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Background Ozone effects on lung function are particularly important to understand in the context of the air pollution-health outcomes epidemiologic literature, given the complex relationships between ozone and other air pollutants with known lung function effects. Research Question What has been learned about the association between ozone exposures and lung function from epidemiology studies published from 2013 through 2020? Study Design and Methods On March 18, 2018, and September 8, 2020, PubMed was searched using the terms health AND ozone, filtering to articles in English and about humans, from 2013 or later. An additional focused review searching for ozone AND (lung function OR FEV1 OR FVC) was performed June 26, 2021. Articles were selected for this review if they reported a specific relationship between a lung function outcome and ozone exposure. Results Of 3,271 articles screened, 53 ultimately met criteria for inclusion. A systematic review with assessment of potential for bias was conducted, but a meta-analysis was not carried out because of differences in exposure duration and outcome quantification. Consistent evidence exists of small decreases in children’s lung function, even associated with very low levels of short-term ozone exposure. The effects on adult lung function from exposure to low-level, short-term ozone are less clear, although ozone-associated decrements may occur in the elderly. Finally, long-term ozone exposure decreases both lung function and lung function growth in children, although few new studies have examined long-term ozone and lung function in adults. Interpretation Much of this literature involves concentrations below the current US Environmental Protection Agency’s National Ambient Air Quality Standard of 70 parts per billion over an 8-h averaging time, suggesting that this current standard may not protect children adequately from ozone-related decrements in lung function.

Purpose To establish and investigate the effects of dose, linear energy transfer (LET), and O2 concentration on biologic response to ultrahigh dose rate (uHDR; FLASH) helium ion beams compared with standard dose rate (SDR) irradiation. Methods and Materials Beam delivery settings for raster-scanned helium ions at both uHDR and SDR were tuned to achieve >100 Gy/s and ∼0.1 Gy/s, respectively. For both SDR and uHDR, plan optimization and calibration for 10 × 10-mm 2 fields were performed to assess in vitro response at an LET range of 4.5 to 16 keV/µm. Clonogenic survival assay was conducted at doses ranging from 2 to 12 Gy in 2 human lung epithelial cell lines (A549 and H1437). Radiation-induced nuclear γH2AX foci (RIF) were assessed in both epithelial cell lines and primary human pulmonary fibroblasts. Results Average dose rates achieved were 185 Gy/s and 0.12 Gy/s for uHDR and SDR, respectively. No differences in cellular response to SDR versus uHDR were observed for all tested doses at 21% O2, and at 2 and 4 Gy at 1% O2. In contrast, at 1% O2 and a dose threshold of ≳8 Gy cell survival was higher and correlated with reduced nuclear γH2AX RIF signal, indicating FLASH sparing effect in the investigated cell lines irradiated with uHDR compared with SDR. Conclusions The first uHDR delivery of raster-scanned particle beams was achieved using helium ions, reaching FLASH-level dose-rates of >100 Gy/s. Baseline oxygen levels and delivered dose (≳8 Gy) play a pivotal role, irrespective of the studied cell lines, for observation of a sparing effect for helium ions.

Microplastics (MPs) have been detected in all environmental locations, including the atmosphere. However, few studies have investigated the presence of airborne MPs in the human respiratory system. Our research purpose was to investigate these pollutants in the lower human airways of 44 adult European citizens, using bronchoalveolar lavage fluid (BALF) collection as a minimally invasive method, that enables the detection of these pollutants in living patients. We studied the relationship between the patients' life habits and physiological parameters, based on background information and medical and occupational history, and the concentration of MPs isolated from their respiratory systems. Our results indicate that most MPs were in the form of microfibers (MFs) (97.06%), with an average concentration of 9.18 ± 2.45 items/100 mL BALF, and only 5.88% (0.57 ± 0.27 items/100 mL BALF) were particulate MPs, without a significant relationship with environmental, physiological, or clinical factors. The average size was 1.73 ± 0.15 mm, with the longest dimension (9.96 mm) corresponding to a polyacrylic fiber. Taken together, the results demonstrated the occurrence of MPs in the lower human airway, although more studies are necessary to elucidate the negative effects these pollutants could induce in the human respiratory system and its associated diseases.

Bicyclic isothioureas of N-(4-methoxyphenyl)-2-aminocycloalkane[d]thiazole type were obtained using intramolecular electrophilic cyclization of N-(cycloalk-2-enyl)-N′-(4-methoxyphenyl)thioureas. Isothiourea fused with sevenmembered ring caused noticeable changes of the morphology of human lung carcinoma cells A549, but without affecting their microtubule net.

