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

Abstract

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.

• Authors: Adam V Wisnewski, Jian Liu, Carrie A Redlich
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 63 Issue 1 Pg. 25-35 (07 2020) ISSN: 1535-4989 [Electronic] United States
• PMID: 32101465 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chloride Channels
• Isocyanates
• Immunoglobulin E
• 4,4'-diphenylmethane diisocyanate

Topics

• Animals
• Asthma (metabolism, pathology)
• Bronchoalveolar Lavage Fluid
• Chloride Channels (metabolism)
• Disease Models, Animal
• Eosinophilia (chemically induced, metabolism)
• Eosinophils (metabolism, pathology)
• Gene Expression (drug effects, physiology)
• Immunoglobulin E (metabolism)
• Isocyanates (pharmacology)
• Lung (drug effects, metabolism, pathology)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Monocytes (drug effects, metabolism)