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Toxicology Reports 2015Bronchiolitis obliterans (BO) is a rare disease involving concentric bronchiolar fibrosis that develops rapidly following inhalation of certain irritant gases at... (Review)
Review
Bronchiolitis obliterans (BO) is a rare disease involving concentric bronchiolar fibrosis that develops rapidly following inhalation of certain irritant gases at sufficiently high acute doses. While there are many potential causes of bronchiolar lesions involved in a variety of chronic lung diseases, failure to clearly define the clinical features and pathological characteristics can lead to ambiguous diagnoses. Irritant gases known to cause BO follow a similar pathologic process and time course of disease onset in humans. Studies of inhaled irritant gases known to cause BO (e.g., chlorine, hydrochloric acid, ammonia, nitrogen oxides, sulfur oxides, sulfur or nitrogen mustards, and phosgene) indicate that the time course between causal chemical exposures and development of clinically significant BO disease is typically limited to a few months. The mechanism of toxic action exerted by these irritant gases generally involves widespread and severe injury of the epithelial lining of the bronchioles that leads to acute respiratory symptoms which can include lung edema within days. Repeated exposures to inhaled irritant gases at concentrations insufficient to cause marked respiratory distress or edema may lead to adaptive responses that can reduce or prevent severe bronchiolar fibrotic changes. Risk of BO from irritant gases is driven substantially by toxicokinetics affecting concentrations occurring at the bronchiolar epithelium. Highly soluble irritant gases that cause BO like ammonia generally follow a threshold-dependent cytotoxic mechanism of action that at sufficiently high doses results in severe inflammation of the upper respiratory tract and the bronchiolar epithelium concurrently. This is followed by acute respiratory distress, pulmonary edema, and post inflammatory concentric fibrosis that become clinically obvious within a few months. In contrast, irritant gases with lower solubility like phosgene also follow a threshold-dependent mechanism of cytotoxicity action but can exhibit more insidious and isolated bronchiolar tissue damage with a similar latency to fibrosis. To date, animal and human studies on the highly soluble gas, diacetyl, have not identified a coherent pattern of pathology and latency that would be expected based on studies of other known causes of bronchiolitis obliterans disease.
PubMed: 28962489
DOI: 10.1016/j.toxrep.2015.10.012 -
BioMed Research International 2021Phosgene exposure can cause acute lung injury (ALI), for which there is no currently available effective treatment. Mesenchymal stem cells (MSCs) which have been proven...
Phosgene exposure can cause acute lung injury (ALI), for which there is no currently available effective treatment. Mesenchymal stem cells (MSCs) which have been proven to have therapeutic potential and be helpful in the treatment of various diseases, but the mechanisms underlying the function of MSCs against phosgene-induced ALI are still poorly explored. In this study, we compared the expression profiles of mRNAs, lncRNAs, and circRNAs in the lung tissues from rats of three groups-air control (group A), phosgene-exposed (group B), and phosgene + MSCs (group C). The results showed that 389 mRNAs, 198 lncRNAs, and 56 circRNAs were differently expressed between groups A and B; 130 mRNAs, 107 lncRNAs, and 35 circRNAs between groups A and C; and 41 mRNAs, 88 lncRNAs, and 18 circRNAs between groups B and C. GO and KEGG analyses indicated that the differentially expressed RNAs were mainly involved in signal transduction, immune system processes, and cancers. In addition, we used a database to predict target microRNAs (miRNAs) interacting with circRNAs and the network software package to construct a circRNA-targeted miRNA gene network map. Our study showed new insights into changes in the RNA expression in ALI, contributing to explore the mechanisms underlying the therapeutic potential of MSCs in phosgene-induced ALI.
Topics: Acute Lung Injury; Animals; Disease Models, Animal; Lung; Mesenchymal Stem Cells; Phosgene; RNA; Rats; Transcriptome
PubMed: 33506021
DOI: 10.1155/2021/6278526 -
Toxicology Letters Feb 2016Toxic industrial chemicals are used throughout the world to produce everyday products such as household and commercial cleaners, disinfectants, pesticides,...
Toxic industrial chemicals are used throughout the world to produce everyday products such as household and commercial cleaners, disinfectants, pesticides, pharmaceuticals, plastics, paper, and fertilizers. These chemicals are produced, stored, and transported in large quantities, which poses a threat to the local civilian population in cases of accidental or intentional release. Several of these chemicals have no known medical countermeasures for their toxic effects. Phosgene is a highly toxic industrial chemical which was used as a chemical warfare agent in WWI. Exposure to phosgene causes latent, non-cardiogenic pulmonary edema which can result in respiratory failure and death. The mechanisms of phosgene-induced pulmonary injury are not fully identified, and currently there is no efficacious countermeasure. Here, we provide a proposed mechanism of phosgene-induced lung injury based on the literature and from studies conducted in our lab, as well as provide results from studies designed to evaluate survival efficacy of potential therapies following whole-body phosgene exposure in mice. Several therapies were able to significantly increase 24h survival following an LCt50-70 exposure to phosgene; however, no treatment was able to fully protect against phosgene-induced mortality. These studies provide evidence that mortality following phosgene toxicity can be mitigated by neuro- and calcium-regulators, antioxidants, phosphodiesterase and endothelin receptor antagonists, angiotensin converting enzymes, and transient receptor potential cation channel inhibitors. However, because the mechanism of phosgene toxicity is multifaceted, we conclude that a single therapeutic is unlikely to be sufficient to ameliorate the multitude of direct and secondary toxic effects caused by phosgene inhalation.
