carried out. Here, we establish a murine model with controlled, reproducible lung contamination using two different radionuclides, 89Zr and 241Am, for orthogonal biodistribution validation by positron emission tomography and ex vivo radioanalysis, respectively. In addition, we report effective chelation treatment of 241Am-contaminated lungs using HOPO, which improves decorporation by up to 40% compared to Ca-DTPA, the current standard of care.

Arino, Trevor↗
DOE OSTI2022

Wood combustion nanoparticles emitted by conventional and advanced technology cordwood boilers, and their interactions in vitro with human lung epithelial monolayers

Biomass-burning boilers and stoves are widely used in many parts of the world, producing combustion emissions linked with health risks. Here, combustion emission nanoparticles (NPs) were collected from four representative wood burning boilers using oak cordwood at specific times in the burn cycle. The morphology and composition of the NPs was characterized using transmission electron microscopy and energy dispersive X-ray analysis. To determine the degree of NP cytotoxicity with human lung tissue, the combustion NPs were introduced to incubated lung bronchial epithelial monolayers (NCI-H292) in vitro at doses of 0.1×10 -6 and 3.0×10 -6 kg/L for 2 and 4 h. Histochemical analysis showed that cell death increased by a factor of 3.5 for both doses after 4 h when compared to the control. Ultrapure NPs prepared by wet chemical methods were also introduced to the epithelial lung cells for similar doses and exposure times and the cultures exhibited significantly reduced mortality. Electron microscopy was used to study the mechanism of cell mortality for the synthesized and combustion-based NPs by examining how the NP byproducts interacted with individual cell organelles. It was found that cell survival was strongly correlated with the absence of contaminants (salts, heavy metals, poly aromatic hydrocarbons) associated with the NPs entering the cells. Synthesized NPs consisting of pure carbon were relatively well tolerated and could be excreted without damaging the cell ultrastructure. Thus, careful removal of extraneous contaminants by controlling the burn cycle with a catalyst is essential to minimize the health and environmental effects of wood biofuel combustion. In better words, optimized advanced technology wood-burning boilers and stoves can provide a CO 2 -neutral energy source and significantly contribute to a future where fossil fuels have a reduced role.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗
DOE OSTI2026

Human Lung Cellular Response to HCoV-229E Infection, Post-Translational Modification Proteomics Time Course (ACS-TZ-DP6)

The purpose of this experiment was to evaluate the human lung cellular response to wild type human coronavirus strain 229E (HCoV-229E) infection. Sample data was obtained for mock-infected and HCoV-229E infected immortalized human lung epithelial cells (A549) (MOI 3) and immortalized human lung fibroblasts (MRC-5) (MOI 3). Whole cell lysates were collected at 8, 16, and 24 hours post infection and were processed for post translational modification (PTM) proteomics analysis to determine the HCoV-229E phosphoproteome, redox proteome, and acetylation proteome.

Sims, Amy C [Pacific Northwest National Laboratory↗
NASA NTRS1971

Airway structure and alveolar emptying in the lungs of sea lions and dogs.

Investigation of the effects of various cycles of compression and decompression on the alveolar volumes of the excised lungs of sea lions and dogs. The results obtained include the finding that, in comparison to dog lungs, sea lion lungs empty more completely on mild compression and much more completely on severe compression. These findings support Scholander's (1940) hypothesis that some marine mammals are protected from decompression sickness by cartilaginous reinforcement of the small airways which permits alveolar emptying during a dive, so isolating compressed gas from pulmonary capillary blood.

Denison, D. M.↗
NASA NTRS1975

Preflight studies on tolerance of pocket mice to oxygen and heat. II - Effects on lungs

An electron microscope examination was carried out on the lungs of 11 pocket mice (Perognathus longimembris) that breathed oxygen at 10 psi or 12 psi partial pressure over a period of 7 d, at the end of which time they were decompressed to sea-level O2 pressure, either suddenly or in 30, 60, or 90 min. Vesiculation was noted in the endothelium of the alveolar-capillary wall in most of the animals and, occasionally, blebbing. Some mitochrondria were swollen in a few of the animals. Alveolar exudate was, in general, sparse. Compared with the lungs of other rodents, the lungs of pocket mice appeared relatively resistant to the toxic effects of oxygen. This conclusion needs, however, to be tempered by the fact that 5% N2 was used in the tests reported here. Nonetheless, the results suggest that the oxygen pressures anticipated on the flight of Apollo XVII should be well tolerated by the pocket mice.