The purpose of this study was to identify the transporter involved in the release of prostaglandin E2 (PGE2). In the present study, transport assays were conducted using membrane vesicles prepared from human lung adenocarcinoma A549 cells, thus enabling identification of the novel exporter present in A549 cells. PGE2 transport into A549 vesicles was higher in the presence of a proton (H+)-gradient, thus suggesting the involvement of PGE2 H+ symporter in PGE2 transport. Results from our experiments showed enhanced PGE2 release in A549 cells in the presence of H+-gradient ([H+]extracellular

The cell-free dithiothreitol (DTT) assay is widely used and the DTT consumption rate is interpreted to assess the oxidative potential (OP). Most researchers use an experimental procedure developed by Cho et al. (2005) while some adopt a procedure by Li et al. (2009). The key difference between the two procedures is the initial DTT concentration, 100 μM used in the former and 20 μM in the latter, raising an unaddressed issue of comparability. We examine in this work this issue using metal-free humic-like substance (HULIS) samples isolated from ambient aerosol and two metals (i.e. copper and manganese). We found that higher initial DTT concentrations led to higher DTT consumption rates for both HULIS and metals. For HULIS, the increase in DTT consumption rate was proportional to the initial DTT concentration (i.e., roughly by 5-fold), allowing correction of the concentration effect and direct comparison of results from the two protocols. However, the proportionality did not hold for the metals or metal-organic mixtures. The increase was much lower than the proportionality of 5 and metal concentration-dependent, specifically, 1.2–1.3 for Cu and from negligible to 2.0 for Mn. For six water extracts of ambient aerosol samples, in which HULIS and metals co-exist, the proportionality ranged from 1.3 to 2.2. This deviation from a linear dependence on initial DTT concentration, plausibly due to metal-DTT binding, impedes assessing and comparing OP of metals and metal-organic mixtures using different implementations of the DTT assay. Considering the different antioxidants concentrations in real human lung fluid, this work raises caution about using the DTT assay to assess metal-containing mixtures, such as ambient aerosol samples.

Particulate matter (PM) air pollution has gradually become a widespread problem in East Asia. PM may cause unfamiliar inflammatory responses, oxidative stress, and pulmonary tissue damage, and a comprehensive understanding of the underlying mechanisms is required in order to develop effective anti-inflammatory agents. In this study, fine dust collected from Beijing, China (CPM) (size PM13 with majority PM2.5) was evaluated for its oxidative stress- and inflammation-inducing effects, which cause cell damage, in A459 human lung epithelial cells. Oxidative stress was marked by an increase in intracellular ROS levels and the production of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and heme oxygenase-1 (HO-1). Upon induction of oxidative stress, a marked increase was observed in the expression of key inflammatory mediators such as COX-2 and PGE

Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces lung pathology remains elusive. Here we describe a high-throughput platform to generate self-organizing, nearly identical, and genetically-matched human lung buds derived from hESCs cultured on micropatterned substrates. Synthetic lung buds resemble human fetal lungs and display proximo-distal patterning of alveolar and airway tissue directed by KGF. They are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-specific cytopathic effects in hundreds of lung buds in parallel. We detected an increased susceptibility to infection in alveolar cells and identified cycling alveolar stem cells as new targets of SARS-CoV-2. We used this platform to test neutralizing antibodies that efficiently blocked SARS-CoV-2 infection and transmission. Synthetic lung buds offer unlimited, rapid and scalable access to disease-relevant tissue that recapitulates human lung morphogenesis to identify key vulnerabilities for COVID-19 and respiratory viruses. Funding: This work was supported by the Pershing Square Foundation, NIH grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1, a George Mason University Fast Grant, the BAWD Foundation, the G. Harold and Leila Y. Mathers Charitable Foundation, and private funding from the Rockefeller University. Conflict of Interest: A.H.B. is a co-founder of 2 startup companies: Rumi Scientific Inc. and OvaNova Laboratories, LLC and serves on their scientific advisory boards. C.M.R. is a founder of Apath LLC, a Scientific Advisory Board member of Imvaq Therapeutics, Vir Biotechnology, and Arbutus Biopharma, and an advisor for Regulus Therapeutics and Pfizer. All other authors declare no competing interests.

Understanding the mechanisms involved in retention and clearance of actinides from the lungs after accidental intake is essential for the evaluation of the associated radiological risks. Although the absorption of radioelements has been shown in vivo to depend on their nature and physico-chemical properties, their mechanisms of translocation remain unknown. In this study, we have evaluated in vitro the binding and uptake by bronchial epithelial cells Calu-3 of 2 transuranic actinides, plutonium (Pu) and americium (Am), as the first steps of translocation across the pulmonary barrier. For this purpose, Calu-3 cells grown to confluence in 24-well plates were exposed to the radioelements for 24 h under various culture conditions. Two compartments were identified for the association of actinides to cells, corresponding to the membrane bound and internalized fractions. Binding of Pu was slightly higher than of Am, and depended on its initial chemical form (nitrate, citrate, colloids). Uptake of Pu and Am nitrate was higher in serum-free conditions than in supplemented medium, with an active mechanism involved in Pu internalization. Overall, our results suggest that complexation of actinides to bioligands may have an influence on their uptake by pulmonary epithelial cells, and therefore possibly on their subsequent absorption into blood.

