November 3, 2009 Feature

Mechanisms of Noise-Induced Hair Cell Death

Understanding Molecular Mechanisms Yields Promising Treatments

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Cochlear sensory cells include outer hair cells and inner hair cells that act as a mechano-electrical transducer and convert mechanical stimuli to neural activities. Acoustic trauma—such as exposure to intense noise—causes these cells to die. Loss of hair cells leads to permanent hearing loss, a common cause of acquired hearing loss in adults. Understanding how cochlear hair cells respond to acoustic overstimulation is pivotal for exploring protective strategies for reducing noise-induced hearing loss (NIHL). In the past, investigators focused on the physiological and morphological impacts of acoustic trauma. Now as scientists probe the molecular mechanisms of hair cell damage, studies show multiple modes of acoustic trauma. These mechanisms may one day influence the treatment for hearing loss.

Q: How do hair cells die following acoustic trauma?

Exposure to intense noise traumatizes hair cells. If damage exceeds the cells' ability to repair themselves, they die. Recent studies have shown that hair cells can die through different pathways (Bohne et al., 2007; Hu et al., 2002). Some cells die through apoptosis, an active mode of cell death that requires a persistent energy supply, whereas others die from necrosis, a passive mode of cell death due to early disintegration of cells.

Apoptosis and necrosis are two distinct modes of cell death that differ substantially in their morphological and biological characteristics. Morphologically, apoptotic cells shrink. Their nuclei condense and their cell bodies shrink. In contrast, necrotic cells have a swollen cell body and nucleus. The increase in the cell volume breaks down the cell membrane. Biologically, apoptotic cells feature activation of a group of apoptosis-related enzymes that digest the cellular structures.

Recent studies have identified multiple apoptotic molecules (e.g., Hu et al., 2009; Yamashita et al., 2008) that participate in relaying cell death signals from one cellular organelle to another. This cascade signal transduction provides potential targets for pharmacological intervention that could block the transduction of the death signal, delaying or even reversing cellular death.

Q: Why do hair cells die differently?

The causes of hair cell death are complex. Mechanical forces due to acoustic overstimulation can directly traumatize cochlear structures. Hair cells can be torn from their structural anchors following exposure to impulse noises, such as gunshots or blasts. Cochlear structures are also the target of toxic molecules generated by metabolic stress following acoustic trauma. One type of toxic molecule is a reactive oxidative species, which are highly reactive due to the presence of an unpaired valence shell electrode. Although they are a natural byproduct of normal cellular energy production, overproduction due to excessive energy production or disruption of antioxidant capacity leads to oxidative stress. Oxidative stress targets many cellular structures that are vital for the cell's survival, such as the plasma membrane, the mitochondria, and the nuclei of cells.

Whether a damaged cell undergoes the apoptotic or the necrotic pathway when under stress is associated with a number of factors. One factor is the level of oxidative stress that a cell sustains. Studies have shown that a moderate level of oxidative stress drives damaged cells to die by apoptosis (Galan et al., 2001; Teramoto et al., 1999). In contrast, severe oxidative stress leads to necrotic cell death. Another factor that regulates the propensity to cell death is the energy status of cells (Hu, 2007; Hu et al., 2008). Because apoptosis is energy-dependent, lack of energy will block the apoptotic process. Specifically, if a cell maintains its energy production, the cell will die by apoptosis. If a cell loses its energy production, it will die by necrosis.

Q: Why is the knowledge of the cell death process important?

Therapeutic treatments of NIHL are a critical challenge for clinical professionals. Investigations into the cell death cascade can provide potential targets for pharmacological intervention. For example, studies have shown that the stress-activated protein molecule cellular kinase (known as c-Jun N-terminal kinase) is triggered during apoptosis and can be activated by reactive oxygen species (Bogoyevitch et al., 1996; Silva et al., 2005). This finding has prompted exploration into the effect of the inhibition of c-Jun N-terminal kinase on noise-induced cochlear damage. Emerging evidence has shown that inhibiting this kinase protects hearing from acoustic overstimulation (Pirvola et al., 2000; Wang et al., 2003). Another promising treatment is antioxidant therapies, which have been reviewed in several recent articles in The ASHA Leader (Campbell, 2009; Henderson & Tanaka, 2009).

Although previous studies on NIHL have yielded promising results, the effectiveness of the treatments is usually limited because individual treatments usually target only one aspect of the cell death mechanism. Because noise-induced hair cell death is triggered by a combination of multiple signaling pathways, blocking one pathway may drive cells to die through other pathways. The timing of the treatment also may affect treatment outcome. Acute hair cell death can occur within minutes of noise exposure and can progress rapidly in the first few hours after exposure (Hu et al., 2002; Hu et al., 2006). This pattern of hair cell lesion development calls for early intervention to improve treatment outcomes.

