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Background: Lungs are adversely affected by repeated exposure to thinner fumes. This study aimed to examine the pulmonary toxic effects of chronic thinner inhalation and the possible protection by chamomile administration. Adult male Wistar rats were exposed to thinner fumes for 8 weeks (4 h/day, 6 days/week), while chamomile flower extract (400 mg/kg body weight) was given orally during thinner exposure for the same period. Results: The study showed lung damage following chronic thinner exposure through increased cytochrome P2E1 (CYP2E1), superoxide anion (O2•−), hydrogen peroxide (H2O2), and malondialdehyde (MDA), with decreased antioxidant enzymes; superoxide dismutase (SOD), and catalase (CAT). Moreover, an elevation of lung enzymes; alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH) with depletion in total protein and albumin contents in serum and bronchoalveolar lavage fluid were observed. Thinner exposure also exhibited increased lung deoxyribonucleic acid (DNA) damage, transforming growth factor-β1 (TGF-β1), insulin-like growth factor-1 (IGF-1), hydroxyproline (HYP), and collagen type 1 (COL-1), with decreased serum surfactant protein-A (SP-A), total and differential leukocytes (WBCs) count, except for neutrophils. Histological investigations revealed deteriorative changes along with accumulated collagen fibers affecting the lung and other respiratory organs. Conclusion: Supplementation of chamomile extract succeeded in preventing thinner-induced lung oxidative stress, enzyme leakage, surfactant deficiency, DNA damage, fibrosis, and histological injury. Therefore, consumption of chamomile extract could be recommended for alleviating thinner-induced health hazards and lung toxicity. [ABSTRACT FROM AUTHOR]

Abstract Background Lungs are adversely affected by repeated exposure to thinner fumes. This study aimed to examine the pulmonary toxic effects of chronic thinner inhalation and the possible protection by chamomile administration. Adult male Wistar rats were exposed to thinner fumes for 8 weeks (4 h/day, 6 days/week), while chamomile flower extract (400 mg/kg body weight) was given orally during thinner exposure for the same period. Results The study showed lung damage following chronic thinner exposure through increased cytochrome P2E1 (CYP2E1), superoxide anion (O2 •−), hydrogen peroxide (H2O2), and malondialdehyde (MDA), with decreased antioxidant enzymes; superoxide dismutase (SOD), and catalase (CAT). Moreover, an elevation of lung enzymes; alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH) with depletion in total protein and albumin contents in serum and bronchoalveolar lavage fluid were observed. Thinner exposure also exhibited increased lung deoxyribonucleic acid (DNA) damage, transforming growth factor-β1 (TGF-β1), insulin-like growth factor-1 (IGF-1), hydroxyproline (HYP), and collagen type 1 (COL-1), with decreased serum surfactant protein-A (SP-A), total and differential leukocytes (WBCs) count, except for neutrophils. Histological investigations revealed deteriorative changes along with accumulated collagen fibers affecting the lung and other respiratory organs. Conclusion Supplementation of chamomile extract succeeded in preventing thinner-induced lung oxidative stress, enzyme leakage, surfactant deficiency, DNA damage, fibrosis, and histological injury. Therefore, consumption of chamomile extract could be recommended for alleviating thinner-induced health hazards and lung toxicity.

ObjectivesThis practice parameter was revised collaboratively by the American College of Radiology (ACR) and the American Radium Society (ARS). This practice parameter provides updated reference literature regarding both clinical-based conventional total body irradiation and evolving volumetric modulated total body irradiation.MethodsThis practice parameter was developed according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website ( https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards ) by the Committee on Practice Parameters-Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ARS.ResultsThis practice parameter provides a comprehensive update to the reference literature regarding conventional total body irradiation and modulated total body irradiation. Dependence on dose rate remains an active area of ongoing investigation in both the conventional setting (where instantaneous dose rate can be varied) and in more modern rotational techniques, in which average dose rate is the relevant variable. The role of imaging during patient setup and the role of inhomogeneity corrections due to computer-based treatment planning systems are included as evolving areas of clinical interest notably surrounding the overall dose inhomogeneity. There is increasing emphasis on the importance of evaluating mean lung dose as it relates to toxicity during high-dose total body irradiation regimens.ConclusionsThis practice parameter can be used as an effective tool in designing and evaluating a total body irradiation program that successfully incorporates the close interaction and coordination among the radiation oncologists, medical physicists, dosimetrists, nurses, and radiation therapists.

Cigarette smoking is a risk factor for several diseases such as cancer, cardiovascular disease (CVD), and chronic obstructive pulmonary diseases (COPD), however, the underlying mechanisms are not fully understood. Alternative nicotine products with reduced risk potential (RRPs) including tobacco heating products (THPs), and e-cigarettes have recently emerged as viable alternatives to cigarettes that may contribute to the overall strategy of tobacco harm reduction due to the significantly lower levels of toxicants in these products’ emissions as compared to cigarette smoke. Assessing the effects of RRPs on biological responses is important to demonstrate the potential value of RRPs towards tobacco harm reduction. Here, we evaluated the inflammatory and signaling responses of human lung epithelial cells to aqueous aerosol extracts (AqE) generated from the 1R6F reference cigarette, the glo™ THP, and the Vype ePen 3.0 e-cigarette using multiplex analysis of 37 inflammatory and phosphoprotein markers. Cellular exposure to the different RRPs and 1R6F AqEs resulted in distinct response profiles with 1R6F being the most biologically active followed by glo™ and ePen 3.0. 1R6F activated stress-related and pro-survival markers c-JUN, CREB1, p38 MAPK and MEK1 and led to the release of IL-1α. glo™ activated MEK1 and decreased IL-1β levels, whilst ePen 3.0 affected IL-1β levels but had no effect on the signaling activity compared to untreated cells. Our results demonstrated the reduced biological effect of RRPs and suggest that targeted analysis of inflammatory and cell signaling mediators is a valuable tool for the routine assessment of RRPs.

Metal oxide nanoparticles (MONP/s) induce DNA damage, which is influenced by their physicochemical properties. In this study, the high-throughput CometChip and micronucleus (MicroFlow) assays were used to investigate DNA and chromosomal damage in mouse lung epithelial cells induced by nano and bulk sizes of zinc oxide, copper oxide, manganese oxide, nickel oxide, aluminum oxide, cerium oxide, titanium dioxide, and iron oxide. Ionic forms of MONPs were also included. The study evaluated the impact of solubility, surface coating, and particle size on response. Correlation analysis showed that solubility in the cell culture medium was positively associated with response in both assays, with the nano form showing the same or higher response than larger particles. A subtle reduction in DNA damage response was observed post-exposure to some surface-coated MONPs. The observed difference in genotoxicity highlighted the mechanistic differences in the MONP-induced response, possibly influenced by both particle stability and chemical composition. The results highlight that combinations of properties influence response to MONPs and that solubility alone, while playing an important role, is not enough to explain the observed toxicity. The results have implications on the potential application of read-across strategies in support of human health risk assessment of MONPs. [ABSTRACT FROM AUTHOR]

Immune-checkpoint inhibitors have profoundly changed cancer treatment, improving the prognosis of many oncologic patients. However, despite the good efficacy of these drugs, their mechanism of action, which involves the activation of the immune system, can lead to immune-related adverse events, which may affect almost all organs. Pulmonary adverse events are relatively common, and potentially life-threatening complications may occur. The diagnosis is challenging due to the wide and non-specific spectrum of clinical and radiological manifestations. The role of the radiologist is to recognize and diagnose pulmonary immune-related adverse events, possibly even in the early stages, to estimate their extent and guide patients' management. [ABSTRACT FROM AUTHOR]

This study explores the impact of silymarin, a potent natural flavonoid with robust antioxidant properties, on paclitaxel-induced lung injury. Paclitaxel, a widely used chemotherapeutic agent for cancer, is known for its adverse effects on various organs. The research involved four groups: the Control group (6 animals) received oral saline; the SIL group (6 animals) received 200 mg/kg silymarin orally for 10 days; the PAX group (6 animals) received intraperitoneal paclitaxel (2 mg/kg) for 5 days; and the PAX+SIL group (6 animals) received both treatments. All groups were sacrificed on the 10th day. Histopathological analysis revealed pathological changes in the lung tissue of the PAX group. Immunopositivity of Bax, iNOS, Nf-kB, and IL-6 antibodies was higher in the PAX group compared to silymarin-treated groups. Conversely, Bcl-2 and MUC1 immunopositivity was lower in the PAX group but higher in silymarintreated groups. Silymarin administration decreased IL-6, Caspase-3, P2x7 and NFkB p65 immunoreactivity, while increased Bcl-2 immunoreactivity. Protein expression levels of IL-6, Caspase-3, P2x7, and NF-κB were higher in the PAX group but decreased in the PAX+SIL group. Bcl-2 protein expression was lower in the PAX group but higher in the PAX+SIL group. Additionally, antioxidant enzyme levels increased, while MDA levels decreased in the PAX+SIL group. In conclusion, the findings indicate that silymarin effectively ameliorated paclitaxel-induced lung damage, highlighting its potential therapeutic role in mitigating chemotherapy-related side effects. [ABSTRACT FROM AUTHOR]

