Учебники / Auditory Trauma, Protection, and Repair Fay 2008

Contributors xi

jochen schacht

Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI 48109-0506, USA, Email: schacht@umich.edu

ella shalit

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel, Email: shalitel@post.tau.ac.il

andra e. talaska

Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI 48109-0506, USA, Email: atalaska@umich.edu

philine wangemann

Department of Anatomy & Physiology, Kansas State University, Manhattan, KS 66506, USA, Email: wange@vet.ksu.edu

xvi Volume Preface

While the preceding chapters primarily deal with the peripheral auditory system as the site of the initial lesion of auditory trauma, Morest and Potashner detail the pathophysiology of central auditory pathways and its molecular basis in Chapter 9.

The complexity of the cellular regulation of cell death pathways, as well as endogenous protective mechanisms, are considered in Chapter 10 by Green, Altschuler, and Miller. In addition to a detailed consideration of cell death pathways, the authors outline the state-of-the-art attempts to protect the cochlea against environmental insults, with special attention to the spiral ganglion neurons.

Finally, Heller and Raphael introduce the most recent revolutionary developments in hair cell regeneration and stem cell therapy in Chapter 11. They give us a vision of a future when hearing loss and loss of hair cells may be reversed by genetic or pharmacological manipulation.

As often is the case, earlier volumes of the Springer Handbook of Auditory Research Series also provide background or additional information about material covered in this volume. Related topics in Vol. 7 of the series (Clinical Aspects of Hearing, edited by Van de Water, Popper, and Fay) include chapters on molecular genetics (Steel and Kimberling), ototoxicity (Garetz and Schacht), and the psychophysical study of tinnitus (Penner and Jastreboff). An additional discussion of homeostasis is found in a chapter by Wangemann and Schacht in Vol. 8 (The Cochlea, edited by Dallos, Popper, and Fay). Supplementing the summary of genetics in this volume are the chapters of Vol. 14 (Genetics and Auditory Disorders, edited by Keats, Popper, and Fay) that discuss genes and mutations in hearing impairment (Avraham and Hasson), genetic epidemiology of deafness (Nance and Pandya), and genetic counseling (Arnos and Oelrich). Finally, Vol. 26 (Development of the Inner Ear, edited by Kelley, Wu, Popper, and Fay) includes several relevant chapters on the molecular biology of ear development, including a chapter by Herzano and Avraham on developmental genes associated with hearing loss in humans. The current volume thus builds on and expands the information presented in earlier volumes of the Handbook of Auditory Research.

Jochen Schacht, Ann Arbor, MI

Arthur N. Popper, College Park, MD

Richard R. Fay, Chicago, IL

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the predecessors to today’s victims of noise-induced hearing loss, which ranks as the most common occupational disease.

In recent times, several events contributed to the growing medical and public awareness of disorders of the inner ear. One of the first was the arrival of chemotherapy and, in particular, the discovery and therapeutic application of aminoglycoside antibiotics (Schatz et al. 1944; Hinshaw and Feldman 1945). These miracle drugs and long-sought cure for tuberculosis presented a novel side effect: an unexpected predilection for killing the sensory cells and devastating the ears and the lives of thousands of patients. Another event was the epidemic of German measles that hit the United States in the early 1960s and brought with it deafness in newborns. The resulting public health campaign for vaccinations became a source of popular knowledge about disabilities. Finally, the follies of self-inflicted hearing loss through modern leisure activities ranging from highly amplified rock concerts to personal music delivery through ear phones produced a prominent casualty in rock musician Pete Townshend of The Who. Prompted by his partial deafness and tinnitus, Townshend supported the formation of the advocacy group H.E.A.R., Hearing Education and Awareness for Rockers, in the late 1980s.

2. The Life and Death of Cells

The chapters in this book provide the reader with an overview of the current knowledge of mechanisms underlying the most common auditory traumas and the present concepts of protection and potential treatment. Nevertheless, the reader will note omissions of some clinically important disorders, such as sudden hearing loss, about which we know too little to discuss their cellular and molecular basis.

