Mechanisms of apoptosis induced by cisplatin in marginal cells in mouse stria vascularis.
Degeneration of the stria vascularis (SV) is amongst the major causes of cisplatin (CDDP)-induced hearing impairment. The pathways of apoptosis occurring in the SV due to CDDP were examined using a mouse experimental model. Temporal bones of adult C57BL/6 mice were collected on days 3, 7 and 14 after the local application of CDDP. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and immunostaining for apoptosis-related proteins or reactive radical species were employed for analysis. Local application of CDDP caused apoptotic cell death of marginal cells 3 days after CDDP treatment. Immunohistochemical analyses demonstrated activation of caspase-3 and -9, but not -8, and redistribution of cytochrome c in affected marginal cells, indicating a caspase-dependent, mitochondrion-mediated apoptotic pathway in marginal cells. Temporary expression of hydroxynonenal, nitrotyrosine and inducible nitric oxide synthase in the SV was observed at the induction of apoptosis in marginal cells. CDDP toxicity generates reactive radical species in the SV, which causes mitochondrial membrane permeabilization leading to apoptosis of marginal cells.
Department of Otolaryngology - Head and Neck Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Ji Eun
JE
Lee
Takayuki
T
Nakagawa
Tomoko
T
Kita
Tae Soo
TS
Kim
Fukuichiro
F
Iguchi
Tsuyoshi
T
Endo
Atsushi
A
Shiga
Sang Heun
SH
Lee
Juichi
J
Ito
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D017382:Reactive Oxygen Species / Q000378:metabolism; D013316:Stria Vascularis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D000447:Aldehydes; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; C002744:3-nitrotyrosine; D014443:Tyrosine; D045304:Cytochromes c; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020169:Caspases; C027576:4-hydroxy-2-nonenal; D002945:Cisplatin