Topics: Animals; Antidotes; Chemical Warfare Agents; Disease Models, Animal; Inhalation Exposure; Lung; Lung Injury; Male; Mice; Molecular Targeted Therapy; Phosgene; Signal Transduction
PubMed: 26562770
DOI: 10.1016/j.toxlet.2015.10.010 -
Scientific Reports Apr 2016Direct polymerization of CO2 and diols is promising as a simple and environmental-benign method in place of conventional processes using high-cost and/or hazardous...
Direct polymerization of CO2 and diols is promising as a simple and environmental-benign method in place of conventional processes using high-cost and/or hazardous reagents such as phosgene, carbon monoxide and epoxides, however, there are no reports on the direct method due to the inertness of CO2 and severe equilibrium limitation of the reaction. Herein, we firstly substantiate the direct copolymerization of CO2 and diols using CeO2 catalyst and 2-cyanopyridine promotor, providing the alternating cooligomers in high diol-based yield (up to 99%) and selectivity (up to >99%). This catalyst system is applicable to various diols including linear C4-C10 α,ω-diols to provide high yields of the corresponding cooligomers, which cannot be obtained by well-known methods such as copolymerization of CO2 and cyclic ethers and ring-opening polymerization of cyclic carbonates. This process provides us a facile synthesis method for versatile polycarbonates from various diols and CO2 owing to simplicity of diols modification.
PubMed: 27075987
DOI: 10.1038/srep24038 -
Journal of Emergencies, Trauma, and... Oct 2013Here, authors present a review on clinical presentation and management of exposure of phosgene gas after reviewing the literature by searching with keywords phosgene... (Review)
Review
Here, authors present a review on clinical presentation and management of exposure of phosgene gas after reviewing the literature by searching with keywords phosgene exposure on Google, Cochrane, Embase and PubMed with a background of experience gained from 10 patients who were admitted to our institute after an accidental phosgene exposure in February 2011 nearby a city in India. Phosgene is a highly toxic gas, occupational workers may have accidental exposure. The gas can also be generated inadvertently during fire involving plastics and other chemicals and solvents containing chlorine, which is of concern to emergency responders. Phosgene inhalation may cause initially symptoms of respiratory tract irritation, patients feel fine thereafter, and then die of choking a day later because of build up of fluid in the lungs (delayed onset non-cardiogenic pulmonary edema). Phosgene exposure is associated with significant morbidity and mortality. Patients with a history of exposure should be admitted to the hospital for a minimum of 24 h for observation because of the potential for delayed onset respiratory failure and acute respiratory distress syndrome.
PubMed: 24339660
DOI: 10.4103/0974-2700.120372 -
The Korean Journal of Internal Medicine Jan 1996Phosgene (COCl2) is a colorless oxidant gas which is heavier than air and the lethal exposure dose (LC50) in humans is 500 ppm/min. This gas was originally manufactured... (Review)
Review
Phosgene (COCl2) is a colorless oxidant gas which is heavier than air and the lethal exposure dose (LC50) in humans is 500 ppm/min. This gas was originally manufactured as an agent for chemical warfare during World War I and there had been a great deal of studies on phosgene poisoning during the early years of industrial use. It is still widely used in the synthesis of chemicals and plastics. In the modern era, however, phosgene poisoning is relatively uncommon except in accidental exposures. In Korea, there has been no report about lung injury from phosgene inhalation. We present a clinical experience with six patients accidentally exposed to phosgene.
Topics: Accidents, Occupational; Acute Disease; Adult; Chemical Industry; Chemical Warfare Agents; Combined Modality Therapy; Female; Humans; Lung Injury; Male; Phosgene; Pulmonary Edema
PubMed: 8882481
DOI: 10.3904/kjim.1996.11.1.87 -
Toxicology Mechanisms and Methods May 2021The elemental halogens include chlorine, bromine, and phosgene. Halogen gas can be directly weaponized and employed in warfare or terrorism. Industrial stockpiles or...
The elemental halogens include chlorine, bromine, and phosgene. Halogen gas can be directly weaponized and employed in warfare or terrorism. Industrial stockpiles or halogen transport can provide targets for terrorist attack as well as an origin for accidental release creating a risk for potential mass-casualty incidents. Pregnant and post-partum women represent a substantial and vulnerable subset of the population who may be at particular risk during an attack or accidental exposure. We review the effects of halogen exposure on the parturient with a focus on bromine toxicity. Bromine is the most extensively studied agent in the context of pregnancy and to-date murine models form the basis for the majority of current knowledge. Pregnancy potentiates the acute lung injury after halogen exposure. In addition, halogen exposure precipitates a preeclamptic-like syndrome in mice. This phenotype is characterized by systemic and pulmonary hypertension, endothelial dysfunction, decreased cardiac output, placental injury and fetal growth restriction. This constellation contributes to increased maternal and fetal mortality observed after bromine exposure. Angiogenic imbalance is noted with overexpression of the soluble fms-like tyrosine kinase-1 (sFlt-1) form of the vascular endothelial growth factor receptor 1 reminiscent of human preeclampsia. Additional research is needed to further explore the effect of halogen gas exposure in pregnancy and to develop therapeutic interventions to mitigate risk to this unique population.