The increased mass production of graphene related materials (GRM), intended for a broad spectrum of applications, demands a thorough assessment of their potential hazard to humans and the environment. Particularly, the paramount concern has been expressed in regard to their interaction with the respiratory system in occupational exposure settings. It has been shown that GRM are easily respirable and can interact with lung cells resulting in the induction of oxidative stress or pulmonary inflammation. However, a comprehensive assessment of potential biological effects induced by GRM is currently hardly feasible to accomplish due to the lack of well-defined GRM materials and realistic exposure data. Herein, a 3D human lung model was combined with a commercial aerosolization system to study potential side effects of GRM. Two representative types of GRM were aerosolized onto the lung epithelial tissue surface. After 24 h post exposure, selected biological endpoints were evaluated, such as cell viability, morphology, barrier integrity, induction of (pro-)inflammation and oxidative stress reactions and compared with the reference material carbon black. Single exposure to all tested GRM at the two different exposure concentrations (∼300 and 1000 ng/cm2) did not initiate an observable adverse effect to the 3D lung model under acute exposure scenarios.

Lung diseases impose a significant socioeconomic burden and are a leading cause of morbidity and mortality worldwide. Moreover, respiratory medicine, unlike several other therapeutic areas, faces a disappointingly low number of new approved therapies. This is partly due to lack of reliable in vitro or in vivo models that can reproduce organ-level complexity and pathophysiological responses of human lung. Here, we examine new opportunities in application of recently emerged organ-on-chip technology to model human lung alveolus and small airway in preclinical drug development and biomarker discovery. We also discuss challenges that need to be addressed in coming years to further enhance the physiological and clinical relevance of these microsystems, enable their increased accessibility, and support their leap into personalized medicine.

Diwali is one of the main festivals in India when firecrackers bursting lead to short term increase in particulate matter (PM) concentration in atmosphere. In this study, real time observations of size segregated particles number and mass concentration have been made during Diwali campaign in November 2015 at Kanpur. Results show that particle concentrations were highest during Post Diwali night as compared to Diwali night. This is attributable to build up of pollutants concentration from local and upwind region during Post Diwali. The PM2.5 mass concentration during Post Diwali was higher by a factor of 1.8 (day) and 1.3 (night) as compared to Pre Diwali. The average particle number concentration in ultrafine size (0.01 to 0.2 μm) and cumulative particle size (0.01 to 1 μm) during Post Diwali was higher by a factor of 6.8 and 3.7, respectively as compared to Pre Diwali nighttime. Size segregated PM data set for Pre Diwali, Diwali and Post Diwali periods were assessed for their deposition in human lung utilizing a computational model viz. MPPD (Multiple Path Particle Dosimetry). Results from lung deposition modeling have been systematically discussed. One of the major highlights of this study relates to penetration and significant deposition of fine particles in the pulmonary region during the study period in IGP. Our study, first of its own kind over Indian region, shows clearly the implications of air pollution on human health.

Lungs are pharmacologically active organs and the pulmonary drug metabolism is of interest for inhaled drugs design. Carboxylesterases (CESs) are enzymes catalyzing the hydrolysis of many structurally different ester, amide and carbamate chemicals, including prodrugs. For the first time, the presence, kinetics, inhibition and inter-individual variations of the major liver CES isozymes (CES1 and CES2) were investigated in cytosol and microsomes of human lungs from 20 individuals using 4-nitrophenyl acetate (pNPA), 4-methylumbelliferyl acetate (4-MUA), and fluorescein diacetate (FD) as substrates the rates of hydrolysis (V-max) for pNPA and 4-MUA, unlike FD, were double in microsomes than in cytosol. In these cellular fractions, the V-max of pNPA, as CES1 marker, were much greater (30-50-fold) than those of FD, as a specific CES2 marker. Conversely, the K-m values were comparable suggesting the involvement of the same enzymes. Inhibition studies revealed that the FD hydrolysis was inhibited by bis-p-nitrophenylphosphate, phenylmethanesulfonyl fluoride, and loperamide (specific for CES2), whereas the pNPA and 4-MUA hydrolysis inhibition was limited. Inhibitors selective for other esterases missed having any effect on above-mentioned activities. In cytosol and microsomes of 20 lung samples, inter-individual variations were found for the hydrolysis of pNPA (2.5-5-fold), FD or 4-MUA (8-15-fold). Similar variations were also observed in CES1 and CES2 gene expression, although determined in a small number (n = 9) of lung samples. The identification of CES1 and CES2 and their variability in human lungs are important for drug metabolism and design of prodrugs which need to be activated in this organ.