Introduction: Radiation-induced lung toxicity (RILT) is a major concern in patients who receive radiation to thorax. The purpose of the study was to evaluate the changes of pulmonary function tests (PFTs) in lung carcinoma patients treated with three-dimensional conformal radiation therapy (3-D CRT) and relation RILT with dosimetric and nondosimetric factors. Methods: This was a prospective observational study which included 65 patients of lung carcinoma treated with 3-D CRT. PFTs were assessed before the radiotherapy and at third and sixth month post-radiation therapy. Radiation pneumonitis (RP) was graded according to National Cancer Institute Common Toxicity Criteria (CTCAE) version 4.0. Results: Majority of patients already had poor lung function before commencing the radiotherapy. There was a modest decrease in pulmonary function after radiation therapy with (3-D CRT). Postradiotherapy, at third month, eight patients (12%) and at the sixth month, 16 patients (25%) were observed with Grade II RP. At the third month, the nondosimetric factors, age >65 years (P = 0.027) and pretreatment Diffusion capacity of the Lung for Carbon monoxide (DLCO) 60% (P = 0.03) were significantly related to grade ≥ II Radiation pneumonitis (RP). Among dosimetric factors, mean lung dose ≥20 Gy (P = 0.001) and volume receving 20Gy ≥35% (P = 0.05) were significantly related to grade ≥ II RP. These factors were also related to grade ≥ II RP at the sixth month with a significant P value. Conclusion: There is a progressive decrease in pulmonary function after (3-D CRT) in lung carcinoma patients. The study suggested that the baseline PFT may be utilized for the identification of high-risk patients for RILT before starting the radiotherapy in lung carcinoma. [ABSTRACT FROM AUTHOR]

Background: Pulmonary toxicities caused by immune checkpoint inhibitors are a prominent concern for clinicians. Clinical Practice Guidelines (CPGs) are critical for managing these toxicities. Methods: A systematic search of CPGs on checkpoint-associated pulmonary toxicities (ca-PT) was conducted in October 2022. PubMed, Embase, Cochrane Library, CINAHL, and Web of Science were searched. AGREE II and AGREE-REX were used to appraise CPGs and recommendations quality, respectively. Descriptive statistics, intraclass correlation coefficient, Kruskal-Wallis (H) test, and Spearman's correlation were used for analyses. P-values <.05 were considered statistically significant. Matrices were used to determine recommendation differences between CPGs. The study's design was based on the PRISMA 2020 checklist for systematic reviews. Protocol registration number: CRD42022358435. Results: Eight CPGs (two high-quality, three moderate-quality, and three low-quality) were identified. All CPGs covered pneumonitis. One CPG covered pleural effusions and pneumonitis/SARs-CoV-2-infection. Three CPGs covered sarcoidosis-like-reactions. CPGs for pulmonary fibrosis, airway disease, bronchiolitis, and diffuse alveolar damage, were unavailable. No CPG recommendation was based on a prospective study, and none were appraised as high-quality. Also, recommendations were not specific to histopathologic subtypes. AGREE II's "rigor of development," the domain that evaluates a guideline's methodological approach and strategies in gathering scientific evidence, correlated strongly with AGREE-REX's "overall quality" pneumonitis recommendations, r =.952; P <.01. Approximately 73% of recommendations on pneumonitis were similar between high-quality CPGs. About 16% to 74% of low-quality CPGs were similar to those recommended by high-quality CPGs. Conclusion: Prospectively designed research projects focusing on all types of ca-PT and their histopathologic subtypes are urgently needed. Due to the lack of high-quality recommendations in available CPGs, the disparities in treatment recommendations between high-quality CPGs, and the similarities in recommendations that exists between high-quality and low-quality CPGs, clinicians should thoroughly assess and responsibly appraise all available CPG recommendations in formulating treatment strategies for ca-PT. [ABSTRACT FROM AUTHOR]

Abstract Objectives Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK TKIs) have shown remarkable clinical activity in patients with non‐small‐cell lung cancer (NSCLC). However, pneumonitis is a serious side effect of ALK TKIs in NSCLC patients. In this meta‐analysis, we aimed to determine the incidence of ALK‐TKI‐associated pneumonitis. Materials and Methods We searched electronic databases to identify relevant studies published until August 2022. The incidence of pneumonitis was calculated using a fixed‐effects model when no substantial heterogeneity was observed. Otherwise, a random‐effects model was used. Subgroup analyses of different treatment groups were performed. Statistical analyses were conducted using STATA 17.0. Results Twenty‐six clinical trials involving 4752 patients were eligible for analysis. All‐grade pneumonitis incidence was 2.92% (95% confidence interval [CI]: 1.79%–4.27%), high‐grade (Grade 3–4) pneumonitis incidence was 1.42% (95% CI: 0.84%–2.12%) and Grade 5 pneumonitis incidence was 0.09% (95% CI: 0.00%–0.28%). The subgroup analysis showed that brigatinib was associated with the highest incidence of both all‐grade and high‐grade pneumonitis (7.09% and 3.06%, respectively). ALK TKI treatment after chemotherapy was associated with a higher incidence of all‐grade and high‐grade pneumonitis than first‐line ALK TKI treatment (7.73% vs. 2.26% and 3.64% vs. 1.26%, respectively). Cohorts from Japanese trials had a higher incidence of all‐grade and high‐grade pneumonitis. Conclusion Our study provides precise data on the incidence of pneumonitis in patients receiving treatment with ALK TKIs. Overall, ALK TKIs have tolerable pulmonary toxicity. Early pneumonitis identification and treatment are required to prevent further deterioration in patients receiving treatment with brigatinib and in those who received prior chemotherapy, particularly in the Japanese population.

Micro/nanoplastics (MNP) are ubiquitous in the environment and multiple living organisms. The toxicity of some common types of MNP, e.g., polyethersulfone (PES) MNP, remains poorly understood. Multi-omics approaches were used in this study to determine the effects of foodborne and airborne PES MNP on liver and lung, respectively. Foodborne MNP were capable of inducing gut microbial dysbiosis, gut and serum metabolic disruption, and liver transcriptomic dysregulation, and affecting serum antioxidant activity and liver function, resulting in liver injury. As for the airborne MNP, they were found to induce nasal and lung microbial dysbiosis, serum and lung metabolic disruption, and liver transcriptome disturbance, and cause disrupted serum antioxidant activity and lung injury. Foodborne and airborne PES NP were found to respectively induce greater liver and lung toxicity than MP, which could be associated with the differences between NP and MP exposures. The relevant results suggest that foodborne PES MNP could disrupt the “gut microbiota-gut-liver” axis and induce hepatic injury, while airborne PES MNP could affect the “airborne microbiota-lung” axis and cause lung injury. The findings could benefit the diagnoses of liver and lung injury respectively induced by foodborne and airborne PES MNP, as well as the proper use of PES in human living environment.

Copper (Cu) is an essential trace element for maintaining normal homeostasis in living organisms. Yet, an elevated level of Cu beyond homeostatic capacity may lead to oxidative damage of cellular components in several organs, including the lungs. This work investigated the effects of curcumin (Curc) and nano-curcumin (nCurc) against Cu-induced lung injury, accenting the roles of oxidative stress, inflammation, and the nuclear factor erythroid 2-related factor/heme oxygenase-1 Nrf2/HO-1 pathway. Rats were challenged with 100 mg/kg of copper sulfate (CuSO4) while being treated with Curc or nCurc for 7 days. Cu-triggered lung oxidative stress detected as dysregulation of oxidative/antioxidant markers, a downregulation of Nrf-2/HO-1 signaling, and an increase in the inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and intracellular adhesion molecule-1 (ICAM-1). Additionally, it decreased the expression of lung-specific proteins, surfactant protein-C (SP-C), and mucin-1 (MUC-1), induced apoptosis, and caused changes in lung histology. Curc and nCurc alleviated CuSO4-induced lung injury by suppressing oxidative damage and inflammation and activating Nrf-2/HO-1. They also prevented apoptosis and restored the normal expression of SP-C and MUC-1. We concluded that nCurc exhibited superior efficacy compared with Curc in mitigating CuSO4-induced lung injury. This was associated with reduced oxidative stress, inflammation, and apoptotic responses and increased Nrf2/HO-1 signaling and expression of SP-C and MUC-1. [ABSTRACT FROM AUTHOR]

Objective Amiodarone (AD) is a benzofuran derivative, a lipophilic anti-arrhythmic agent structurally similar to thyroxine. It is one of the drugs used against ventricular tachycardia types and atrial fibrillation as a class III potassium channel blocker in the Waughn-Williams drug classification system. Gilaburu (Viburnum opulus L.) is a red, berry-like fruit that is found around the forests in Eurasia and North Africa in the world and most commonly in Kayseri province in our country and has medicinal uses. Many studies has been shown Gilaburu (GL) to high antioxidative, antiproliferative, anti-inflammatory activity with the contain organic acids, phenolic compounds, various amino acids and vitamins. In our study, we aimed to investigated whether gilaburu has a protective effect on the toxicity of amiodarone on rat lung tissue. Material and Methods In the study, 32 male Wistar rats weighing 300-350 g were randomly selected and divided 4 groups as, Control, AD, AD+GL and GL group. In the experiment, 100 mg/kg AD was administered ip to rats for 10 days, and 100 mg/kg gilaburu powdered fruit extract was dissolved in physiological saline by oral gavage. At the end of the experiment, lung tissues were taken and examined by immunohistochemical and histochemical techniques. Results In the histochemical examinations, it was observed that the damage occurred in the lung tissues of the AD group, but the damage decreased in the combined group. As a result of immunohistochemical staining (TNF-a and iNOS), it was observed that the staining was more in the AD group and less in the combined group. Conclusion As a result, we think that gilaburu has a protective effect against lung damage caused by Amiodarone. [ABSTRACT FROM AUTHOR]