Harrison, G. A.↗
NASA NTRS1980

Blood filling and flow in lungs during change in body position in space

In the horizontal position (supine and lateral), in the upright position (head up and head down) and during change of the cat body position in space, quantitative responses of regional blood volume and blood flow in the lungs (ml/100 cu cm) revealed presence of the gradient in the gravitation direction. Blood volume and blood flow of different lung portions changed qualitatively and quantitatively in different ways. These changes occurred only in the direction producing the equality of regional hydrostatical and hemodynamic loads in the lungs at either horizontal level.

Pogodin, A. S.↗
NASA NTRS1991

COSMOS 2044: Lung morphology study, experiment K-7-28

Researchers examined the effect of microgravity during spaceflight on lung tissue. The ultrastructure of the left lungs of 5 Czechoslovakian Wister rats flown on the 13 day, 19+ hour Cosmos 2044 mission was examined and compared to 5 vivarium and 5 synchronous controls at 1-g conditions, and 5 rats exposed to 14 days of tail suspension. Pulmonary hemorrage and alveolar adema of unknown origin occurred to a greater extent in the flight, tail-suspended, and synchronous control animals, and in the dorsal regions of the lung when compared with the vivarium controls. The cause of these changes, which are possibly due to an increase in pulmonary vascular pressure, requires further investigation.

Elliott, Ann R.↗
NASA NTRS1991

Microgravity and the lung

Results are presented from studies of the effect of microgravity on the lungs of rats flown on the Cosmos 2044 mission, and from relevant laboratory experiments. The effects of microgravity fall into five categories: topographical structure and function, the lung volumes and mechanics, the intrathoracic blood pressures and volumes, the pulmonary deposition of aerosol, and denitrogenaton during EVA. The ultrastructure of the left lungs of rats flown for 14 days on the Cosmos 2044 spacecraft and that of some tail-suspended rats disclosed presence of red blood cells in the alveolar spaces, indicating that pulmonary hemorrhage and pulmonary edema occurred in these rats. Possible causes for this phenomenon are discussed.

West, John B.↗
NASA NTRS1994

Lung volumes during sustained microgravity on Spacelab SLS-1

Gravity is known to influence the mechanical behavior of the lung and chest wall. However, the effect of sustained microgravity (microgravity) on lung volumes has not been reported. Pulmonary function tests were performed by four subjects before, during, and after 9 days of microgravity exposure. Ground measurements were made in standing and supine postures. Tests were performed using a bag-in-box-and-flowmeter system and a respiratory mass spectrometer. Measurements included functional residual capacity (FRC), expiratory reserve volume (ERV), residual volume (RV), inspiratory and expiratory vital capacities (IVC and EVC), and tidal volume (V9sub T)). Total lung capacity (TLC) was derived from the measured EVC and RV values. With preflight standing values as a comparison, FRC was significantly reduced by 15% (approximately 500 ml) in microgravity and 32% in the supine posture. ERV was reduced by 10 - 20% in microgravity and decreased by 64% in the supine posture. RV was significantly reduced by 18% (310 ml) in microgravity but did not significantly change in the supine posture compared with standing. IVC and EVC were slightly reduced during the first 24 h of microgravity but returned to 1-G standing values within 72 h of microgravity exposure. IVC and EVC in the supine posture were significantly reduced by 12% compared with standing. During microgravity, V(sub T) decreased by 15% (approximately 90 ml), but supine V(sub T) was unchanged compared with preflight standing values. TLC decreased by approximately 8% during microgravity and in the supine posture compared with preflight standing. The reductions in FRC, ERV, and RV during microgravity are probably due to the cranial shift of the diaphragm, an increase in intrathoracic blood volume, and more uniform alveolar expansion.

Elliott, Ann R.↗
NASA NTRS1995

Regional volume changes in canine lungs suspended in air

The purpose of this study was to determine the effect of the absence of a pleural pressure gradient (simulating the presumed condition found in microgravity) upon regional expansion of the lung. We attempted to produce a uniform pressure over the surface of the lung by suspending excised lungs in air. Such studies should help determine whether or not the absence of a pleural pressure gradient leads to uniform ventilation. A preparation in which there is no pleural pressure gradient should also be useful in studying non-gravitational effects on ventilation distribution.