Inhalation of the airborne short-lived radon progeny is regarded as the most crucial way of internal exposure to the natural radiation dose delivered to the human lung. In this respect, this study aims to determine the unattached and aerosol-attached activities of radon progeny and to estimate some important physical parameters employed to assess the radiological impact of this radiation on humans. For this purpose, radioactive aerosol samples collected on polycarbonate membrane filters to measure total alpha activity by passive alpha dosimetric technique using CR-39 detectors in sixteen different locations including some houses and workplaces in El Jadida city, in Morocco. In addition, the room-specific parameters and aerosol physical processes that affect the unattached and attached activity concentrations were determined. The obtained experimental results by the three-count method and room model parameters were used as input data on a developed PC-based software that we have developed to solve mathematical equations and calculate required physical quantities. Accordingly, the individual activities of radon progeny namely 218Po, 214Pb, and 214Po as well as radon activity concentration were determined. Simultaneously, the unattached and aerosol-attached activity concentrations ( C j u and C j a ) of radon progeny were calculated based on the room model calculation. Consequently, some radiological quantities used in the calculation of the lung dose were estimated. The results showed that the indoor radon activity concentration in different targeted locations ranges between 38 and 143 Bq. m−3 with an average value of 84.8 ± 9.5 Bq. m−3. The average obtained values of the equilibrium-equivalent concentration ( C e q ) , unattached fraction ( f p ) , and equilibrium factor ( F ) at low and good ventilation rates change respectively from (24 Bq. m−3, 0.08, and 0.25) to (34 Bq. m−3, 0.02, and 0.41). Under normal environmental conditions, the average obtained values of C e q , f p , and F , in houses and at workplaces were (17 Bq. m−3, 0.07, and 0.25) and (32 Bq. m−3, 0.04, and 0.35) respectively. Depending on the different aerosol conditions and obtained values of unattached fraction f p , the calculated average values of dose conversion factors (DCFs) were 8.70 mSv.WLM−1 and 11 mSv.WLM−1 in houses and workplaces respectively. These values were in good agreement with the recommended values by ICRP, which are in the order of 9 mSv.WLM−1 and 12 mSv.WLM−1 for houses and workplaces respectively.

Plastics are ubiquitously used by societies, but most of the plastic waste is deposited in landfills and in the natural environment. Their degradation into submillimetre fragments, called microplastics, is a growing concern due to potential adverse effects on the environment and human health. Microplastics are present in the air and may be inhaled by humans, but whether they have deleterious effects on the respiratory system remain unknown. In this study, we determined the presence of microplastics in human lung tissues obtained at autopsies. Polymeric particles (n = 33) and fibres (n = 4) were observed in 13 of 20 tissue samples. All polymeric particles were smaller than 5.5 µm in size, and fibres ranged from 8.12 to 16.8 µm. The most frequently determined polymers were polyethylene and polypropylene. Deleterious health outcomes may be related to the heterogeneous characteristics of these contaminants in the respiratory system following inhalation.

Varicella pneumonia is one of the most serious, potentially life-threatening complications of primary varicella-zoster virus (VZV) infection in adults and immunocompromised individuals. However, studies on the lung pathogenesis of VZV infection as well as development and testing of antivirals have long been hindered by limited access to clinical samples and a lack of suitable animal models. In this study, we report for the first time the use of human lung xenografts in SCID mice for investigating VZV infection. Human fetal lung tissues grafted under the kidney capsule of SCID mice rapidly grew and developed mature structures closely resembling normal human lung. Following infection, VZV replicated and spread efficiently in human lung xenografts, where the virus targeted both alveolar epithelial and mesenchymal cells, and resulted in formation of large viral lesions. VZV particles were readily detected in the nuclei and cytoplasm of infected lung cells by electron microscopy. Additionally, VZV infection resulted in a robust pro-inflammatory cytokine response in human lung xenografts. In conclusion, infecting human lung xenografts in SCID mice provides a useful, biological relevant tool for future mechanistic studies on VZV lung pathogenesis, and may potentially facilitate the evaluation of new antiviral therapies for VZV lung infection.

As air pollution is a major problem in Tehran, this study aimed to investigate the physicochemical characterization of the water-soluble and organic contents of ambient PM2.5 in Tehran and determine its in vitro toxicological impact on human lung epithelial cells (A549). A total of 11 sampling stations were selected, including three categories: traffic, urban, and suburban. All sampling was carried out in the spring and summer of 2015. Ion chromatography (IC), inductively coupled plasma atomic emission spectroscopy (ICP-AES), and GC-MS were used to analyze ionic compounds, heavy metals, and polycyclic aromatic hydrocarbons (PAHs), respectively, and an ELISA reader was used for cytotoxicity analysis. The most prevalent ionic species found for all three categories was SO42-. PAH concentrations were 43.45±32.71, 50.51±37.27, and 29.13±33.29ng/m3 for traffic, urban, and suburban stations, respectively. For all sampling stations, Al and Fe had the highest values among the investigated heavy metals. Cell viability measurements, carried out using the MTT assay, showed that all three categories of samples cause cytotoxicity, although the urban station samples showed higher cytotoxicity than those from the other stations (p˂0.05). Based on the results of the present study, organic compounds and insoluble particles could be the main causes of cytotoxicity.