The present study aimed to develop fast melting tablets (FMTs) using silymarin (SM) owing to FMTs rapid disintegration and dissolution. FMTs represent a pathway to help patients to increase their compliance level of treatment via facile administration without water or chewing beside reduction cost. One of the methods for FMTs formulation is lyophilization. Optimization of SM-FMTs was developed via a 32 factorial design. All prepared SM-FMTs were evaluated for weight variation, thickness, breaking force, friability, content uniformity, disintegration time (DT), and % SM released. The optimized FMT formula was selected based on the criteria of scoring the fastest DT and highest % SM released after 10 min (Q10). Optimized FMT was subjected to Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), and scanning electron microscopy (SEM) besides investigating its lung-protective efficacy. All SM-FMT tablets showed acceptable properties within the pharmacopeial standards. Optimized FMT (F7) scored a DT of 12.5 ± 0.64 Sec and % SM released at Q10 of 82.69 ± 2.88%. No incompatibilities were found between SM and excipients, it showed a porous structure under SEM. The optimized formula decreased cytokines, up-regulated miRNA133a, and down-regulated miRNA-155 and COX-2 involved in the protection against lung toxicity prompted by HgCl2 in a manner comparable to free SM at the same dosage.

Background: The optimal strategy for the treatment of recurrent and/or advanced endometrial cancer is still undefined. Recently, despite the lack of any predictive biomarker, the combination of pembrolizumab with lenvatinib has improved survival outcomes. We here report the long-term management of lung toxicity in a patient with endometrial cancer, and we critically review the current therapeutic options for this disease. Results: A patient with heavily pretreated endometrial cancer took pembrolizumab plus lenvatinib for 1 year, achieving a persistent partial response with a time to treatment failure of 18 months, despite relevant lung toxicity that did not affect the remarkable overall clinical benefit. A systematic review of this combination underlines the efficacy outcome despite toxicity. Interestingly, the literature review on lung toxicity suggested the role of antiangiogenetic agents in the pathogenesis of lung cavitation, probably related to direct treatment activity, and disclosed a potential radiological sign predictive of the activity of anti-angiogenetic agents. Conclusion: We underline the efficacy of pembrolizumab plus lenvatinib in the current treatment landscape of endometrial cancer, underscoring the relevance of a correct management of toxicity. [ABSTRACT FROM AUTHOR]

Objectives: Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK TKIs) have shown remarkable clinical activity in patients with non‐small‐cell lung cancer (NSCLC). However, pneumonitis is a serious side effect of ALK TKIs in NSCLC patients. In this meta‐analysis, we aimed to determine the incidence of ALK‐TKI‐associated pneumonitis. Materials and Methods: We searched electronic databases to identify relevant studies published until August 2022. The incidence of pneumonitis was calculated using a fixed‐effects model when no substantial heterogeneity was observed. Otherwise, a random‐effects model was used. Subgroup analyses of different treatment groups were performed. Statistical analyses were conducted using STATA 17.0. Results: Twenty‐six clinical trials involving 4752 patients were eligible for analysis. All‐grade pneumonitis incidence was 2.92% (95% confidence interval [CI]: 1.79%–4.27%), high‐grade (Grade 3–4) pneumonitis incidence was 1.42% (95% CI: 0.84%–2.12%) and Grade 5 pneumonitis incidence was 0.09% (95% CI: 0.00%–0.28%). The subgroup analysis showed that brigatinib was associated with the highest incidence of both all‐grade and high‐grade pneumonitis (7.09% and 3.06%, respectively). ALK TKI treatment after chemotherapy was associated with a higher incidence of all‐grade and high‐grade pneumonitis than first‐line ALK TKI treatment (7.73% vs. 2.26% and 3.64% vs. 1.26%, respectively). Cohorts from Japanese trials had a higher incidence of all‐grade and high‐grade pneumonitis. Conclusion: Our study provides precise data on the incidence of pneumonitis in patients receiving treatment with ALK TKIs. Overall, ALK TKIs have tolerable pulmonary toxicity. Early pneumonitis identification and treatment are required to prevent further deterioration in patients receiving treatment with brigatinib and in those who received prior chemotherapy, particularly in the Japanese population. [ABSTRACT FROM AUTHOR]

Introduction . Amiodarone is often used in the treatment of arrhythmias. Despite its undoubtedly excellent antiarrhythmic effect, its use can also causa serious adverse effects. This case report presents a patient who, after several months of treatment with amiodarone, developed severe pulmonary complications and transient liver injury. Despite discontinuation of the drug and implementation of optimal treatment aimed at harm reduction, a full resolution of the pulmonary lesions was not achieved. Objective . The aim of the report is to draw attention to the risks to the respiratory system associated with the use of amiodarone. It is worth noting that some symptoms of post-amiodarone lung damage may resemble the exacerbation of heart failure, which contributes to the delay of a correct diagnosis and prolongs the time to the start treatment.

BackgroundThe optimal strategy for the treatment of recurrent and/or advanced endometrial cancer is still undefined. Recently, despite the lack of any predictive biomarker, the combination of pembrolizumab with lenvatinib has improved survival outcomes. We here report the long-term management of lung toxicity in a patient with endometrial cancer, and we critically review the current therapeutic options for this disease.ResultsA patient with heavily pretreated endometrial cancer took pembrolizumab plus lenvatinib for 1 year, achieving a persistent partial response with a time to treatment failure of 18 months, despite relevant lung toxicity that did not affect the remarkable overall clinical benefit. A systematic review of this combination underlines the efficacy outcome despite toxicity. Interestingly, the literature review on lung toxicity suggested the role of anti-angiogenetic agents in the pathogenesis of lung cavitation, probably related to direct treatment activity, and disclosed a potential radiological sign predictive of the activity of anti-angiogenetic agents.ConclusionWe underline the efficacy of pembrolizumab plus lenvatinib in the current treatment landscape of endometrial cancer, underscoring the relevance of a correct management of toxicity.

E-cigarette consumption is under scrutiny by regulatory authorities due to concerns about product toxicity, lack of manufacturing standards, and increasing reports of e-cigarette- or vaping-associated acute lung injury. In vitro studies have demonstrated cytotoxicity, mitochondrial dysfunction, and oxidative stress induced by unflavored e-cigarette aerosols and flavoring additives. However, e-cigarette effects on the complex lung parenchyma remain unclear. Herein, the impact of e-cigarette condensates with or without menthol flavoring on functional, structural, and cellular responses was investigated using mouse precision cut lung slices (PCLS). PCLS were exposed to e-cigarette condensates prepared from aerosolized vehicle, nicotine, nicotine + menthol, and menthol e-fluids at doses from 50 to 500 mM. Doses were normalized to the glycerin content of vehicle. Video-microscopy of PCLS revealed impaired contractile responsiveness of airways to methacholine and dampened ciliary beating following exposure to menthol-containing condensates at concentrations greater than 300 mM. Following 500 mM menthol-containing condensate exposure, epithelial exfoliation in intrabronchial airways was identified in histological sections of PCLS. Measurement of lactate dehydrogenase release, mitochondrial water-soluble-tetrazolium salt-1 conversion, and glutathione content supported earlier findings of nicotine or nicotine + menthol e-cigarette-induced dose-dependent cytotoxicity and oxidative stress responses. Evaluation of PCLS metabolic activity revealed dose-related impairment of mitochondrial oxidative phosphorylation and glycolysis after exposure to menthol-containing condensates. Taken together, these data demonstrate prominent mentholinduced pulmonary toxicity and impairment of essential physiological functions in the lung, which warrants concerns about e-cigarette consumer safety and emphasizes the need for further investigations of molecular mechanisms of toxicity and menthol effects in an experimental model of disease. [ABSTRACT FROM AUTHOR]

Pollution from fine particulate matter (PM2.5) has become a major threat to public health and has been related to lung toxicity. One of the key regulators of the Hippo signaling system, Yes-associated protein 1 (YAP1), is speculated to play a role in ferroptosis development. Here, we focused on investigating the function of YAP1 in pyroptosis and ferroptosis, aiming to explore its therapeutic potential in PM2.5-induced lung toxicity. PM2.5-induced lung toxicity was induced in Wild-type WT and conditional YAP1-knockout mice, and lung epithelial cells were stimulatd by PM2.5 in vitro. We used western blot, transmission electron microscopy, and fluorescence microscopy to investigate pyroptosis- and ferroptosis-related characteristics. We found that PM2.5 leads to lung toxicity using mechanisms involving pyroptosis and ferroptosis. YAP1 knockdown impeded pyroptosis, ferroptosis, and PM2.5-induced lung damage, as shown by increased histopathology, higher levels of proinflammatory cytokines, GSDMD protein, lipid peroxidation, and iron accumulation, as well as increased NLRP3 inflammasome activation and decreased SLC7A11 expression. YAP1 silencing consistently promoted NLRP3 inflammasome activation and reduced SLC7A11 levels, aggravating PM2.5-induced cellular damage. In contrast, YAP1-overexpressing cells inhibited NLRP3 inflammasome activation and increased SLC7A11 levels, preventing pyroptosis and ferroptosis. Overall, our data suggest that YAP1 ameliorates PM2.5-induced lung injury by inhibiting NLRP3-mediated pyroptosis and SL7A11-dependent ferroptosis.