Two themes run like a red thread through the chapters: cellular homeostasis and cell death. In the broadest sense, all auditory pathologies are disorders of cellular homeostasis. Under the impact of mutated genes or environmental insults, cells are challenged and eventually overwhelmed and unable to maintain their integrity and function. The importance of this maintenance of the cellular environment was recognized more than a century ago and first formulated as the “milieu interne” by Claude Bernard (1878) in his “Leçons sur les Phénomènes de la Vie.” Walter Cannon then coined the term “homeostasis” in his treatise on the “Organization for Physiological Homeostasis” (1929). Every cell expends large resources to the defense of its internal balance through intricate barriers, transport systems, and regulatory pathways. In Chapter 3, Wangemann provides an introduction to these mechanisms and a background to most of the other chapters, touching on such topics as energy metabolism, free radical formation, ionic homeostasis, and regulation of blood flow.

Failing to maintain homeostasis, cells will embark on pathways that lead to their demise. Even in dying, the cell attempts to contain the damage to surrounding partners and preferably invokes apoptosis. Apoptosis is an orderly

deconstruction of the cell where debris is internalized and not spilled out, an active process that requires energy and coordinated metabolic signaling networks. Necrosis is the fate of the cell that is unable to plan and execute its own funeral, thereby jeopardizing still intact neighboring tissues. Chapter 10 by Green and colleagues summarizes the essentials of cell death pathways and serves well as background reading for other pathologies described in this book.

3. The Many Facets of Hearing Loss

Although the subsequent chapters in some way build upon one another, each chapter is self-contained and will provide the reader with all necessary information. Inevitably, this attempt to make each chapter complete in itself will expose some redundancy should the reader engage in a cover-to-cover exploration of the book. For example, although the detailed description of homeostasis and cell death pathways was reserved for Chapters 3 and 10, brief discussions of these topics can be found in the appropriate context in other sections.

While the majority of this book is concerned with the many facets of acquired hearing loss, it is appropriate to start with a consideration of genetic factors that determine the function and the dysfunction of the auditory organ and may predispose it to environmental insults. At least one-half of all auditory impairment is of genetic origin, and 3 out of 1000 newborns carry a significant hearing loss. Shalit and Avraham (Chapter 2) review the revolution in genetics that, over the past decades, has given us profound insight into the genes that are involved in inner ear disorders.

In part overlapping with and extending the chapter on genetics from a physiological angle is Chapter 3 by Wangemann. The chapter considers disorders of the cochlea on a background of our understanding of cellular metabolism and regulation. Following an assessment of the principles of homeostatic mechanisms, Chapter 3 discusses the most prominent or well understood homeostatic disorders including connexin-related deafness, Pendred syndrome, Jervell Lange Nielsen syndrome, renal tubular acidosis with sensorineural deafness syndrome, Usher syndrome type 2B, Alport’s syndrome, and Ménière’s disease.

Tinnitus, a major enigma among hearing disorders, is the topic of Chapter 4. Most adults experience transient “ringing in the ears” as a minor discomfort. However, about 15% of the population are chronic sufferers, some of them to the extent of severe impairment of daily activities. Studies in a variety of animal models are now giving us insight into possible etiologies of the different forms of tinnitus, and even the human model is becoming accessible to objective research techniques. Bauer and Brozoski review current theories, potential mechanisms, and promising treatments.

During the last three decades, autoimmune inner ear disease has not only gained recognition as a genuine inner ear disorder but has also been an expanding subject of experimental research. The immune response in the inner ear, which can be beneficial in protecting from invading pathogens, can cause specific

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and significant pathology. In Chapter 5, Gopen and Harris discuss the basic immunology of the inner ear, the pathophysiology of the disease including animal models, as well as clinical diagnosis and treatment of autoimmune hearing loss.

