Theophylline treatment restores smell function in some patients with hyposmia (loss of smell) as demonstrated by objective testing using fMRI. Theophylline is a phosphodiesterase (PDE) inhibitor; it restores smell function through PDE inhibition, thereby increasing cAMP, a growth factor which stimulates maturation of olfactory epithelial stem cells, cells whose functions are inhibited among patients with hyposmia. Theophylline may also restore smell function through other mechanisms. One such mechanism may operate through inhibition of excessive apoptosis, a normal process which, if excessively increased, can become pathological and impair cellular anatomy of the olfactory epithelium and cause hyposmia. To study this putative mechanism we measured TNF α, and soluble TNF receptors 1 and 2, moieties which are increased in systems undergoing excessive apoptosis. We measured these moieties in nasal mucus, the biological fluid in which these moieties are present, and by which olfactory system function is reflected. In 24 patients with hyposmia before treatment with theophylline levels of TNF α, TNFR1 and TNFR2 were 12.6, 2279 and 2324 pg/mL nasal mucus, respectively. After treatment with 600 mg theophylline, which restored smell function to or toward normal in these patients, these levels decreased significantly by 50-70% to 5.8, 695 and 891 pg/mL nasal mucus, respectively. There was a significant dose-response decrease in each moiety related to a stepwise increase in theophylline treatment associated and a stepwise improvement in olfactory acuity; e.g., with theophylline treatment at 200 mg, TNF α, was 8.9 ± 2 pg/mL nasal mucus (mean ± SEM); theophylline at 400 mg, TFF α was 8.8 ± 2, theophylline at 600 mg TFNF α was 5.8 ± 2. These results suggest that pathological apoptosis of olfactory epithelial anatomy causes smell loss in patients with hyposmia; this process is reversed with theophylline therapy, which restores smell function in these patients. These results illustrate biochemical parameters associated with return of smell function in patients treated with theophylline.
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