Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034063 (pulmonary edema)
 10,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current testing conventions for inhalation toxicity studies require that solid and non-volatile liquid compounds are converted to respirable aerosol, which is often achieved by laboratory-specific technical methodologies. So far, internationally harmonized approaches are lacking that would allow comparison of results from inhalation studies with 'contrived' test aerosols taking into account the actual particle size of the product as it might be encountered in normal handling and use. The focus of this paper is to consider aerosols of irritant substances eliciting their mode of action on sites of initial deposition within the respiratory tract of rats. Assessment is based on conventional endpoints, such as mortality (LC(50)), and sublethal endpoints that include an analysis for the concentration-effect relationship of protein in bronchoalveolar lavage fluid (BAL-protein) as a sensitive, early marker of lung edema. This retrospective analysis also addresses whether common denominators can be found for different aerosol sizes of direct and indirect irritants, such as monomeric and polymeric diphenylmethane-4,4'-diisocyanate (mMDI and pMDI), naphthylene diisocyanate (NDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), 2,4-triisopropyl-benzene-diisocyanate (TRIDI) and substances (e.g., chlorofluoroalkyl side-chain fungicides) known to decompose to irritant intermediates in the lining fluids of the airways. Collectively, this analysis shows that for irritant aerosols both the concentration and the particle size are equally important for the outcome of the test, independent of whether the endpoint chosen is lethality or BAL protein. The scientific value of 1-h exposures to high aerosol concentrations, as required by some regulations, could be challenged because high concentrations and high respirability of aerosol appear to be mutually exclusive, as shown for mMDI and NDI (LC(50 )>2000 mg/m(3)). Thus, for a meaningful risk characterization, test results from inhalation studies with 'contrived properties' due to the specific techniques employed need to be compared with the real properties of substances as marketed, handled and used.
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PMID:Acute inhalation studies with irritant aerosols: technical issues and relevance for risk characterization. 1505 6

Isocyanates are a common cause of occupational lung disease. Hexamethylene diisocyanate (HDI), a component of polyurethane spray paints, can induce respiratory symptoms, inflammation, lung function impairment, and isocyanate asthma. The predominant form of HDI in polyurethane paints is a nonvolatile polyisocyanate known as HDI biuret trimer (HDI-BT). Exposure of mice to aerosolized HDI-BT results in pathological effects, including pulmonary edema, lung inflammation, cellular proliferation, and fibrotic lesions, which occur with distinct time courses following exposure. To identify genes that mediate lung pathology in the distinct temporal phases after exposure, gene expression profiles in HDI-BT-exposed C57BL/6J mouse lungs were analyzed. RNase protection assay (RPA) of genes involved in apoptosis, cell survival, and inflammation revealed increased expression of IkappaBalpha, Fas, Bcl-X(L), TNFalpha, KC, MIP-2, IL-6, and GM-CSF following HDI-BT exposure. Microarray analysis of approximately 10000 genes was performed on lung RNA collected from mice 6, 18, and 90 h after HDI-BT exposure and from unexposed mice. Classes of genes whose expression was increased 6 h after exposure included those involved in stress responses (particularly oxidative stress and thiol redox balance), growth arrest, apoptosis, signal transduction, and inflammation. Types of genes whose expression was increased at 18 h included proteinases, anti-proteinases, cytoskeletal molecules, and inflammatory mediators. Transcripts increased at 90 h included extracellular matrix components, transcription factors, inflammatory mediators, and cell cycle regulators. This characterization of the gene expression profile in lungs exposed to HDI-BT will provide a basis for investigating injury and repair pathways that are operative during isocyanate-induced lung disease.
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PMID:Gene expression profiling in mouse lung following polymeric hexamethylene diisocyanate exposure. 1588 64