Analysis of Lung Gene Expression Reveals a Role for Cl- Channels in Diisocyanate Induced Airway Eosinophilia in a Mouse Model of Asthma Pathology

Details

• Personal Author:
  Liu J ; Redlich CA ; Wisnewski AV
• Description:
  Diisocyanates are well-recognized causes of asthma. However, sensitized workers frequently lack diisocyanate-specific IgE, which complicates diagnosis and suggests the disease involves IgE-independent mechanisms. We used a mouse model of methylene diphenyl diisocyanate (MDI) asthma to identify biological pathways that may contribute to asthma pathogenesis. MDI sensitization and respiratory tract exposure were performed in Balb/c, transgenic B-cell (e.g., IgE)-deficient mice and a genetic background (C57BL/6)-matched strain. Eosinophils in airway fluid were quantitated by flow cytometry. Lung tissue gene expression was assessed using whole-genome mRNA microarrays. Informatic software was used to identify biological pathways affected by respiratory tract exposure and potential targets for disease intervention. Airway eosinophilia and changes (>1.5-fold; P value < 0.05) in expression of 192 genes occurred in all three mouse strains tested, with enrichment in chemokines and a pattern associated with alternatively activated monocytes/macrophages. CLCA1 (calcium-activated chloride channel regulator 1) was the most upregulated gene transcript (>100-fold) in all exposed mouse lungs versus controls, followed closely by SLC26A4, another transcript involved in Cl- conductance. Crofelemer, a U.S. Food and Drug Administration-approved Cl- channel inhibitor, reduced MDI exposure induction of airway eosinophilia, mucus, CLCA1, and other asthma-associated gene transcripts. Expression changes in a core set of genes occurs independent of IgE in a mouse model of chemical-induced airway eosinophilia. In addition to chemokines and alternatively activated monocytes/macrophages, the data suggest a crucial role for Cl- channels in diisocyanate asthma pathology and as a possible target for intervention. [Description provided by NIOSH]
• Subjects:
  Animals Asthma Asthma, Occupational Genetics Immune System Isocyanates Occupational Health Safety
• Keywords:
  4,4-Methylene Diphenyl Diisocyanate Animal Studies Author Keywords: Diisocyanate Biological Effects Channel Chloride Crofelemer Diisocyanates Gene Expression Genes Immune Reaction Pathogenesis

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• ISSN:
  1044-1549
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Connecticut ; OSHA Region 1
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  25-35
• Volume:
  63
• Issue:
  1
• NIOSHTIC Number:
  nn:20059100
• Citation:
  Am J Respir Cell Mol Biol 2020 Jul; 63(1):25-35
• Email:
  adam.wisnewski@yale.edu
• CAS Registry Number:
  Chlorine (CAS RN 7782-50-5) ; Diphenylmethane diisocyanate (CAS RN 101-68-8)
• Federal Fiscal Year:
  2020
• NORA Priority Area:
  Manufacturing ; Construction
• Performing Organization:
  Yale University, New Haven, Connecticut
• Peer Reviewed:
  True
• Start Date:
  20160801
• Source Full Name:
  American Journal of Respiratory Cell and Molecular Biology
• End Date:
  20200731
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:dca2fd870ce56ec361ab5ff8865dd676e792f0d0d88c663d384afa011352e2836cbaa0436d1c47fe16cdc72a7d8a177b8c6763b186d9a3d69e212a832f4e1ff1
• Download URL:
  https://stacks.cdc.gov/view/cdc/223416/cdc_223416_DS1.pdf
• File Type:
  [PDF - 1.11 MB ]