Year: 2021
Type: conference-abstract
Abstract: Rationale. The orally-administered prostacyclin analog iloprost improves endobronchial dysplasia in former smokers. Both oral iloprost and prostacyclin synthase overexpression decrease overall lung tumor multiplicity in various murine lung carcinogenesis models. Iloprost has been shown to regulate carcinogenesis through regulation of epithelial to mesenchymal (EMT) genes. In addition, iloprost may increase immunosurveillance by reprogramming macrophage phenotype. Currently, inhaled iloprost is being tested in Veterans with preneoplastic lesions. Our preclinical study models this current trial by administering intranasal treatments of iloprost to wildtype FVB mice. We hypothesize that mice treated with inhaled iloprost will have decreased tumor burden, and this will be in part mediated by changes in EMT gene expression and lung macrophage populations. Methods. Wild-type FVB/N mice were injected IP with 1 mg/g urethane, and lung tissue, bronchoalveolar lavage (BAL), and adenomas were harvested after 14 weeks. Starting at week 9 following urethane injection, 5g iloprost in 100l saline or saline vehicle were administered intranasally to mice daily for 5 weeks. Inflammatory cell content was measured in nave and tumor-bearing wild-type mice by differential counts of BAL cells. Adenoma diameter was measured and BALF (BAL fluid), tumors, and lung tissue were analyzed for downstream markers of iloprost activity, cytokine production, and PPAR activation. Results. Inhaled iloprost significantly reduced the number of urethane-induced lung tumors compared to saline controls. The average tumor size and total macrophage counts were similar in iloprost and saline treated mice. qPCR analysis from whole tumor and lung tissue of various gene targets revealed a significant increase of PPAR fold expression, and significant decrease of COX-2, vimentin, and IL1 fold expression between iloprost-treated and control mice. Conclusions. Inhaled Iloprost acts as a chemopreventive agent in the urethane model. Gene expression analysis suggests that iloprost is working through PPAR to down regulate known EMT genes COX-2 and vimentin. While we did not observe increased BAL macrophages, we are currently examining downstream markers of macrophage programming (i.e. cytokines and chemokines) to determine if iloprost alters macrophage function. Moreover, IL1 gene expression was significantly reduced in iloprost treated mice, suggesting an immune regulatory role. This chemoprevention model will be a valuable tool for investigating mechanisms of inhaled iloprost chemoprevention complemented by our ongoing clinical trial.
Authors: A. Smith, L.D. Nield, M. Tennis, R.L. Keith
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4237146696