The present study aimed to develop fast melting tablets (FMTs) using silymarin (SM) owing to FMTs rapid disintegration and dissolution. FMTs represent a pathway to help patients to increase their compliance level of treatment via facile administration without water or chewing beside reduction cost. One of the methods for FMTs formulation is lyophilization. Optimization of SM-FMTs was developed via a 32 factorial design. All prepared SM-FMTs were evaluated for weight variation, thickness, breaking force, friability, content uniformity, disintegration time (DT), and % SM released. The optimized FMT formula was selected based on the criteria of scoring the fastest DT and highest % SM released after 10 min (Q10). Optimized FMT was subjected to Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), and scanning electron microscopy (SEM) besides investigating its lung-protective efficacy. All SM-FMT tablets showed acceptable properties within the pharmacopeial standards. Optimized FMT (F7) scored a DT of 12.5 ± 0.64 Sec and % SM released at Q10 of 82.69 ± 2.88%. No incompatibilities were found between SM and excipients, it showed a porous structure under SEM. The optimized formula decreased cytokines, up-regulated miRNA133a, and down-regulated miRNA-155 and COX-2 involved in the protection against lung toxicity prompted by HgCl2 in a manner comparable to free SM at the same dosage. [ABSTRACT FROM AUTHOR]

Ultrafine particulate matter with less than 2.5 μm diameter (PM2.5) is an air pollutant that causes severe lung damage. Currently, effective treatment and preventive methods for PM2.5-induced lung damage are limited. Cirsilineol (CSL) is a small natural compound isolated from Artemisia vestita. In this study, the efficacy of CSL on PM2.5-induced lung toxicity was tested, and its mechanism was identified. Lung injury was caused by intratracheal administration of PM2.5 suspension in animal models. Two days after PM2.5 pretreatment, CSL was injected via mouse tail vein for two days. The effects of CSL on PM2.5-induced lung damage, autophagy, apoptosis, and pulmonary inflammation in a mouse model and their mechanisms were investigated. CSL significantly suppressed histological lung damage and lung wet/dry weight proportion. CSL also significantly reduced PM2.5-induced autophagy dysfunction, apoptosis, lymphocyte suppression, and inflammatory cytokine levels in bronchoalveolar fluid (BALF). Furthermore, CSL increased mammalian target of rapamycin (mTOR) phosphorylation and significantly inhibited the expression of Toll-like receptors (TLR) 2 and 4, MyD88, and the autophagy proteins, Beclin1 and LC3II. Thus, CSL exerts protective effects on pulmonary damage by regulating mTOR and TLR2,4–myD88 autophagy pathways. Therefore, CSL can be used as an effective treatment for PM2.5-induced lung damage. [ABSTRACT FROM AUTHOR]

Intricate crosstalk among various lung cell types is crucial for orchestrating diverse physiological processes. Traditional two-dimensional and recent three-dimensional (3D) assay platforms fail to precisely replicate these complex communications. Many in vitro lung models do not effectively reflect the multicellular complexity of lung tissue. Here, we fabricated an advanced multicellular 3D lung-on-a-chip system that properly replicates the dynamic pulmonary microenvironment and its intricate microarchitecture. Diverse lung cells were incorporated into a microstructure formed from a mixture of natural polymers, including collagen and hyaluronic acid, and blood coagulation factors acting as natural crosslinking agents. The system accurately reflects the complex 3D architecture of the lung. Biomarkers demonstrate more rapid and sensitive responses to toxic substances than functional indicators, such as cell proliferation and apoptosis. SERPINB2 was identified as a biomarker of lung toxicity; it was activated in small airway epithelial cells exposed to various toxic substances. We then developed a fluorescence-linked toxicity biomarker screening platform that enables both intuitive and quantitative evaluation of lung toxicity by measuring the converted fluorescent signal strength. This fluorescent tagging system was incorporated into small airway epithelial cells within a fabricated chip platform; enabling lung-on-a-chip enabled evaluation of the lung toxicity of prospective drug candidates., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Although rare, taxane-induced interstitial pneumonitis is a well-recognized toxicity following chemotherapy. Data on taxane rechallenge in patients who developed taxane-induced interstitial pneumonitis following chemotherapy are limited. Here, we share our experience of acute interstitial pneumonitis following taxane chemotherapy for breast cancer and its clinical outcome following steroids and subsequent rechallenge with taxanes in selected patients without residual lung abnormalities on imaging following steroid treatment. Objectives: To study the taxane-induced acute interstitial pneumonitis in patients with breast cancer receiving chemotherapy and outcome of taxane rechallenge in these patients. Materials and Methods: Patients with breast cancer who developed taxane-induced acute interstitial pneumonitis following chemotherapy either with paclitaxel or docetaxel were included. Results: Among 1240 patients with breast cancer, who received chemotherapy with either docetaxel or paclitaxel, 41 patients developed taxane-induced acute interstitial lung disease (ILD) during the study period. The interstitial pneumonitis was more seen with docetaxel. Among paclitaxel regimens, weekly schedules showed more cases of ILD than 2 weekly paclitaxel. After steroid pulse/maintenance treatment, complete resolution of lung abnormalities was seen in 76%, but residual interstitial pattern on imaging was noted in 24% of patients. Taxane rechallenge was done in 20 (49%) patients. Agents used were paclitaxel, nab-paclitaxel, or docetaxel. All rechallenged patients received short-course oral steroids for one week following taxane rechallenge as a safety measure. Rechallenge was not done in 51% either due to patient unwillingness for rechallenge (27%) or patient with residual interstitial pattern on imaging (24%). None of the patients experienced any recurrence of pneumonitis or any mortality following taxane rechallenge. Conclusion: Acute interstitial pneumonitis is a well-known toxicity following taxanes in breast cancer and taxane rechallenge is an option in those patients without any residual pneumonitis following steroid pulse/maintenance. We also advise short-course oral steroids for 1 week following taxane rechallenge as a safety measure. We strongly do not recommend rechallenge in patients with residual lung abnormalities after steroids.

Abstract Background Open burning of anthropogenic sources can release hazardous emissions and has been associated with increased prevalence of cardiopulmonary health outcomes. Exposure to smoke emitted from burn pits in military bases has been linked with respiratory illness among military and civilian personnel returning from war zones. Although the composition of the materials being burned is well studied, the resulting chemistry and potential toxicity of the emissions are not. Methods Smoke emission condensates from either flaming or smoldering combustion of five different types of burn pit-related waste: cardboard; plywood; plastic; mixture; and mixture/diesel, were obtained from a laboratory-scale furnace coupled to a multistage cryotrap system. The primary emissions and smoke condensates were analyzed for a standardized suite of chemical species, and the condensates were studied for pulmonary toxicity in female CD-1 mice and mutagenic activity in Salmonella (Ames) mutagenicity assay using the frameshift strain TA98 and the base-substitution strain TA100 with and without metabolic activation (S9 from rat liver). Results Most of the particles in the smoke emitted from flaming and smoldering combustion were less than 2.5 µm in diameter. Burning of plastic containing wastes (plastic, mixture, or mixture/diesel) emitted larger amounts of particulate matter (PM) compared to other types of waste. On an equal mass basis, the smoke PM from flaming combustion of plastic containing wastes caused more inflammation and lung injury and was more mutagenic than other samples, and the biological responses were associated with elevated polycyclic aromatic hydrocarbon levels. Conclusions This study suggests that adverse health effects of burn pit smoke exposure vary depending on waste type and combustion temperature; however, burning plastic at high temperature was the most significant contributor to the toxicity outcomes. These findings will provide a better understanding of the complex chemical and combustion temperature factors that determine toxicity of burn pit smoke and its potential health risks at military bases.