Abbrecht, Peter H.↗
NASA NTRS1994

Gravity in mammalian organ development: differentiation of cultured lung and pancreas rudiments during spaceflight

Organ culture of embryonic mouse lung and pancreas rudiments has been used to investigate development and differentiation, and to assess the effects of microgravity on culture differentiation, during orbital spaceflight of the shuttle Endeavour (mission STS-54). Lung rudiments continue to grow and branch during spaceflight, an initial result that should allow future detailed study of lung morphogenesis in microgravity. Cultured embryonic pancreas undergoes characteristic exocrine acinar tissue and endocrine islet tissue differentiation during spaceflight, and in ground controls. The rudiments developing in the microgravity environment of spaceflight appear to grow larger than their ground counterparts, and they may have differentiated more rapidly than controls, as judged by exocrine zymogen granule presence.

STS-54 Shuttle Project↗
NASA NTRS2009

Toxicity of Lunar Dust in Lungs Assessed by Examining Biomarkers in Exposed Mice

NASA plans to build an outpost on the Moon for prolonged human habitation and research. The lunar surface is covered by a layer of soil, of which the finest portion is highly reactive dust. NASA has invited NIOSH to collaboratively investigate the toxicity of lunar dust. Dust samples of respirable sizes were aerodynamically isolated from two lunar soil samples of different maturities (cosmic exposure ages) collected during the Apollo 16 mission. The lunar dust samples, titanium dioxide, or quartz, suspended in normal saline or in Survanta (a bovine lung surfactant), were given to groups of 5 mice (C-57 male) by intrapharyngeal aspiration at 1, 0.3, or 0.1 mg/mouse. The mice were euthanized 7 or 30 days later, and their lungs were lavaged to assess the toxicity biomarkers in bronchioalveolar lavage fluids. The acellular fractions were assayed for total proteins, lactate dehydrogenase activities, and cytokines; the cellular portions were assessed for total cell counts and cell differentials. Results from the high-dose groups showed that lunar dust, suspended in saline, was more toxic than TiO 2, but less toxic than quartz. Lunar dust particles aggregate and settle out rapidly in water or saline, but not in Survanta. Lunar dust suspended in Survanta manifested greater toxicity than lunar dust in saline. The increase in toxicity presumably was due to that Survanta gave a better particle dispersion in the lungs. The two lunar dust samples showed similar toxicity. The overall results showed that lunar dust is more toxic than TiO 2 but less toxic than quartz.

Lam, C.-W.↗
DOE OSTI2021

Prospective Single-Arm Phase 1 and 2 Study: Ipilimumab and Nivolumab With Thoracic Radiation Therapy After Platinum Chemotherapy in Extensive-Stage Small Cell Lung Cancer

Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Lung Cancer and Heart Disease Risks Associated With Low-Dose Pulmonary Radiotherapy to COVID-19 Patients With Different Background Risks

The respiratory disease COVID-19 reached global pandemic status in 2020. Excessive inflammation is believed to result in the most severe symptoms and death from this disease. Because treatment options for patients with severe COVID-19 related pulmonary symptoms remain limited, whole-lung low-dose radiation therapy is being evaluated as an anti-inflammatory modality. However, there is concern about the long-term risks associated with low-dose pulmonary irradiation. To help quantify the benefit-risk balance of low-dose radiation therapy for COVID-19, we estimated radiation-induced lifetime risks of both lung cancer and heart disease (major coronary events) for patients of different sexes, treated at ages 50 to 85, with and without other relevant risk factors (cigarette smoking and baseline heart disease risk).

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Synchrotron Microbeam Radiation Therapy for the Treatment of Lung Carcinoma: A Preclinical Study

In the past 3 decades, synchrotron microbeam radiation therapy (S-MRT) has been shown to achieve both good tumor control and normal tissue sparing in a range of preclinical animal models. However, the use of S-MRT for the treatment of lung tumors has not yet been investigated. This study is the first to evaluate the therapeutic efficacy of S-MRT for the treatment of lung carcinoma, using a new syngeneic and orthotopic mouse model.

62 RADIOLOGY AND NUCLEAR MEDICINE↗