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

Details

• Alternative Title:
  Chem Res Toxicol
• Personal Author:
  Wisnewski, Adam V. ; Liu, Jian
• 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.
• Subjects:
  Adenosine Deaminase Allergens Animals Asthma Gene Expression Interferons Isocyanates Lung Mice Ovalbumin
• Source:
  Chem Res Toxicol. 37(3):476-485
• DOI:
  http://dx.doi.org/10.1021/acs.chemrestox.3c00325
• Pubmed ID:
  38494904
• Pubmed Central ID:
  PMC11748834
• Document Type:
  Journal Article
• Funding:
  R01 OH010941/OH/NIOSH CDC HHSUnited States/ ; R01 OH012726/OH/NIOSH CDC HHSUnited States/ ; R21 OH012524/OH/NIOSH CDC HHSUnited States/
• Volume:
  37
• Issue:
  3
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:2d91dc190dd941f077ba7bc7a252b0d790886959e16116ba1b864207e3c09c9da91fb05f07c8364e13c23acc2eacc5cf37cb20db9ef9162c2559d7b0eab1c986
• Download URL:
  https://stacks.cdc.gov/view/cdc/175936/cdc_175936_DS1.pdf
• File Type:
  [PDF - 1.68 MB ]