In this study, gallic acid-conjugated chitooligosaccharides (gallate-COS) was evaluated for its enhancing capabilities in free radical scavenging and anti-inflammatory activities in human lung epithelial A549 cells. It was found that gallate-COS possesses significantly high DPPH radical scavenging activity and protective effect against H2O2-induced DNA damage. Likewise, gallate-COS decreased the production of intracellular reactive oxygen species in H2O2-stimulated A549 cells. Moreover, the suppressive effects of gallate-COS on COX-2 expression and PGE2 production from LPS-stimulated A549 cells were evidenced. Finally, the productions of cytokines including IL-8 and TNF-α were also inhibited by gallate-COS in a dose-dependent manner. Collectively, these results suggest that gallate-COS could be used as a functional ingredient with potent antioxidant and anti-inflammatory benefits.

Three new diterpenoids, vulgarisins B–D (1–3), have been isolated from a medicinal plant Prunella vulgaris Linn. These diterpenoids contain a rare 5/6/4/5 fused tetracyclic ring skeleton. Their structures were determined through the analysis of spectroscopic data, and the absolute configuration were further confirmed by single crystal X-ray diffraction as well as CD analysis. All the compounds were evaluated for their cytotoxicity activity, vulgarisins B (1) and C (2) demonstrated modest cytotoxicity activity against human lung carcinoma A549 cell line.

Chemical investigation of the leaves of Baeckea frutescens (Myrtacea) led to the isolation and characterization of five new phloroglucinol derivatives, baeckenones G−K (1–5), together with two known compounds, ursolic acid (6) and humulene (7). The chemical structures were determined by extensive 1D- and 2D-NMR, and MS spectroscopic analyses. Baeckenones J (4) and K (5) exhibited antiproliferative activities against human lung A549 and pancreatic PSN-1 cancer cell lines, with IC50 values ranging from 11.8 to 19.2 μM.

The diagnosing of drowning remains one of the most challenging activities for the forensic pathologist. There is little information on the impact on the lung as a target organ in death by drowning. We aimed to investigate the concentration of trace elements in the lungs of people who had suffered different types of death to evaluate the discriminating ability of trace elements to identify seawater drowning (SWD). A total of 11 trace elements were analyzed by Inductively Coupled Plasma-Mass Spectrometry in 74 forensic cases. Sampler scanning electron microscopy and Energy Dispersive X-ray spectroscopy (EDX) were used to identify ultrastructural lung alterations. A Principal Component Analysis (PCA) of trace elements was carried out. The trace elements in SWD lungs were detected in the following order of concentration: Br˃Zn˃Sr˃Cr˃Cu˃As˃Pb˃Se˃Mn˃Ni˃Cd. Our results showed significantly higher concentrations of Br and Sr (P = 0.010 and P = 0.000) and significantly lower concentrations of Zn, Pb, Cu, Cd, and Se in SWD compared with other causes of death. After adjusting by confounder factors, Sr and Br remained as predictive independent factors for diagnosis of drowning (p = 0.042, in both cases). These results were confirmed by PCA, which revealed a wide separation between SWD and the rest of the causes of death. Our SWD cohort was characterized by high concentrations of the trace elements Br and Sr and low concentrations of Zn, Pb, Cu, Cd, and Se in lung tissue, while PCA showed its discriminatory capacity to identify death by seawater drowning. These findings, together with those obtained using other techniques, can be of great importance in the diagnosis of SWD.

Luminescent chemical sensors have been proven to be a valuable asset in cell cultures and generally in microbiological studies. We present microfluidic cell culture devices with integrated optical chemical sensors. The integrated sensors offer the possibility to monitor dissolved oxygen and pH levels and enable the measurement of respiration and acidification rates. The cell metabolism was observed using this method by temporarily stopping the incubation flow, barely influencing the cell culture. A thermoplastic polymer is used as oxygen impermeable chip material to enable the measurement of respiration rates, which is not possible with widely used PDMS-based microfluidics. Hence, an innovative fast prototyping strategy is utilized to enable the replication of small series of thermoplastic microfluidic chips. We were able to demonstrate the suitability of this measurement method by monitoring the metabolic response of a human lung carcinoma epithelial-like cell line (A549) to the exposure of FCCP (Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone), a drug known for its up-regulating effect on respiration and acidification rates. This universal measurement approach can potentially be deployed in all sorts of microfluidic devices and help to retrieve valuable data from inside those systems beyond classical end-point detection methods. It therefore complements modern 3D cell cultures and organ-on-chip research with a powerful analytical technology for gathering information about ongoing cell metabolism.

