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L.D. Dwyer-Nield
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-062 - Temporal Programming of Murine Pulmonary Macrophages in N-Nitroso-Tris-(2-Chloroethyl) Urea (NTCU)-Induced Squamous Dysplasia (ID 2955)
09:30 - 09:30 | Author(s): L.D. Dwyer-Nield
- Abstract
Background:
Continuous topical application of N-Nitroso-tris-(2-chloroethyl)urea (NTCU) twice per week for 32 weeks causes the development of squamous dysplasia and lung carcinoma (SCC) in certain strains of inbred mice including A/J and FVB mice. In A/J mice, short term/high dose topical application of NTCU induces higher grade squamous lung lesions at earlier times with less toxicity than the 32 week, continuous dosing model. In lung adenocarcinoma, alveolar macrophages become alternatively programmed shortly after carcinogen exposure, before lung lesions are detected indicating that inflammation may be important in lesion development. Herein we examine whether short term/high dose NTCU exposure produces squamous dysplastic lesions in FVB mice. In addition, we characterize macrophage programming as a function of time during lesion development.
Methods:
FVB/N mice were treated with 20mM NTCU twice/week for 2, 4, 8, or 32 weeks and lungs were harvested at 16, 20, 24, 28, and 32 weeks after the initial application. The appearance of squamous lesions was monitored by stereology at the later time point and by the appearance of cytokeratin 5-positive bronchial cells at the earlier time points. Inflammatory cell content was determined by flow cytometry at the 16, 20, 24, and 32 week time in the mice continuously exposed to NTCU and compared to vehicle control. Macrophage programming was assessed by immunofluorescent detection iNOS or arginase I expression .
Results:
Squamous dysplasia appeared in the tracheas of NTCU-treated mice after 16 continual weeks of NTCU exposure, but lung dysplasia was not evident until 8-10 weeks later. The appearance of cytokeratin 5 positive cells in the airways preceded the appearance of these lesions. In mice treated with 8 weeks of NTCU, cytokeratin 5 positive cells in the airways appeared at 24 weeks and dysplastic lesions were also detected. Alveolar macrophage numbers also increased at the 24 week time point in these mice. Data from 28 and 32 week time points is currently being analyzed. Alveolar macrophages displayed little change in iNOS or arginase I staining through 20 weeks, however there were isolated iNOS[+] and arginase I[+] macrophages at 24 weeks. There were also weakly activated macrophages present in mice treated with NTCU continuously for 32 weeks although alveolar macrophage numbers did not increase significantly.
Conclusion:
The short term/high dose NTCU treatment regimen is less toxic and produces dysplastic lesions at times similar to those in continuous exposure groups. Alveolar macrophage numbers also increase as a function of time in the short term/high dose model whereas there is less reproducibility of this increase in the continuous dosing model. Changes in alveolar macrophage programming occur during dysplastic lesion development, but not to the same extent as that seen in progression of adenomas and adenocarcinomas.
