Analysis of Lung Gene Expression Reveals a Role for Cl- Channels in Diisocyanate-induced Airway Eosinophilia in a Mouse Model of Asthma Pathology.
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.
['Wisnewski|Adam V|AV|', 'Liu|Jian|J|', 'Redlich|Carrie A|CA|']
D000818:Animals D001249:Asthma D001992:Bronchoalveolar Lavage Fluid D018118:Chloride Channels D004195:Disease Models, Animal D004802:Eosinophilia D004804:Eosinophils D015870:Gene Expression D007073:Immunoglobulin E D017953:Isocyanates D008168:Lung D008264:Macrophages D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008810:Mice, Inbred C57BL D009000:Monocytes
channel asthma diisocyanate chloride crofelemer