Summary CD103+CD8+ tumor-resident memory T cells (TRM) are important components of anti-tumor immunity. However, their role in response to cancer immunotherapy is not fully understood. The protocol describes how to isolate CD8+ T cells and autologous tumor cells from human lung tumors to study the functional activities of CD8+ T cells. Tumors are heterogeneous in terms of the quantity and quality of immune cell types, so the yield of TRM cells depends on the features of the tumor. For complete details on the use and execution of this protocol, please refer to Corgnac et al. (2020)., Graphical Abstract, Highlights • Isolation of human CD8+ tumor-resident memory T cells • Isolation of tumor cells from fresh human lung tumor samples • Adaptable for isolation of diverse populations of tumor-infiltrating T cells • Suitable for in vitro expansion, functional tests, RNA-seq, CD103+CD8+ tumor-resident memory T cells (TRM) are important components of anti-tumor immunity. However, their role in response to cancer immunotherapy is not fully understood. The protocol describes how to isolate CD8+ T cells and autologous tumor cells from human lung tumors to study the functional activities of CD8+ T cells. Tumors are heterogeneous in terms of the quantity and quality of immune cell types, so the yield of TRM cells depends on the features of the tumor.

Novel hydrolytically stable gelatin nanofibers modified with sodium or calcium salt of oxycellulose were prepared by electrospinning method. The unique inhibitory effect of these nanofibers against Escherichia coli bacteria was examined by luminometric method. Biocompatibility of these gelatin/oxycellulose nanofibers with eukaryotic cells was tested using human lung adenocarcinoma cell line NCI-H441. Cells firmly adhered to nanofiber surface, as determined by scanning electron microscopy, and no signs of cell dying were detected by fluorescent live/dead assay. We propose that the newly developed gelatin/oxycellulose nanofibers could be used as promising scaffold for lung disease modeling and anti-cancer drug testing.

An alpha particle irradiator has been built in the Radiation Bioengineering Laboratory at Seoul National University (SNU) to investigate the cellular responses to alpha emissions from radon and the progeny. This irradiator is designed to have the energy of alpha particles entering target cells similar to that of alpha emissions from the radon progeny Po-218 and Po-214 residing in the human respiratory tract. For the SNU alpha particle irradiator, an irradiation system is equipped with cell dishes of 4 µm thick Mylar bottom and a special setup of cells on slide for gamma-H2AX assay. Dose calibration for the alpha particle irradiator was performed by dual approaches, detection and computer simulation, in consideration of the source-to-target distance (STD) and the size of a cell dish. The uniformity of dose among cells in a dish is achieved by keeping the STD and the size of cell dish in certain ranges. The performance of the SNU alpha particle irradiator has been proven to be reliable through the gamma-H2AX assay with the human lung epithelial cells irradiated.

Two new cyclopentenones, frutescencenones A ( 1 ) and B ( 2 ), and a new furanone derivative, frutescencenone C ( 3 ), together with two known cyclopentenones ( 4 and 5 ), were isolated from the leaves of Baeckea frutescens . Their structures were deduced by comprehensive spectroscopic analyses, including 1D and 2D NMR, and HREIMS data. Frutescencenone A ( 1 ) showed moderate growth inhibitory activity against human lung A549, pancreatic PSN-1, and breast MDA-MB-231 cancer cell lines, with IC 50 values of 36.3 μM, 38.2 μM, and 29.3 μM, respectively. In contrast, frutescencenone C ( 3 ) showed selective cytotoxic activity against PSN-1, with an IC 50 value of 20.1 μM.

To put forward an accurate and effective registration method based on improved Demons algorithm, and to register three-dimensional pulmonary medical images of the same individual whose lung has the deformation under different respiration state. The experimental data are the maximum and minimum respiratory phase of the three-dimensional pulmonary images within a cycle of respiratory movement. First, images for registration are registered globally and non-rigidly. Feature points are extracted and matched by scale invariant feature transform algorithm. Afterwards, the global registration is finished according to the transformation parameter computed based on matching results. Finally, images after global registration are registered non-rigidly utilizing improved Demons algorithm. Image registration of human lung is realized employing improved method. The mean-square error between images before registration is 25,835.3 and it is reduced to 11,790.9 after registration. After further deal with improved Demons algorithm, the mean-square error between images is reduced to 3726.31 and the descent rate of mean-square is up to 85.58%. The proposed method effectively registers three-dimensional pulmonary images, which provides a solid foundation for doctors to estimate pulmonary respiratory movement and analyze respiratory function.

Using cholesterol as a starting material, two novel steroidal thiadiazole derivatives possessing a structure of A-homo lactam and a B-nor steroidal skeleton were designed and synthesized by six steps of reactions, and their antiproliferative activities were assayed against various cancer cell lines. The result shows that compound 7b displays an excellent selective inhibition to A-549 (human lung carcinoma) cancer cell lines with an IC50 value of 8.0 μM.