Age-related hearing loss is a condition that will eventually affect all humans who live long enough. It represents the most prevalent neurodegenerative disease of aging, affecting 40% of the population by age 65 and 90% by age 80. The changes in hearing associated with presbycusis reflect alterations in both the cochlea and the central auditory pathways. In Chapter 6, Ohlemiller and Frisina discuss our current understanding of the various forms of age-related hearing impairment derived from clinical observations and animal models.

Noise-induced hearing loss and drug-induced hearing loss are probably the two forms of auditory trauma that have historically been most amenable to basic research because suitable animal models have long existed. Pathology akin to that seen in the human can be induced by noise exposure or the injection of ototoxic drugs, and it was a century ago that experimental studies of noise trauma in animals were initiated by Wittmaack (1907; see also Hawkins and Schacht 2005). Recent insights into the underlying mechanisms of noise trauma are reviewed by Henderson, Hu, and Bielefeld in Chapter 7.

Rybak, Talaska, and Schacht summarize the latest on drug-induced hearing loss in Chapter 8. Although more than 100 drugs are potentially “ototoxic,” two classes in particular demand attention today. Antineoplastic compounds such as cisplatin are indispensable tools against certain cancers, and aminoglycoside antibiotics are commonly used worldwide because of their efficacy paired with low cost. Promising clinical prevention to attenuate the toxic side effects is now emerging from basic studies on the underlying mechanisms by which these drugs kill the auditory sensory cells.

While these chapters primarily deal with the peripheral auditory system as the site of the initial lesion of auditory trauma, we must not underestimate the role that central defects can play in various pathologies, as mentioned in Chapter 4 on tinnitus by Bower and Brozoski and in Chapter 6 on presbycusis by Ohlemiller and Frisina. Morest and Potashner further detail the pathophysiology of central auditory pathways and its molecular basis in Chapter 9.

The complexity of the cellular regulation of cell death pathways and endogenous protective mechanisms are the topics of Chapter 10 by Green, Altschuler, and Miller. This chapter is not only a primer on the multifaceted nature of cell death, but the authors also outline the state-of-the-art attempts to protect the cochlea against environmental insults. In addition, this chapter contributes a detailed deliberation of the spiral ganglion neurons, which are affected by so many of the pathologies introduced in the other chapters.

Finally, in Chapter 11 Heller and Raphael tackle the question of how the deaf ear can be restored. This chapter is based on the most recent revolutionary developments in hair cell regeneration and stem cell therapy in the mammalian auditory system. It gives us the vision for the future when an already existing loss of hair cells and auditory function may be amenable to genetic and pharmacological manipulation.

4. Tomorrow

Despite the impressive progress in elucidating auditory pathologies and establishing the principles of intervention and repair, there still are major challenges ahead. The various chapters of this volume touch on some of the unresolved questions, which may range from the choice of an appropriate experimental model (e.g., in tinnitus, autoimmune hearing loss, homeostatic disorders) to the most effective therapies for prevention or reversal of hearing loss.

One overarching motif is the delineation of the basic principles of sensory cell death. While individual pathways to cell suicides or funerals are already beginning to be elucidated, we must realize that such pathways cannot be viewed in isolation, but constitute a complex and infinitely interrelated network. This network operates in a continuous fashion. The initial death throes of a cell are balanced by attempts at restoring homeostasis until one outweighs the other. Therefore, we cannot expect “only” apoptotic or necrotic signaling in a cell undergoing a challenge to its integrity and, even when a cell is committed to its demise, not a single but a plethora of intimately connected pathways will be activated. Once we know more about the intricacies of such networks, it may also become apparent whether different noxious stimuli act by distinctly different mechanisms or whether they provide trigger points through which eventually the same networks of cellular responses are invoked. As a case in point, drug-induced, noiseinduced, and age-related hearing loss all cause oxidative stress in the sensory cells and current research presents both differences and commonalities in the pathways of their death. With further understanding, the networks of cell death may turn out to be indeed distinct or essentially identical, which would have considerable consequences for any attempts at preventing cochlear pathologies.

