An Investigation of the Ciliotoxicity of Tofacitinib and Tonaberstat on Sinonasal Mucosa
Bosco Yue, Medical Student, University of Auckland, Auckland, NZ
Authors List
B. Yue1, S. Hale1, D. Rawlinson1, D. Broderick1, K. Biswas1, P. Agarwal2, R. Kim1, R. Douglas1
1 The University of Auckland, Faculty of Medical and Health Sciences, Department of Surgery
2 The University of Auckland, Faculty of Medical and Health Sciences, Department of Ophthalmology
Background: Tofacitinib (a Janus kinase inhibitor) and tonabersat (an inflammasome inhibitor) are novel drugs that inhibit some of the inflammatory pathways active in CRS.
Aims: This study aims to determine whether they are toxic to nasal cilia, as an indication of their safety profiles for their potential topical use on sinonasal mucosa.
Materials and Methods: Mucosa from the inferior turbinates of patients having turbinate reduction surgery (n=9) were divided into four portions of approximately 1 cm in diameter. The mucosal samples were immersed for 30 minutes in either medium 199 (negative control), fluticasone 0.005 mg/mL, tofacitinib 0.1 mg/mL or tonabersat 10 μM, and an additional mucosal sample from one participant was placed in Triton X-100 0.1% (positive control) in the pilot experiment. After incubation, the samples were rinsed, and epithelial cells were collected using cytobrushes. High-speed video recordings were captured using differential interference contrast microscopy on three regions of interest (ROI) immediately after incubation and following two 60-minute intervals. Cilia beat frequency (CBF) in each ROI was recorded using the software Cilialyzer, and motile ciliated cell counts were performed.
Results: Cells exposed to either drug retained intact cilial structure, and the mean CBF recorded immediately after incubation in tofacitinib and tonabersat was 5.9 and 6.2 Hz, respectively. There were no statistically significant differences in CBF and the relative motile ciliated cell counts between the treatment groups and negative controls at each time point (p>0.05).
Conclusions: These results suggest that tofacitinib and tonabersat are likely to be non-toxic to nasal cilia. Our group is currently conducting further measurements of proinflammatory interleukins using cytometric bead arrays and immunohistochemistry before and after drug exposure to determine whether tofacitinib and tonabersat may be both safe and effective topical therapeutic agents for CRS.
B. Yue1, S. Hale1, D. Rawlinson1, D. Broderick1, K. Biswas1, P. Agarwal2, R. Kim1, R. Douglas1
1 The University of Auckland, Faculty of Medical and Health Sciences, Department of Surgery
2 The University of Auckland, Faculty of Medical and Health Sciences, Department of Ophthalmology
Background: Tofacitinib (a Janus kinase inhibitor) and tonabersat (an inflammasome inhibitor) are novel drugs that inhibit some of the inflammatory pathways active in CRS.
Aims: This study aims to determine whether they are toxic to nasal cilia, as an indication of their safety profiles for their potential topical use on sinonasal mucosa.
Materials and Methods: Mucosa from the inferior turbinates of patients having turbinate reduction surgery (n=9) were divided into four portions of approximately 1 cm in diameter. The mucosal samples were immersed for 30 minutes in either medium 199 (negative control), fluticasone 0.005 mg/mL, tofacitinib 0.1 mg/mL or tonabersat 10 μM, and an additional mucosal sample from one participant was placed in Triton X-100 0.1% (positive control) in the pilot experiment. After incubation, the samples were rinsed, and epithelial cells were collected using cytobrushes. High-speed video recordings were captured using differential interference contrast microscopy on three regions of interest (ROI) immediately after incubation and following two 60-minute intervals. Cilia beat frequency (CBF) in each ROI was recorded using the software Cilialyzer, and motile ciliated cell counts were performed.
Results: Cells exposed to either drug retained intact cilial structure, and the mean CBF recorded immediately after incubation in tofacitinib and tonabersat was 5.9 and 6.2 Hz, respectively. There were no statistically significant differences in CBF and the relative motile ciliated cell counts between the treatment groups and negative controls at each time point (p>0.05).
Conclusions: These results suggest that tofacitinib and tonabersat are likely to be non-toxic to nasal cilia. Our group is currently conducting further measurements of proinflammatory interleukins using cytometric bead arrays and immunohistochemistry before and after drug exposure to determine whether tofacitinib and tonabersat may be both safe and effective topical therapeutic agents for CRS.
