2. Academic Validation
  3. The pyroptosis mechanism of ototoxicity caused by unconjugated bilirubin in neonatal hyperbilirubinemia

The pyroptosis mechanism of ototoxicity caused by unconjugated bilirubin in neonatal hyperbilirubinemia

  • Biomed Pharmacother. 2023 Jul 17;165:115162. doi: 10.1016/j.biopha.2023.115162.
Shihan Sun 1,  Shuyuan Yu 2,  Hong Yu 2,  Gang Yao 3,  Xinyi Guo 2,  Fengyang Zhao 4,  Jiannan Li 4,  Ping Wang 5
Affiliations

Affiliations

  • 1 Department of Otolaryngology-Head and Neck Surgery, First Hospital of Jilin University, Changchun 130021, China; Bethune First Clinical Medical College, Jilin University, Changchun, Jilin, China.
  • 2 Department of Otolaryngology-Head and Neck Surgery, First Hospital of Jilin University, Changchun 130021, China.
  • 3 Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China.
  • 4 Bethune First Clinical Medical College, Jilin University, Changchun, Jilin, China.
  • 5 Department of Otolaryngology-Head and Neck Surgery, First Hospital of Jilin University, Changchun 130021, China. Electronic address: [email protected].
PMID: 37467648 DOI: 10.1016/j.biopha.2023.115162
Abstract

When activated by unconjugated bilirubin (UCB), inflammatory mediators such as IL - 18 and TNF contribute to the neurotoxicity and ototoxicity observed in severe neonatal hyperbilirubinemia. However, in cell and molecular level, the regulation and mechanism of UCB-induced ototoxicity are remained unclear. In this study, 7-day-old mammary rats were exposed to various concentrations of UCB to imitate the infant auditory damage. The auditory brainstem response result (ABR) indicated severe hearing loss, which occurred with increasing concentration. Morphological analysis of organotypic cochlear cultures treated with different concentrations of UCB indicated that auditory nerve fibers (ANF) were demyelinated and the density of spiral ganglion neurons (SGN) were decreased. In addition, HEI-OC1 cells treated with different concentrations of UCB showed severe necrosis by Flow Cytometry. The morphologic feature of Pyroptosis has been observed by scanning electronic microscope. Cleaved Caspase-1, GSDMD and NLRP3 expression were significantly increased in cochlear explants with UCB-induced. To further clarify the molecular mechanism of UCB-induced inner ear cell Pyroptosis, specific inhibitors of Pyroptosis were applied, the protein associated with pyrotosis such as Cleaved Caspase-1, GSDMD, ASC, IL-18 and NLRP3 were significantly lower than the group with UCB alone. All the data above indicated that ERK /NLRP3/GSDMD signaling pathway involved in UCB-induced ototoxicity.

Keywords

Epicophosis; Inner ear; Neurodegeneration; Ototoxicity; Pyroptosis; SGNs; Unconjugated Bilirubin.

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