In the context of cell death and its prevention, two problems will continue to demand our attention. One is the question why, among the different cell types of the cochlea and the vestibular system, the hair cells are so singularly sensitive to environmental insults. A few suggestions have been made, such as a heightened intrinsic susceptibility to oxidative stress (Sha et al. 2001), but a more thorough understanding is needed. Is there a difference in inducible survival pathways? Is there a difference in the readiness for apoptotic pathways? The answer to this question has direct bearing on our ability to design effective treatments for protection which may include pharmacological or genetic manipulations to confer improved resistance to hair cells. The other issue, already beginning to be addressed, is the “window of opportunity” for rescue, the time frame following an insult during which the damage to sensory cells or the spiral ganglion neurons can still be contained. We know that, depending on the severity of the insults, hair cells may be destroyed instantaneously, such as by an aggravated noise exposure, but this is only the initiation of a slow cascade of death that expands from the point of original insult to adjacent sites. Likewise drug-exposed and, in particular, aging hair cells die over an extended period of time, and it remains to be seen how attempts at rescue can capitalize on such delayed time courses of cell death.

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Even though we lack detailed knowledge of some of the basic pathological mechanisms, the next decade will likely see effective pharmacological protection against a number of the disorders that are discussed in this volume. Animal experimentation has clearly shown the principles of intervention for noiseinduced hearing loss, drug-induced hearing loss, and to a lesser extent for other pathologies. Although successful animal experimentation does not guarantee a translation into the clinic, initial trials on the prevention of gentamicin-induced hearing loss are highly encouraging by showing that a mechanism-based intervention can indeed have clinical utility. Formulation of protective medications should thus be possible based on already existing results. Additional drugs will, of course, be discovered and powerful models for high-throughput screening would be helpful in this context. Such high-throughput screening requires appropriate models for different disorders, and at the moment seems plausible only for drug-induced hearing loss. In vivo experimentation, although tedious, time consuming, and costly, will remain indispensable in studying most pathologies and will remain the ultimate test before any treatment can be translated into the clinic.

The future of clinical treatment will also go beyond pharmacological intervention. For the spiral ganglion, a protection by neurotrophic factors can be coupled with physiological stimuli such as sustained depolarization to activate survival mechanisms. Such a treatment may be integrated into cochlear implants that then serve both the delivery of sound sensation and survival or regenerative factors. Even deafness-induced plastic changes in central synaptic activities and signaling pathways may similarly come under pharmacological control.

Restoration of cochlear hair cells is currently considered the final frontier, and new tantalizing results may be boosted by developments in the areas of stem cell therapy and gene therapy. Thus, genetic hearing loss may become amenable to intervention based on success in correcting hearing function in mouse models (Probst et al. 1998). The problems of restoring hearing after the loss of hair cells, however, surpass those posed for intervention strategies. Even if such issues as cell-specific transfection and guided differentiation are being resolved, the auditory system poses exquisite challenges that go beyond simple restoration of cells. Hair cells must not only be restored and functional, they also must be arranged in the appropriate tonotopical organization with neural connections. Yet, we know very little at the moment about the molecular control of the cytoarchitecture of the mammalian cochlea.

While the challenges to resolve mechanisms of auditory trauma, design protection and accomplish repair are formidable, they are not—given time and resources—insurmountable. The unprecedented progress of the last decades that is documented in this volume is encouraging for the future of our field.

References

Bernard C (1878) Leçons sur les phénomènes de la vie. Paris: Ballière.

Cannon W (1929) Organization for physiological homeostasis. Physiol Rev 9:399–431. Hawkins JE, Schacht J (2005) Sketches of otohistory. Part 10: Noise-induced hearing

loss. Audiol Neurotol 10:305–309.