Lung Gene Expression Suggests Roles for Interferon-Stimulated Genes and Adenosine Deaminase Acting Against RNA-1 in Pathologic Responses to Diisocyanate

Details

• Personal Author:
  Liu J ; Wisnewski AV
• Description:
  Mechanisms underlying methylene diphenyl diisocyanate (MDI) and other low molecular weight chemical-induced asthma are unclear and appear distinct from those of high molecular weight (HMW) allergen-induced asthma. We sought to elucidate molecular pathways that differentiate asthma-like pathogenic vs nonpathogenic responses to respiratory tract MDI exposure in a murine model. Lung gene expression differences in MDI exposed immune-sensitized and nonsensitized mice vs unexposed controls were measured by microarrays, and associated molecular pathways were identified through bioinformatic analyses and further compared with published studies of a prototypic HMW asthmagen (ovalbumin). Respiratory tract MDI exposure significantly altered lung gene expression in both nonsensitized and immune-sensitized mice, vs controls. Fifty-three gene transcripts were altered in all MDI exposed lung tissue vs controls, with levels up to 10-fold higher in immune-sensitized vs nonsensitized mice. Gene transcripts selectively increased in MDI exposed immune-sensitized animals were dominated by chitinases and chemokines and showed substantial overlap with those increased in ovalbumin-induced asthma. In contrast, MDI exposure of nonsensitized mice increased type I interferon stimulated genes (ISGs) in a pattern reflecting deficiency in adenosine deaminase acting against RNA (ADAR-1), an important regulator of innate, as well as "sterile" or autoimmunity triggered by tissue damage. Thus, MDI-induced changes in lung gene expression were identified that differentiate nonpathogenic innate responses in nonsensitized hosts from pathologic adaptive responses in immune-sensitized hosts. The data suggest that MDI alters unique biological pathways involving ISGs and ADAR-1, potentially explaining its unique immunogenicity/allergenicity. [Description provided by NIOSH]
• Subjects:
  Animals Asthma Asthma, Occupational Immune System Isocyanates Occupational Health Safety
• Keywords:
  4,4-Methylene Diphenyl Diisocyanate Animal Studies Diisocyanates Gene Expression Immune Reaction Pathogenesis
• ISSN:
  0893-228X
• 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:
  476-485
• Volume:
  37
• Issue:
  3
• NIOSHTIC Number:
  nn:20069493
• Citation:
  Chem Res Toxicol 2024 Mar; 37(3):476-485
• Contact Point Address:
  Adam V. Wisnewski, Department of Internal Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut United States
• Email:
  adam.wisnewski@yale.edu
• CAS Registry Number:
  Diphenylmethane diisocyanate (CAS RN 101-68-8)
• Federal Fiscal Year:
  2024
• Performing Organization:
  Yale University, New Haven, Connecticut
• Peer Reviewed:
  True
• Start Date:
  20160801
• Source Full Name:
  Chemical Research in Toxicology
• End Date:
  20200731
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:752fdd0f86059a99a7b38cf8ba402014986e951dc2141587db387586e5d0c12b25d29046221d922d0398b36641f98d087b71cc6172e9cf0d69f13f8dece5edbc
• Download URL:
  https://stacks.cdc.gov/view/cdc/207926/cdc_207926_DS1.pdf
• File Type:
  [PDF - 1.55 MB ]