Acoustic trauma augments the cochlear immune response to antigen.

OBJECTIVES/HYPOTHESIS: To test whether noise-exposure, which activates a cochlear immune response with cytokine expression and infiltration of circulating leukocytes could augment the response to antigen (Ag). STUDY DESIGN: Randomized, prospective, mice. METHODS: We sensitized mice to an Ag, injected it intrathecally, and subsequently exposed the mice to noise (8-16 kHz, 90, 100, or 118 dB for 2 hours). Control mice received either noise exposure alone (100 or 118 dB), Ag challenge alone, intrathecal surgery and phosphate-buffered saline injection or no treatment. Four hours or 7 days later the mice were killed and cochlear sections were evaluated immunohistochemically for CD45, ICAM-1, and phospho-nuclear transcription factor-kappaB expression. RESULTS: Intrathecal Ag injection caused no hearing loss, but did result in a small immune response. Loud noise (118 dB) caused severe hearing loss and slight inflammation. The number of CD45-positive cells was significantly greater in the Ag plus-118 dB noise group relative to the Ag-alone group or 118 dB noise-exposure group. ICAM expression was seen in the lower part of the spiral ligament and small vessels within the normal cochlea. The amount of expression increased after Ag injection and acoustic trauma. Activated nuclear transcription factor-kappaB occurred in the nuclei of hair cells, supporting cells, spiral ligament fibrocytes, and neurons 4 hours after noise exposure. CONCLUSIONS: It seems that noise exposure can activate a cochlear immune response, which in the presence of Ag, allows for greater recruitment of inflammatory cells than occurred in response to Ag alone.

Caspase-3, caspase-8, and nuclear factor-kappaB expression in human cholesteatoma.

BACKGROUND: Cholesteatoma is characterized by the accumulation of keratinizing epithelium resulting from the proliferation and differentiation of epithelium. Researchers are presently unraveling the role that apoptosis plays in the disease seen in cholesteatoma epithelium. Caspases play a key role in apoptosis. Caspase-8, which is activated by the induction of tumor necrosis factor-alpha, leads to activation of caspase-3, which activates apoptotic nucleases. Nuclear factor-kappaB is a transcription factor known to inhibit apoptosis induced by tumor necrosis factor-alpha. HYPOTHESIS: In this study, we hypothesized that expression of caspase-3, caspase-8, and nuclear factor-kappaB is uniquely connected to the proliferation, differentiation, and programmed cell death of keratinocytes during the growth and development of cholesteatoma. METHODS: We obtained 41 cholesteatoma specimens for this study. The presence of these proteins in cholesteatoma was examined using immunohistochemistry and a colorimetric assay system. We also examined the patterns of apoptosis by using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining. RESULTS: Using the immunoperoxidase staining method, caspase-3 was found to be densely localized in the spinous and granular layers of cholesteatoma epithelium; caspase-8 was also found in the granular layer. Nuclear factor-kappaB was localized densely in the perinuclear region of the epithelium. The results obtained with immunoperoxidase staining agreed with those obtained with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining. In addition, the colorimetric assay method was used to measure the activity of caspase-3. CONCLUSION: These findings suggest that caspase-3 and caspase-8 play important roles in programmed cell death, which results in the accumulation of keratin debris during the growth of cholesteatoma. Nuclear factor-kappaB was found in cholesteatoma epithelium, but the transcription factor appeared to be inactivated.