Topics: Animals; Female; Fetal Growth Retardation; Halogens; Mice; Placenta; Pre-Eclampsia; Pregnancy; Vascular Endothelial Growth Factor A
PubMed: 32131668
DOI: 10.1080/15376516.2020.1736702 -
ACS Omega Nov 2022Amino acid -carboxyanhydrides (NCAs) are conventionally synthesized from α-amino acids and phosgene. The present study reports in situ photo-on-demand phosgenation...
Amino acid -carboxyanhydrides (NCAs) are conventionally synthesized from α-amino acids and phosgene. The present study reports in situ photo-on-demand phosgenation reactions of amino acids with CHCl for synthesizing NCAs. A series of NCAs were obtained on a gram scale upon photo-irradiation of a mixture solution of CHCl and CHCN containing an amino acid at 60-70 °C under O bubbling. This method presents a safe and convenient reaction controlled by light without special apparatuses and reagents.
PubMed: 36340075
DOI: 10.1021/acsomega.2c05299 -
International Journal of Molecular... Dec 2022Alveolar epithelial cells (AECs) play a role in chemically induced acute lung injury (CALI). However, the mechanisms that induce alveolar epithelial type 2 cells (AEC2s)...
Alveolar epithelial cells (AECs) play a role in chemically induced acute lung injury (CALI). However, the mechanisms that induce alveolar epithelial type 2 cells (AEC2s) to proliferate, exit the cell cycle, and transdifferentiate into alveolar epithelial type 1 cells (AEC1s) are unclear. Here, we investigated the epithelial cell types and states in a phosgene-induced CALI rat model. Single-cell RNA-sequencing of bronchoalveolar lavage fluid (BALF) samples from phosgene-induced CALI rat models (Gas) and normal controls (NC) was performed. From the NC and Gas BALF samples, 37,245 and 29,853 high-quality cells were extracted, respectively. All cell types and states were identified and divided into 23 clusters; three cell types were identified: macrophages, epithelial cells, and macrophage proliferating cells. From NC and Gas samples, 1315 and 1756 epithelial cells were extracted, respectively, and divided into 11 clusters. The number of AEC1s decreased considerably following phosgene inhalation. A unique SOX9-positive AEC2 cell type that expanded considerably in the CALI state was identified. This progenitor cell type may develop into alveolar cells, indicating its stem cell differentiation potential. We present a single-cell genome-scale transcription map that can help uncover disease-associated cytologic signatures for understanding biological changes and regeneration of lung tissues during CALI.
Topics: Rats; Animals; Phosgene; Disease Models, Animal; Acute Lung Injury; Lung; Epithelial Cells; Alveolar Epithelial Cells; Lung Injury; Bronchoalveolar Lavage Fluid; RNA
PubMed: 36613719
DOI: 10.3390/ijms24010277 -
Basic & Clinical Pharmacology &... Mar 2010Chemical carcinogenesis is a complex, multi-stage process and the relationship between dose and tumour formation is an important consideration in the risk assessment of... (Review)
Review
Chemical carcinogenesis is a complex, multi-stage process and the relationship between dose and tumour formation is an important consideration in the risk assessment of chemicals. Extrapolation from empirical dose-response relationships obtained in experimental studies has been criticized, as it fails to take into account information on mode of action. Strategies for incorporating mode of action information into the risk assessment of chemical carcinogens are described, with a focus on hepatic cancer. Either toxicokinetic or toxicodynamic processes can be addressed. Whilst the former have been the focus of more attention to date, for example by using physiologically based modelling, there is increasing interest in the development of mode of action-based toxicodynamic models. These have the advantage that they do not require extreme assumptions, and may be amenable to paramaterization using human data. This is rarely if ever possible when using conventional dose-tumour response relationships. The approaches discussed are illustrated using chloroform as a case study. This compound is converted to a cytotoxic metabolite, phosgene, by CYP2E1 in liver and/or kidney. Cytotoxicity results in proliferative regeneration, with increased probability of tumour formation. Both physiologically based toxicokinetic and toxicodynamic models have been developed, and it is possible to use probabilistic approaches incorporating, for example, data on the distribution of hepatic CYP2E1 levels. Mode of action can provide an invaluable link between observable, experimental data, on both toxicokinetics and toxicodynamics, and chemical-specific risk assessment, based on physiological approaches.
Topics: Animals; Carcinogenicity Tests; Cell Proliferation; Chloroform; Dose-Response Relationship, Drug; Humans; Kidney; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Models, Biological; Risk Assessment
PubMed: 20030633
DOI: 10.1111/j.1742-7843.2009.00505.x