Ga-68 labeled prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET/CT) is increasingly recognized as the best imaging modality for disease staging and detection of recurrent prostate cancer. Despite its name, PSMA expression has been reported in the neovasculature of several nonprostatic benign and malignant pathologies. Docetaxel, a taxane antineoplastic agent, is the mainstay of treatment in castration-resistant prostate cancer and high-volume hormone-sensitive prostate cancer. Although the occurrence of docetaxel-related interstitial lung disease is rare, it may lead to respiratory failure if treatment is delayed. We present a case of metastatic castration-resistant prostate cancer, wherein docetaxel-induced interstitial pneumonitis was detected on Ga-68 PSMA PET/CT after docetaxel administration. [ABSTRACT FROM AUTHOR]

Background and Objective: The study aims to evaluate the histopathological changes, enzymatic alterations, and DNA damage in rat lungs induced by whole-body gamma irradiation as well as evaluation of the protective effect of pycnogenol.Materials and Methods: A hundred adult male rats were equally divided into ten groups including control, four antioxidants, γ-irradiation, four antioxidant + γ-irradiations. This study began the day before radiation treatment and continued for 3 days. The pycnogenol was dissolved 5% dimethyl sulfoxide and then administered orally through a gastric tube at a dose of 37.5 mg/kg, 75 mg/kg, 150 mg/kg, and 300 mg/kg in 24, 48, and 72 h before irradiation. Irradiation was applied with a whole-body irradiation dose of 900 cGy in one fraction. DNA damage, histopathological changes, catalase (CAT), and superoxide dismutase (SOD) activities and malondialdehyde (MDA) levels in lung tissue of rats were evaluated 3 days after irradiation.Results: CAT and SOD activities were found to be significantly lower in the irradiation group than control (P < 0.001). CAT and SOD activities were higher in the antioxidant + γ-irradiation group than both irradiation and control groups. MDA levels were significantly higher in the irradiation group compared to control (P < 0.001), whereas MDA levels decreased in the antioxidant + γ-irradiation group compared to the irradiation group. The antioxidant groups were significantly increased comet parameters depend on pycnogenol doses compared to control. The antioxidant + γ-irradiation was decreased comet parameter compared to γ-irradiation. As a result of the histopathologically, the antioxidant groups were different than the control group that in the areas of alveolar sacs and connective tissue areas were seen hemorrhage areas similar to the irradiation group.Conclusion: We demonstrate that 300 mg/kg of pycnogenol might provide significant protection against deleterious effects from whole-body ionizing radiation on the lung tissue. P300+ γ-ray group was significantly reduced radiation-induced lung injury and was possible to observe significantly preservation. [ABSTRACT FROM AUTHOR]

Inhaled toxic chemicals and particulates are known to disrupt lung homeostasis causing pulmonary toxicity and tissue injury. However, biomarkers of such exposures and their underlying mechanisms are poorly understood, especially for emerging toxicants such as engineered nanoparticles and chemical threat agents such as chlorine gas (Cl2). Aquaporins (AQPs), commonly referred to as water channels, are known to play roles in lung homeostasis and pathophysiology. However, little is known on their regulation in toxicant-induced lung injuries. Here, we compared four lung toxicity models namely, acute chemical exposure (Cl2)-, chronic particulate exposure (carbon nanotubes/CNT)-, chronic chemical exposure (cigarette smoke extract/CSE)-, and a chronic co-exposure (CNT + CSE)- model, for modulation of lung aquaporins (AQPs 1, 3, 4, and 5) in relation to other pathophysiological endpoints. These included markers of compromised state of lung mucosal lining [mucin 5b (MUC5B) and surfactant protein A (SP-A)] and lung-blood barrier [protein content in bronchoalveolar lavage (BAL) fluid and, cell tight junction proteins occludin and zona-occludens]. The results showed toxicity model-specific regulation of AQPs measured in terms of mRNA abundance. A differential upregulation was observed for AQP1 in acute Cl2 exposure model (14.71-fold; p = 0.002) and AQP3 in chronic CNT exposure model (3.83-fold; p = 0.044). In contrast, AQP4 was downregulated in chronic CSE model whereas AQP5 showed no significant change in any of the models. SP-A and MUC5B expression showed a decreasing pattern across all toxicity models except the acute Cl2 toxicity model, which showed a highly significant upregulation of MUC5B (25.95-fold; p = 0.003). This was consistent with other significant pathophysiological changes observed in this acute model, particularly a compromised lung epithelial-endothelial barrier indicated by significantly increased protein infiltration and expression of tight junction proteins, and more severe histopathological (structural and immunological) changes. To our knowledge, this is the first report on lung AQPs as molecular targets of the study toxicants. The differentially regulated AQPs, AQP1 in acute Cl2 exposure versus AQP3 in chronic CNT nanoparticle exposure, in conjunction with the corresponding differentially impacted pathophysiological endpoints (particularly MUC5B) could potentially serve as predictive markers of toxicant type-specific pulmonary injury and as candidates for future investigation for clinical intervention. [ABSTRACT FROM AUTHOR]

BackgroundThe wide application of engineered nanoparticles has induced increasing exposure to humans and environment, which led to substantial concerns on their biosafety. Some metal oxides (MOx) have shown severe toxicity in cells and animals, thus safe designs of MOx with reduced hazard potential are desired. Currently, there is a lack of a simple yet effective safe design approach for the toxic MOx. In this study, we determined the key physicochemical properties of MOx that lead to cytotoxicity and explored a safe design approach for toxic MOx by modifying their hazard properties.ResultsTHP-1 and BEAS-2B cells were exposed to 0-200 μg/mL MOx for 24 h, we found some toxic MOx including CoO, CuO, Ni2O3 and Co3O4, could induce reactive oxygen species (ROS) generation and cell death due to the toxic ion shedding and/or oxidative stress generation from the active surface of MOx internalized into lysosomes. We thus hypothesized that surface passivation could reduce or eliminate the toxicity of MOx. We experimented with a series of surface coating molecules and discovered that ethylenediamine tetra (methylene phosphonic acid) (EDTMP) could form stable hexadentate coordination with MOx. The coating layer can effectively reduce the surface activity of MOx with 85-99% decrease of oxidative potential, and 65-98% decrease of ion shedding. The EDTMP coated MOx show negligible ROS generation and cell death in THP-1 and BEAS-2B cells. The protective effect of EDTMP coating was further validated in mouse lungs exposed to 2 mg/kg MOx by oropharyngeal aspiration. After 40 h exposure, EDTMP coated MOx show significant decreases of neutrophil counts, lactate dehydrogenase (LDH) release, MCP-1, LIX and IL-6 in bronchoalveolar lavage fluid (BALF), compared to uncoated particles. The haematoxylin and eosin (H&E) staining results of lung tissue also show EDTMP coating could significantly reduce the pulmonary inflammation of MOx.ConclusionsThe surface reactivity of MOx including ion shedding and oxidative potential is the dominated physicochemical property that is responsible for the cytotoxicity induced by MOx. EDTMP coating could passivate the surface of MOx, reduce their cytotoxicity and pulmonary hazard effects. This coating would be an effective safe design approach for a broad spectrum of toxic MOx, which will facilitate the safe use of MOx in commercial nanoproducts.

Inhaled toxic chemicals and particulates are known to disrupt lung homeostasis causing pulmonary toxicity and tissue injury. However, biomarkers of such exposures and their underlying mechanisms are poorly understood, especially for emerging toxicants such as engineered nanoparticles and chemical threat agents such as chlorine gas (Cl2). Aquaporins (AQPs), commonly referred to as water channels, are known to play roles in lung homeostasis and pathophysiology. However, little is known on their regulation in toxicant-induced lung injuries. Here, we compared four lung toxicity models namely, acute chemical exposure (Cl2)-, chronic particulate exposure (carbon nanotubes/CNT)-, chronic chemical exposure (cigarette smoke extract/CSE)-, and a chronic co-exposure (CNT + CSE)- model, for modulation of lung aquaporins (AQPs 1, 3, 4, and 5) in relation to other pathophysiological endpoints. These included markers of compromised state of lung mucosal lining [mucin 5b (MUC5B) and surfactant protein A (SP-A)] and lung-blood barrier [protein content in bronchoalveolar lavage (BAL) fluid and, cell tight junction proteins occludin and zona-occludens]. The results showed toxicity model-specific regulation of AQPs measured in terms of mRNA abundance. A differential upregulation was observed for AQP1 in acute Cl2 exposure model (14.71-fold; p = 0.002) and AQP3 in chronic CNT exposure model (3.83-fold; p = 0.044). In contrast, AQP4 was downregulated in chronic CSE model whereas AQP5 showed no significant change in any of the models. SP-A and MUC5B expression showed a decreasing pattern across all toxicity models except the acute Cl2 toxicity model, which showed a highly significant upregulation of MUC5B (25.95-fold; p = 0.003). This was consistent with other significant pathophysiological changes observed in this acute model, particularly a compromised lung epithelial-endothelial barrier indicated by significantly increased protein infiltration and expression of tight junction proteins, and more severe histopathological (structural and immunological) changes. To our knowledge, this is the first report on lung AQPs as molecular targets of the study toxicants. The differentially regulated AQPs, AQP1 in acute Cl2 exposure versus AQP3 in chronic CNT nanoparticle exposure, in conjunction with the corresponding differentially impacted pathophysiological endpoints (particularly MUC5B) could potentially serve as predictive markers of toxicant type-specific pulmonary injury and as candidates for future investigation for clinical intervention.