5-Aminoisoxazoles containing trimethoxy- and methylenedioxyphenyl moieties were prepared by heterocyclization of electrophilic alkenes with tetranitromethane in the presence of triethylamine with subsequent reduction of resulting 5-nitroisoxazoles. The crystal structure of 3,4,5-trimethoxybenzyl 5-aminoisoxazole-3-carboxylate was determined by X-ray analysis. Two novel 5-aminoisoxazoles demonstrated moderate antimitotic activity to human lung carcinoma A549 cell line.

The herein synthesized 7-(4-methylphenyl)thiomethyl and 7-morpholylmethyl derivatives of natural phaeosphaeride A have lower cytotoxic activity towards the human lung adenocarcinoma A549 cell line compared to phaeosphaeride A. The presence of exocyclic C=C bond and N–OMe group in such compounds is suggested to be a factor in their antitumor activity.

Environmental air pollutants pose significant threats to public health, especially the toxicity and diseases caused by the atmospheric fine particulate matters (PM2.5). Since the health risks vary with both the concentrations and compositions of PM2.5 which are determined by aerosol sources, how are their toxic effects relevant to the pollution level becomes an important issue, such as the haze episodes covering clean and polluted days. With the transition from non-pollution to pollution stage, daily PM2.5 samples were collected from both the urban and industrial areas of Nanjing city, eastern China, covering a typical haze event in autumn-winter. Their unpropitious effects on human lung epithelial cells (A549) were compared by in vitro toxicity assays and chemical component analysis. Both air levels and cytotoxic effects of PM2.5 varied with the transition of haze event. Although the concentration of PM2.5 in air is of course the highest in pollution stage driven by local stable meteorological condition, unit mass of them posed higher toxicity (lower cell viability and higher IL-6) but induced lower cell oxidative (evidences of ROS and NQO1 mRNA expression) and inflammatory cytokine TNF-α responses than those particles during non-pollution stage. These patterns were explained by the metals and water-soluble components decreased with the haze development. Non-soluble particulate carbonaceous aerosol compositions might play a significant role in inducing cytotoxicity. Moreover, the regional pattern of episode pollution weakened the spatial variation within a city scale. Since the haze development intensified both the quantity and toxicity of PM2.5 in air, the health risks of overall aerosol exposure were synthetically amplified during haze weather, so the increased air particles with higher toxic components from fuel combustion sources should be key targets of pollution control.

WHO has presented a health-based guideline value for boron in drinking water. That fact indicates that a high level of boron is toxic for humans. However, there is no direct evidence of boron-mediated malignant transformation. In this study, human lung epithelial nontumorigenic BEAS-2B cells and tumorigenic A549 cells were used to investigate the tumorigenic toxicity of boron in vitro. Anchorage-independent growth, a hallmark of malignant transformation, was increased by boron at concentrations of 50, 250 and 500 μM in BEAS-2B cells, though the same concentrations of boron had no influence on anchorage-independent growth of A549 cells. Moreover, boron at concentrations of 250 and 500 μM activated the c-SRC/PI3K/AKT pathway of BEAS-2B cells. The results of our in vitro study suggest that exposure to high levels of boron promotes transforming activity of nontumorigenic cells.

Three new non-cisplatin analogs [Rh(BID1)(CH3OH)]⋅CH3OH (Rh-1), [Rh(BID2)(CH3OH)]⋅CH3OH (Rh-2) and [Rh(BID3)(CH3OH)]⋅2CH3OH (Rh-3) bearing benzimidazole derivatives (BID1−BID-3) were first prepared as potential anti-tumor compounds. The Rh-3 complex with 8-fluoro group in BID-3 ligand exhibited potential antiproliferative activity against multidrug-resistant human lung adenocarcinoma A549/DDP and cisplatin-resistant human ovarian cancer SK-OV-3/DDP cells, at most 5.0 fold more potent than Rh-1, Rh-2 and cisplatin under the same conditions. Importantly, Rh-1−Rh-3 are more selective for A549/DDP cells versus human normal liver HL-7702 cells. The Rh-2 and Rh-3 caused mitochondrial dysfunction was in the following order: Rh-3 > Rh-2. The different biological behavior of Rh-1−Rh-3 may correlate with different 8-substituted groups in benzimidazole derivatives.