Recent advances in the understanding of the biological and molecular mechanisms of noise-induced hair cell damage have paved the way to treat this medical condition with pharmacological agents. In the future, a treatment that targets multiple aspects of cell damage will reduce the effects of NIHL. To achieve this goal, more detailed knowledge of the molecular basis of noise-induced hair cell damage is needed.

Bo Hua Hu, PhD, CCC-A, is an assistant professor in the Department of Communicative Disorders and Sciences at the State University of New York at Buffalo. His research interests focus on the mechanisms and prevention of noise-induced and age-related hearing loss. Contact him at bhu@buffalo.edu.

cite as: Hu, B. H. (2009, November 03). Mechanisms of Noise-Induced Hair Cell Death : Understanding Molecular Mechanisms Yields Promising Treatments. The ASHA Leader.

References

Bogoyevitch, M.A., Gillespie-Brown, J., Ketterman, A.J., Fuller, S.J., Ben-Levy, R., Ashworth, A. et al. (1996). Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circulation Research, 79, 162–73.

Bohne, B.A., Harding, G.W., & Lee, S.C. (2007). Death pathways in noise-damaged outer hair cells. Hearing Research, 223, 61–70.

Campbell, K.C.M. (2009, May 26). Emerging pharmacologic treatments for hearing loss and tinnitus. The ASHA Leader, 14(7), 14–17.

Galan, A., Garcia-Bermejo, L., Troyano, A., Vilaboa, N.E., Fernandez, C., de Blas, E., et al. (2001). The role of intracellular oxidation in death induction (apoptosis and necrosis) in human promonocytic cells treated with stress inducers (cadmium, heat, X-rays). European Journal of Cell Biology, 80, 312–20.

Henderson, D., & Tanaka, C. (2009, March 24). Advances in otoprotective drugs. The ASHA Leader, 14(4), 5–6.

Hu, B.H. (2007). Delayed mitochondrial dysfunction in apoptotic hair cells in chinchilla cochleae following exposure to impulse noise. Apoptosis, 12, 1025–36.

Hu, B.H., Henderson, D., & Nicotera, T.M. (2002). Involvement of apoptosis in progression of cochlear lesion following exposure to intense noise. Hearing Research, 166, 62–71.

Hu, B.H., Henderson, D., & Nicotera, T.M. (2006). Extremely rapid induction of outer hair cell apoptosis in the chinchilla cochlea following exposure to impulse noise. Hearing Research, 211, 16–25.

Hu, B.H., Henderson, D., & Yang, W.P. (2008). The impact of mitochondrial energetic dysfunction on apoptosis in outer hair cells of the cochlea following exposure to intense noise. Hearing Research, 236, 11–12.

Hu, B.H., Cai, Q., Manohar, S., Jiang, H., Ding, D., Coling, D.E., Zheng, G., & Salvi, R. (2009). Differential expression of apoptosis-related genes in the cochlea of noise-exposed rats. Neuroscience, 161, 915–925.

Pirvola, U., Xing-Qun, L., Virkkala, J., Saarma, M., Murakata, C., Camoratto, A.M., Walton, K.M., & Ylikoski, J. (2000). Rescue of hearing, auditory hair cells, and neurons by CEP-1347/KT7515, an inhibitor of c-Jun N-terminal kinase activation. The Journal of Neuroscience, 20, 43–50.

Silva, R.M., Kuan, C.Y., Rakic, P., & Burke, R. E. (2005). Mixed lineage kinase-c-jun N-terminal kinase signaling pathway: a new therapeutic target in Parkinson's disease. Movement Disorders, 20, 653–64.

Teramoto, S., Tomita, T., Matsui, H., Ohga, E., Matsuse, T., & Ouchi, Y. (1999). Hydrogen peroxide-induced apoptosis and necrosis in human lung fibroblasts: protective roles of glutathione. Japanese Journal of Pharmacology, 79, 33–40.

Wang, J., Van De Water, T.R., Bonny, C., de Ribaupierre, F., Puel, J.L., & Zine, A. (2003). A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. The Journal of Neuroscience, 23, 8596–607.

Yamashita, D., Minami, S.B., Kanzaki, S., Ogawa, K., & Miller, & J. M. (2008). Bcl-2 genes regulate noise-induced hearing loss. Journal of Neuroscience Research, 86, 920–928.



  

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