The toxicity of silica nanoparticles (SiNPs) to lung is known. We previously demonstrated that exposure to SiNPs promoted pulmonary impairments, but the precise pathogenesis remains elucidated. Ferroptosis has now been identified as a unique form of oxidative cell death, but whether it participated in SiNPs-induced lung injury remains unclear. In this work, we established a rat model with sub-chronic inhalation exposure of SiNPs via intratracheal instillation, and conducted histopathological examination, iron detection, and ferroptosis-related lipid peroxidation and protein assays. Moreover, we evaluated the effect of SiNPs on epithelial ferroptosis, possible mechanisms using in vitro -cultured human bronchial epithelial cells (16HBE), and also assessed the ensuing impact on fibroblast activation for fibrogenesis. Consequently, fibrotic lesions occurred in the rat lungs, concomitantly by enhanced lipid peroxidation, iron overload, and ferroptosis. Consistently, the in vitro data showed SiNPs triggered oxidative stress and caused the accumulation of lipid peroxides, resulting in ferroptosis. Importantly, the mechanistic investigation revealed miR-21-5p as a key player in the epithelial ferroptotic process induced by SiNPs via targeting GCLM for GSH depletion. Of note, ferrostatin-1 could greatly suppress ferroptosis and alleviate epithelial injury and ensuing fibroblast activation by SiNPs. In conclusion, our findings first revealed SiNPs triggered epithelial ferroptosis through miR-21-5p/GCLM signaling and thereby promoted fibroblast activation for fibrotic lesions, and highlighted the therapeutic potential of inhibiting ferroptosis against lung impairments upon SiNPs exposure. [Display omitted] • Ferroptosis is discovered to be a new form of cell death upon SiNPs exposure. • miR-21-5p was a key player in epithelial ferroptosis by SiNPs via targeting GCLM. • SiNPs-elicited epithelial ferroptosis promoted fibroblast activation. • Anti-ferroptosis strategies maybe a promising strategy for fibrotic lung diseases. [ABSTRACT FROM AUTHOR]

Cyclophosphamide is an anti-neoplastic drug that has shown competence in the management of a broad range of malignant tumors. In addition, it represents a keystone agent for management of immunological conditions. Despite these unique properties, induction of lung toxicity may limit its clinical use. Omarigliptin is one of the dipeptidyl peptidase-4 inhibitors that has proven efficacy in management of diabetes mellitus. Rosinidin is an anthocyanidin flavonoid that exhibited promising results in management of diseases characterized by oxidative stress, inflammation, and apoptosis. The present work investigated the possible effects of omarigliptin with or without rosinidin on cyclophosphamide-induced lung toxicity with an exploration of the molecular mechanisms that contribute to these effects. In a rodent model of cyclophosphamide elicited lung toxicity, the potential efficacy of omarigliptin with or without rosinidin was investigated at both the biochemical and the histopathological levels. Both omarigliptin and rosinidin exhibited a synergistic ability to augment the tissue antioxidant defenses, mitigate the inflammatory pathways, restore glucagon-like peptide-1 levels, modulate high mobility group box 1 (HMGB1)/receptors of advanced glycation end products (RAGE)/nuclear factor kappa B (NF-κB) axis, downregulate the fibrogenic mediators, and create a balance between the pathways involved in apoptosis and the autophagy signals in the pulmonary tissues. In conclusion, omarigliptin/rosinidin combination may be introduced as a novel therapeutic modality that attenuates the different forms of lung toxicities induced by cyclophosphamide. [Display omitted] • The effects of omarigliptin &/or rosinidin on CPA-lung toxicity were investigated. • Omarigliptin &/or rosinidin restored the antioxidant defenses in the lung tissues. • Omarigliptin &/or rosinidin mitigated inflammation & fibrosis in the lung tissues. • Omarigliptin &/or rosinidin restored autophagy/apoptosis balance in the lung. • Omarigliptin/rosinidin combination was better than each of these agents alone. [ABSTRACT FROM AUTHOR]

Nanomaterials (NMs) solve specific problems with remarkable results in several industrial and scientific areas. Among NMs, silver nanoparticles (AgNPs) have been extensively employed as drug carriers, medical diagnostics, energy harvesting devices, sensors, lubricants, and bioremediation. Notably, they have shown excellent antimicrobial, anticancer, and antiviral properties in the biomedical field. The literature analysis shows a selective cytotoxic effect on cancer cells compared to healthy cells, making its potential application in cancer treatment evident, increasing the need to study the potential risk of their use to environmental and human health. A large battery of toxicity models, both in vitro and in vivo, have been established to predict the harmful effects of incorporating AgNPs in these numerous areas or those produced due to involuntary exposure. However, these models often report contradictory results due to their lack of standardization, generating controversy and slowing the advances in nanotoxicology research, fundamentally by generalizing the biological response produced by the AgNP formulations. This review summarizes the last ten years' reports concerning AgNPs' toxicity in cellular respiratory system models (e.g., mono-culture models, co-cultures, 3D cultures, ex vivo and in vivo). In turn, more complex cellular models represent in a better way the physical and chemical barriers of the body; however, results should be used carefully so as not to be misleading. The main objective of this work is to highlight current models with the highest physiological relevance, identifying the opportunity areas of lung nanotoxicology and contributing to the establishment and strengthening of specific regulations regarding health and the environment. [ABSTRACT FROM AUTHOR]

Introduction. Amiodarone is often used in the treatment of arrhythmias. Despite its undoubtedly excellent antiarrhythmic effect, its use can also causa serious adverse effects. This case report presents a patient who, after several months of treatment with amiodarone, developed severe pulmonary complications and transient liver injury. Despite discontinuation of the drug and implementation of optimal treatment aimed at harm reduction, a full resolution of the pulmonary lesions was not achieved. Objective. The aim of the report is to draw attention to the risks to the respiratory system associated with the use of amiodarone. It is worth noting that some symptoms of post-amiodarone lung damage may resemble the exacerbation of heart failure, which contributes to the delay of a correct diagnosis and prolongs the time to the start treatment. [ABSTRACT FROM AUTHOR]

Radiation-induced lung injury (RILI) that is usually divided into an early radiation-induced pneumonitis (RIP) and late chronic radiation-induced lung fibrosis (RILF) remains a clinically significant toxicity in radiation oncology. Thus, a thorough understanding of underlying molecular mechanisms and risk factors is crucial. This review, focused on patients treated with modern radiotherapy (RT ) techniques, describes the different clinical presentations of RIP, with most typical imaging findings and usefulness of pulmonary function tests and laboratory assessment in differential diagnosis. The most critical patient- and treatment- related predictors are summarized and discussed — age and sex, comorbidities, tumour characteristics, concomitant treatment, and RT -plan parameters. The conventional grading scales and contemporary approach to quantitative assessment (radiomics, CT density changes) is described as well as treatment methods. [ABSTRACT FROM AUTHOR]

Objective: To study the regulatory relationship between ozone-induced mitophagy and pyroptosis in lung epithelial cells. Results: First, type I primary alveolar epithelial cells and male Wistar rats were treated with ozone at different dosages. The ATP content and mitochondrial membrane potential significantly decreased in type I primary alveolar epithelial cells. The mitophagy-related markers and PINK1/Parkin pathway-related proteins, and the co-localization of LC3, Parkin, and mitochondria in type I alveolar epithelial cells indicated that ozone exposure triggered mitophagy. On the other hand, the reactive oxygen species (ROS) inhibitor NAC could significantly alleviate mitophagy in epithelial cells. After treatment with the mitophagy inhibitor MDIVI-1, the levels of the NLRP3 inflammasome, cleaved caspase-1, and N-gasdermin D (N-GSDMD) significantly decreased in the cells. Altogether, these results indicated that mitophagy can be triggered by ozone exposure, and subsequently induces cell death mediated by the NLRP3 inflammasome. Finally, the overexpression and knockdown of NLRP3 confirmed this conclusion. Conclusion: Ozone exposure induced oxidative damage, leading to mitochondrial structural and functional damage. Ozone-induced ROS triggered mitophagy through the activation of the PINK1/Parkin signaling pathway, then pyroptosis through activation of the NLRP3 inflammasome.

The electronic properties of single-walled carbon nanotubes (SWCNTs) are potentially useful for electronics, optics, and sensing applications. Depending on the chirality and diameter, individual SWCNTs can be classified as semiconducting (S-SWCNT) or metallic (M-SWCNT). From a biological perspective, the hazard profiling of purified metallic versus semiconducting SWCNTs has been pursued only in bacteria, with the conclusion that aggregated M-SWCNTs are more damaging to bacterial membranes than S-SWCNTs. However, no comparative studies have been performed in a mammalian system, where most toxicity studies have been undertaken using relatively crude SWCNTs that include a M:S mix at 1:2 ratio. In order to compare the toxicological impact of SWCNTs sorted to enrich them for each of the chirality on pulmonary cells and the intact lung, we used density gradient ultracentrifugation and extensive rinsing to prepare S- and M-SWCNTs that are >98% purified. In vitro screening showed that both tube variants trigger similar amounts of interleukin 1β (IL-1β) and transforming growth factor (TGF-β1) production in THP-1 and BEAS-2B cells, without cytotoxicity. Oropharyngeal aspiration confirmed that both SWCNT variants induce comparable fibrotic effects in the lung and abundance of IL-1β and TGF-β1 release in the bronchoalveolar lavage fluid. There was also no change in the morphology, membrane integrity, and viability of E. coli, in contradistinction to the previously published effects of aggregated tubes on the bacterial membrane. Collectively, these data indicate that the electronic properties and chirality do not independently impact SWCNT toxicological impact in the lung, which is of significance to the safety assessment and incremental use of purified tubes by industry.