Silver nanoparticles (AgNP) are commonly used in medical, cosmetics, clothing, and industrial applications for their antibacterial and catalytic properties. As AgNP become more prevalent, the doses to which humans are exposed may increase and pose health risks, particularly through incidental inhalation. This exposure was evaluated through in-vitro methods simulating lung fluids and lung epithelium, and through computational fluid dynamics (CFD) methods of AgNP transport. A high-dose scenario simulated a short-term inhalation of 10 μg AgNP/m3, based on an exposure limit recommended by the National Institute of Occupational Safety and Health for the case of a health-care worker who handles AgNP-infused wound dressings, and regularly wears AgNP-imbedded clothing. Bioaccessibility tests were followed by a Parallel Artificial Membrane Permeability Assay (PAMPA) and supported by CFD models of the lung alveoli, membrane, pores, and blood capillaries. Results indicate that such exposure produces an average and maximum AgNP flux of approximately 4.7 × 10−21 and 6.5 × 10−19 mol m−2·s−1 through lung tissue, respectively, yielding a blood-silver accumulation of 0.46–64 mg per year, which may exceed the lowest adverse effect level of 25 mg for an adult male. Results from in-silico simulations were consistent with values estimated in vitro (within an order of magnitude), which suggest that CFD models may be used effectively to predict silver exposure from inhaled AgNP. Although the average short-term exposure concentrations are 3 orders of magnitude smaller than the reported threshold for mammalian cytotoxicity effects (observed at 5000 ppb), cumulative effects resulting from constant exposure to AgNP may pose risks to human health in the long-term, with predicted bioaccumulation reaching potential toxic effects after only five months of exposure, based on maximum flux.

PM2.5–bound toxic elements and organic pollutants have been extensively investigated, while limited information is available for environmental persistent free radicals (EPFRs) associated with PM2.5, which may lead to oxidative stress in the human lung when exposed to PM2.5. In this study, the levels and types of PM2.5–bound EPFRs present in Nanjing, a mega–city in China, were analyzed. PM2.5–bound EPFRs were found to mainly be a mixture of carbon– and oxygen–centered radicals. The concentration of PM2.5–bound EPFRs ranged from 2.78 × 1012 to 1.72 × 1013 spins m−3, with an average value of 7.61 × 1012 spins m−3. The half–life of the PM2.5–bound EPFRs was calculated to be an average of 83.5 days when stored at room temperature, with only weak correlations observed between EPFRs and conventional air pollutants (NO2, O3, CO and PM2.5)/PM2.5–bound transition metals (Cu, Zn, Cr, Mn, V, Cd, and Ni) and significant correlations between EPFRs and SO2/PM2.5–bound Fe. PM2.5–bound EPFRs can induce the formation of reactive oxygen species (ROS) in both water and a H2O2 solution, which are used to simulate lung solution of a healthy person and patient, respectively. Therefore, PM2.5–bound EPFRs can lead to potential oxidative stress in humans. Overall, PM2.5–bound EPFRs show an obvious temporal variation and can pose potential health risks to humans via the induction of ROS in the lung solution.

Background We determined the effect of human lung fibroblasts (LFs) in metastatic lesion formation in a four-dimensional (4D) lung cancer model. Methods Human cancer-associated fibroblasts (CAFs) were isolated from the primary tumor, and normal LFs were isolated from adjacent lung using fluorescence-activated cell sorting. The 4D metastatic lung cancer model was seeded with the human lung cancer cell lines (H460, A549, and H1299) alone or was seeded with CAFs or LFs. In addition, the 4D model seeded with human lung cancer cell lines was also treated with conditioned media of LFs or CAFs grown on the 4D model. We determined the number of metastatic tumor cells per high-power field on the model. Results There were significantly fewer metastatic lesions per high-power field in the 4D model seeded with the H460 cell line and LFs compared with H460 alone on day 15 ( p = 0.008) or compared with H460 and CAFs ( p = 0.002). This relationship was also seen with A549 and H1299 tumor cells. Moreover, the H460 cell line treated with conditioned media from the 4D model seeded with LFs had significantly fewer metastatic lesions than the 4D model seeded with CAFs. This was also seen with two other pairs of human fibroblasts obtained from patients. Conclusions The secreted factor from LFs grown on the 4D model inhibits the formation of metastatic lesions. The 4D model may be used to determine the role of different components of the tumor's microenvironment in metastatic lesion formation, and this secreted factor may provide a novel therapy for treatment of cancer metastasis.

Fourteen compounds were isolated from the root of Lindera reflexa Hemsl. Among these compounds, reflexan A (compound 1) was discovered to possess a novel skeleton and two stilbenes (compounds 2 and 3) were newly discovered compounds. Eleven known compounds (4-14) were also isolated, which included three alkaloids, one coumarin, four stilbenes, two flavonoids and katsumadain. The unusual structure of compounds 1, 2 and 3, along with their absolute configurations, was determined from UV, IR, HR ESI-MS, and 1D and 2D NMR data and by the comparison of experimental and calculated electronic circular dichroism (ECD) spectra. All of the isolates were tested with antitumor and anti-inflammatory assays. The results revealed that compounds 1, 2, and 3 all showed inhibitory activity toward three tumor cell lines, A549 (human lung carcinoma), BEL-7402 (human liver carcinoma) and HCT-8 (human colon carcinoma). None of the compounds exhibited anti-inflammatory activity.