Background: Although rare, taxane-induced interstitial pneumonitis is a well-recognized toxicity following chemotherapy. Data on taxane rechallenge in patients who developed taxane-induced interstitial pneumonitis following chemotherapy are limited. Here, we share our experience of acute interstitial pneumonitis following taxane chemotherapy for breast cancer and its clinical outcome following steroids and subsequent rechallenge with taxanes in selected patients without residual lung abnormalities on imaging following steroid treatment. Objectives: To study the taxane-induced acute interstitial pneumonitis in patients with breast cancer receiving chemotherapy and outcome of taxane rechallenge in these patients. Materials and Methods: Patients with breast cancer who developed taxane-induced acute interstitial pneumonitis following chemotherapy either with paclitaxel or docetaxel were included. Results: Among 1240 patients with breast cancer, who received chemotherapy with either docetaxel or paclitaxel, 41 patients developed taxane-induced acute interstitial lung disease (ILD) during the study period. The interstitial pneumonitis was more seen with docetaxel. Among paclitaxel regimens, weekly schedules showed more cases of ILD than 2 weekly paclitaxel. After steroid pulse/maintenance treatment, complete resolution of lung abnormalities was seen in 76%, but residual interstitial pattern on imaging was noted in 24% of patients. Taxane rechallenge was done in 20 (49%) patients. Agents used were paclitaxel, nab-paclitaxel, or docetaxel. All rechallenged patients received short-course oral steroids for one week following taxane rechallenge as a safety measure. Rechallenge was not done in 51% either due to patient unwillingness for rechallenge (27%) or patient with residual interstitial pattern on imaging (24%). None of the patients experienced any recurrence of pneumonitis or any mortality following taxane rechallenge. Conclusion: Acute interstitial pneumonitis is a well-known toxicity following taxanes in breast cancer and taxane rechallenge is an option in those patients without any residual pneumonitis following steroid pulse/maintenance. We also advise short-course oral steroids for 1 week following taxane rechallenge as a safety measure. We strongly do not recommend rechallenge in patients with residual lung abnormalities after steroids. [ABSTRACT FROM AUTHOR]

Abstract Background Stereotactic body radiotherapy (SBRT) is the standard care for inoperable early stage non‐small cell lung cancer (NSCLC). The purpose of our study was to investigate whether a prediction model based on cone‐beam CT (CBCT) plus pretreatment CT radiomics features could improve the prediction of tumor control and lung toxicity after SBRT in comparison to a model based on pretreatment CT radiomics features alone. Methods A total of 34 cases of stage I NSCLC patients who received SBRT were included in the study. The pretreatment planning CT and serial CBCT radiomics features were analyzed using the imaging biomarker explorer (IBEX) software platform. Multivariate logistic regression was conducted for the association between progression‐free survival (PFS), lung toxicity and features. The predictive capabilities of the models based on CBCT and CT features were compared using receiver operating characteristic (ROC) curves. Results Five CBCT features and two planning CT features were correlated with disease progression. Six CBCT features and two planning CT features were related to lung injury. The ROC curves indicated that the model based on the CBCT plus planning CT features might be better than the model based on the planning CT features in predicting lung injury. The other ROC curves indicated that the model based on the planning CT features was similar to the model based on the CBCT plus planning CT features in predicting disease progression. Conclusions Both pretreatment CT and CBCT radiomics features could predict disease progression and lung injury. A model with CBCT plus pretreatment CT radiomics features might improve the prediction of lung toxicity in comparison with a model with pretreatment CT features alone. Key points Significant findings of the study: A model with cone‐beam CT radiomics features plus pre‐treatment CT radiomics features might improve the prediction of lung toxicity after SBRT in stage I NSCLC patients. What this study adds: In the prediction of PFS and lung toxicity in early‐stage NSCLC patients treated with SBRT, CBCT radiomics could be another effective method.

Background: Open burning of anthropogenic sources can release hazardous emissions and has been associated with increased prevalence of cardiopulmonary health outcomes. Exposure to smoke emitted from burn pits in military bases has been linked with respiratory illness among military and civilian personnel returning from war zones. Although the composition of the materials being burned is well studied, the resulting chemistry and potential toxicity of the emissions are not. Methods: Smoke emission condensates from either flaming or smoldering combustion of five different types of burn pit-related waste: cardboard; plywood; plastic; mixture; and mixture/diesel, were obtained from a laboratory-scale furnace coupled to a multistage cryotrap system. The primary emissions and smoke condensates were analyzed for a standardized suite of chemical species, and the condensates were studied for pulmonary toxicity in female CD-1 mice and mutagenic activity in Salmonella (Ames) mutagenicity assay using the frameshift strain TA98 and the base-substitution strain TA100 with and without metabolic activation (S9 from rat liver). Results: Most of the particles in the smoke emitted from flaming and smoldering combustion were less than 2.5 µm in diameter. Burning of plastic containing wastes (plastic, mixture, or mixture/diesel) emitted larger amounts of particulate matter (PM) compared to other types of waste. On an equal mass basis, the smoke PM from flaming combustion of plastic containing wastes caused more inflammation and lung injury and was more mutagenic than other samples, and the biological responses were associated with elevated polycyclic aromatic hydrocarbon levels. Conclusions: This study suggests that adverse health effects of burn pit smoke exposure vary depending on waste type and combustion temperature; however, burning plastic at high temperature was the most significant contributor to the toxicity outcomes. These findings will provide a better understanding of the complex chemical and combustion temperature factors that determine toxicity of burn pit smoke and its potential health risks at military bases. [ABSTRACT FROM AUTHOR]

Background: Exposure to ambient air-borne fine particulate matter (PM2.5) increases respiratory morbidity and mortality. The mechanisms underlying PM2.5-induced adverse effects remain unclear. This study aimed to uncover the molecular mechanisms of PM2.5-induced lung toxicity using a mouse model. Methods: Scanning electron microscopy and inductively coupled plasma mass spectrometry were used to examine and analyze PM2.5 morphology and element compositions, respectively. Twenty four male mice were randomly divided into three groups: control (PBS), PM2.5 (4.0 mg/kg b.w.), and PM2.5 + Z-YVAD-FMK. In the latter group, the pan-caspase inhibitor (Z-YVAD-FMK) was intraperitoneally injected into mice at a dose of 12.5 mg/kg body weight prior to intratracheal instillation of PM2.5 (4.0 mg/kg b.w.) every other day for a total of 3 times (n = 8 in each group). Bronchoalveolar lavage fluids (BALFs) were collected 24 h after the last instillation of PM2.5. Levels of total proteins (TP), lactate dehydrogenase (LDH), IL-1β and IL-18 were analyzed for biomarkers of cell injury and inflammation. Additionally, histological alterations of lung tissues were assessed by hematoxylin-eosin staining. mRNA and protein expression of Caspase1, NLRP3 and GSDMD were examined by real-time fluorescent quantitative PCR and immunohistochemical staining. Results: Exposure to PM2.5 increased levels of TP, LDH, IL-1β, IL-18 and inflammatory cell counts in lung. The mRNA and protein expression of Caspase1, NLRP3 and GSDMD were increased. Inhibition of the NALRP3/Caspase-1 signaling pathway ameliorated PM2.5-induced lung injury and inflammation, partially through suppressing pyroptosis in lung. Conclusion: PM2.5 exposure induces lung injury and inflammation, which is mediated by the NALRP3/Caspase-1 signaling pathway.

Cigarettes and other tobacco products are used to obtain nicotine that is responsible for their stimulating effects. However, a lot of other organic and inorganic chemicals are also released along with nicotine. Cadmium (Cd) is one of the several heavy metals that are health hazards and is one of the inorganic elements released in tobacco smoke. The in-vitro investigation focused on exploring the effects of nicotine hydrogen tartrate (NHT) and cadmium (Cd) and their toxic interactions in the A549 cell line. In cell viability assay NHT exhibited its IC 50 at 11.71 mM concentration, and the IC 50 of Cd was found to be 83 µM after a 24 h exposure. Toxic effects of NHT (5 mM and 10 mM), Cd (50 µM and 100 µM), and their combination were also investigated by flowcytometry. The investigation included apoptotic and necrotic events, the effect on different cell cycle phases, and generation of reactive oxygen species by NHT, Cd, and their combination of different concentrations. Data reveal evident toxic effects of NHT, Cd, and NHT + Cd. It also indicates that the toxic interaction of NHT and Cd is not additive and appears to be minimal when compared with NHT or Cd exposures alone. [ABSTRACT FROM AUTHOR]

Bleomycin-induced lung injury manifesting after chemotherapy in patients with Hodgkin's disease is a known fatal entity. The histological picture encompasses from alveolar haemorrhage to diffuse alveolar damage, and the clinical picture is similar to that of interstitial pneumonitis. Radiologically, it is a spectrum of ground-glass opacities and infiltrates to finally consolidation and later fibrosis. This patient presented with atypical radiological sequelae of pneumomediastinum and extensive subcutaneous emphysema. The patient was managed in the intensive care unit with an intercostal drain, mechanical ventilation and vasopressor support. After a week, the intercostal drain was removed, and the patient was weaned off the ventilatory support. The patient was subsequently tracheostomised and shifted to the general ward. This case throws light on the rare radiological pattern of bleomycin-induced lung toxicity that can complicate the management of such patients.

Helei Hou,* Dantong Sun,* Kewei Liu, Man Jiang, Dong Liu, Jingjuan Zhu, Na Zhou, Jing Cong, Xiaochun ZhangDepartment of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workBackground: A total of 2%–7% of non-small cell lung cancer (NSCLC) patients have anaplastic lymphoma kinase (ALK) mutations. At present, three or more generations of ALK inhibitors have been used for ALK-positive NSCLC treatment, including crizotinib, alectinib, ceritinib, and brigatinib. Although most adverse events (AEs) of ALK inhibitors are grades 1 to 2 and generally can be well tolerated, serious adverse events (SAEs) of ALK inhibitors lack data analysis, and the lung toxicity of ALK inhibitors needs attention. Thus, we performed this meta-analysis to evaluate the safety of ALK inhibitors, especially in terms of drug-related SAEs.Methods: A total of 19 studies from 4 databases (PubMed, Science Direct, ClinicalTrials.gov and Cochrane Library) were included in this meta-analysis. All statistical analyses in this meta-analysis were performed with the STATA 14.0 software. We analyzed the incidences of total AEs, total SAEs and SAEs for different ALK inhibitors.Results: AEs of the ALK inhibitors occurred in almost all participants, and SAEs occurred in more than 20% of the participants. For ceritinib and brigatinib, SAEs occurred in more than 40% of the participants. Alectinib is most likely the safest of the two generations of ALK inhibitors. Generally, the ALK inhibitors showed significant lung toxicity.Conclusion: In conclusion, attention should be focused on ALK inhibitor-related SAEs, especially lung toxicity. According to this meta-analysis, alxectinib seems to be the safest ALK inhibitor. Physicians should focus on the related SAEs when prescribing ALK inhibitors.Keywords: ALK inhibitors, safety, serious adverse events, lung toxicity

Abstract Background Exposure to fine particulate matter (PM2.5) has been associated with respiratory morbidity and mortality. Identification of interventional measures that are efficacious against PM2.5-induced toxicity may provide public health benefits. This study examined the inhibitory effects of nutritional supplementation with fish oil as a source of omega-3 fatty acids and vitamin E (Vit E) on PM2.5-induced lung toxicity in rats. Method Sixty four male Sprague Dawley rats were gavaged with phosphate buffered saline (PBS), corn oil (5 ml/kg), fish oil (150 mg/kg), or Vit E (75 mg/kg), respectively, once a day for 21 consecutive days prior to intratracheal instillation of PM2.5 (10 mg/kg) every other day for a total of 3 times. Serum and bronchoalveolar lavage fluids (BALFs) were collected 24 h after the last instillation of PM2.5. Levels of total proteins (TP), lactate dehydrogenase (LDH), superoxide dismutase (SOD), 8-epi-prostaglandin F2α (8-epi-PGF2α), interleukin-1β (IL-1β), C-reactive protein (CRP), IL-6, and tumor necrosis factor-ɑ (TNF-ɑ) were analyzed for markers of cell injury and inflammation. Additionally, histological alterations of lung tissues were examined by hematoxylin-eosin staining. Result Exposure to PM2.5 resulted in lung toxicity, represented as increased levels of total proteins, LDH, 8-epi-PGF2α, IL-1β and TNF-α, and increased infiltration of inflammatory cells, and decreased SOD in the BALFs, and systemic inflammation, as evinced by increased levels of CRP and IL-6 in serum. Strikingly, supplementation with fish oil but not Vit E significantly ameliorated PM2.5-induced lung toxicity and systemic inflammation. Conclusion PM2.5 exposure induces oxidative stress, lung injury and inflammation, which is ameliorated significantly by fish oil and partially by Vit E.

The primary objective is to evaluate the potential dosimetric gains of performing functional avoidance‐based proton treatment planning using 4DCT derived ventilation imaging. 4DCT data of 31 patients from a prospective functional avoidance clinical trial were evaluated with intensity modulated proton therapy (IMPT) plans and compared with clinical volumetric modulated arc therapy (VMAT) plans. Dosimetric parameters were compared between standard and functional plans with IMPT and VMAT with one‐way analysis of variance and post hoc paired student t‐test. Normal Tissue Complication Probability (NTCP) models were employed to estimate the risk of two toxicity endpoints for healthy lung tissues. Dose degradation due to proton motion interplay effect was evaluated. Functional IMPT plans led to significant dose reduction to functional lung structures when compared with functional VMAT without significant dose increase to Organ at Risk (OAR) structures. When interplay effect is considered, no significant dose degradation was observed for the OARs or the clinical target volume (CTV) volumes for functional IMPT. Using fV20 as the dose metric and Grade 2+ pneumonitis as toxicity endpoint, there is a mean 5.7% reduction in Grade 2+ RP with the functional IMPT and as high as 26% in reduction for individual patient when compared to the standard IMPT planning. Functional IMPT was able to spare healthy lung tissue to avoid excess dose to normal structures while maintaining satisfying target coverage. NTCP calculation also shows that the risk of pulmonary complications can be further reduced with functional based IMPT. [ABSTRACT FROM AUTHOR]

Cyclophosphamide (CYL) is a chemotherapeutic medication commonly used in managing various malignancies like breast cancer or leukemia. Though, CYL has been documented to induce lung toxicity. Mechanism of CYL toxicity is through oxidative stress and the release of damage-associated molecular patterns (DAMPs). Sesamol (SES) is a natural antioxidant isolated from Sesamum indicum and its effect against CYL-induced lung toxicity is not studied yet. This study aims to investigate whether SES could prevent any deleterious effects induced by CYL on lung using normal human lung cells, WI-38 cell line, without suppressing its efficacy. Cells were pretreated with SES and/or CYL for 24 h, then cell viability was estimated by MTS and trypan blue assays. The mode of cell death was determined by AO/EB staining. Additionally, caspase-3 level, oxidative stress, and inflammatory markers were evaluated by colorimetric and ELISA techniques. qRT-PCR was performed to evaluate RAGE, NF-κB, and Beclin-1 mRNA-expression. CYL-treated WI-38 cells developed a significantly increased cell death with enhanced oxidative and RAGE/NF-κb/Autophagy signaling, which were all attenuated after pretreatment with SES. Thus, we concluded that SES offered a protective role against CYL-induced lung injury via suppressing oxidative stress and RAGE/NF-κB/Autophagy signaling, which is a natural safe therapeutic option against CYL toxicities. [ABSTRACT FROM AUTHOR]

Background Numerous studies have investigated the relationship of environmental exposure, epigenetic effects, and human diseases. These linkages may contribute to the potential toxicity mechanisms of environmental chemicals. Here, we investigated the epigenetic pulmonary response of hexanal, a major indoor irritant, following inhalation exposure in F-344 rats. Methods Based on DNA methylation profiling in gene promoter regions, we identified hexanal-characterized methylated sites and target genes using an unpaired t-test with a fold-change cutoff of ≥ 3.0 and a p-value < 0.05. We also conducted an integrated analysis of DNA methylation and mRNA expression data to identify core anti-correlated target genes of hexanal exposure. To further investigate the potential key biological processes and pathways of core DNA methylated target genes, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. Results Thirty-six dose-dependent methylated genes and anti-correlated target genes of DNA methylation and mRNA in lung tissue of hexanal exposed F-344 rats were identified. These genes were involved in diverse biological processes such as neuroactive ligand-receptor interaction, protein kinase cascade, and intracellular signaling cascade associated with pulmonary toxicity. These results suggest that novel DNA methylation-based epigenetic biomarkers of exposure to hexanal and elucidate the potential pulmonary toxicological mechanisms of action of hexanal.

Carbon fibers have excellent physicochemical and electrical properties. Vapor-grown carbon fibers are a type of carbon fibers that have a multi-walled carbon tube structure with a high aspect ratio. The representative vapor-grown carbon fiber, VGCFTMH, is extremely strong and stable and has superior thermal and electrical conductivity. Because some high-aspect-ratio multi-walled carbon nanotubes (MWCNTs) have been reported to have toxic and carcinogenic effects in the lungs of rodents, we performed a 13-week lung toxicity study using VGCFTM-H in comparison with one of MWCNTs, MWNT-7, in rats. Male and female F344 rats were intratracheally administered VGCFTM-H at doses of 0.2, 0.4, and 0.8 mg/kg bw or MWNT-7 at doses of 0.4 and 0.8 mg/kg bw once a week for 8 weeks and then up to week 13 without treatment. The lung burden was equivalent in the VGCFTM-H and MWNT-7 groups; however, the lung weight had increased and the inflammatory and biochemical parameters in the broncho-alveolar lavage fluid and histopathological parameters, including inflammatory cell infiltration, alveolar type II cells proliferation, alveolar fibrosis, pleural fibrosis, lung mesothelium proliferation, and diaphragm fibrosis, were milder in the VGCFTM-H group than in the MWNT-7 group. In addition, the proliferating cell nuclear antigen (PCNA)-positive index in the visceral and pleural mesothelium was significantly higher in the MWNT-7 group than in the controls, but not in the VGCFTM-H group. Thus, the results of this study indicate that the lung and pleural toxicities of VGCFTM-H were less than those of MWNT-7. [ABSTRACT FROM AUTHOR]