This review will briefly examine evidence supporting the hypothesis that sound causes changes in cochlear blood flow, intracochlear oxygen levels, and the morphology of cochlear blood vessels. A survey of the literature shows that traditional histopathological studies provided such evidence and that decreased cochlear blood flow can be demonstrated and measured by laser Doppler flowmetry and by direct observation of cochlear microvessels. Oxygen levels also decline and possibly to a greater degree than blood flow. There is also evidence that in certain circumstances sound can increase blood flow.
Reduced blood flow, or reduced oxygenation, is critically important in an organ system with high energy needs like the cochlea. Therefore, a second hypothesis, that sound-induced reduction in CBF represents a functional ischemia, will be explored in examining the relevance of traditional ischemia/reperfusion models to cochlear damage. It is found that reactive oxygen species (free radicals and oxidizing ions) are present in sound-induced hearing loss and thus there is evidence that an ischemia/reperfusion type of injury occurs during loud sound exposures.
|How to cite this article:|
Nuttall AL. Sound-induced cochlear ischemia/hypoxia as a mechanism of hearing loss. Noise Health 1999;2:17-31
| Introduction|| |
Among the many mechanisms by which sound may damage the cochlea is the reduction of cochlear blood flow (CBF). The notion that very loud sound (continuous or impulse noise) has the ability to reduce blood flow comes from morphological studies of the status of blood vessels and the blood cells within those vessels following sound (e.g., Hawkins, 1971). Related earlier studies showed reductions of intracochlear oxygen tension caused by sound (Misrahy et al., 1958a, b). However, it is still not known whether these effects of damaging sound levels are a direct result of sound energy impacting the circulatory system of the cochlea or are secondary to metabolic status or biochemical reactions during and following sound exposure. Similarly there is an uncertain relationship between blood flow changes and the pathophysiological mechanisms of damage to the sensory epithelium. If blood flow is sufficiently decreased by sound then it would follow that organ of Corti pathology should occur. But, it is also possible that sound independently stresses both the organ of Corti and the cochlear circulation. Damage to the sensory epithelium could then result in subsequent pathology in blood vessels, e.g., from toxic by-products of cell degeneration.
Extremely loud sounds have an immediate effect on cellular structures in the cochlea, and it is reasonable to speculate that mechanical (overload) disruption is a principal mechanism (Lurie et al., 1944). Intermediate level sound exposures (e.g., 90 to 130 dB SPL) seem to cause an accumulating pathology in the sensory epithelium. One may ask, what is the role of CBF, or of the blood flow dependent cochlear metabolic status in this pathology? This review examines the evidence for interpretation of moderate level sound-induced damage as an ischaemia and reperfusion type of injury. Ischaemia/reperfusion injury has been well studied in relation to stroke and cardiac disease, and studies of the inner ear can profit from this work (e.g., Nagahiro et al., 1998). The cochlea, and the stria vascularis in particular, have a high metabolic demand (Thalmann et al., 1978) meaning that appropriate blood flow is critical to the delivery of oxygen. Availability of oxygen at the sites of utilisation would be a controlling variable for efficient production of ATP. A shortfall in blood flow that results in a shortfall of oxygen (i.e. a hypoxia) available to mitochondria results in a well known excess production of reactive oxygen species (Chance et al., 1979).
Reactive oxygen species (ROS) are molecules produced in part as a natural by-product of aerobic metabolism. They can result from biochemical reactions involving nitric oxide, ferrous iron and other ions in the cytosol and in extracellular fluids (Wolin, 1996). Every cell and organ of the body has natural defensive molecules to control ROS by combining with them or catalyzing their conversion to less reactive products. In ischaemia/reperfusion injury the damage done by ROS strongly occurs to the plasma membrane of cells, as ROS are powerful oxidizers of lipids (Dormandy, 1989). Damage, therefore, is a balance between the production of ROS and the availability (orproduction) of detoxifying or protective molecules. This review will summarize some of the important evidence that oxygen availability and CBF deficiencies exist with moderate sound exposures and that ROS have a role in sound induced cochlear damage.
Sound-induced changes in cochlear vascular morphology
In 1958, Misrahy and colleagues showed that loud sound could reduce endolymphatic oxygen tension (Misrahy et al., 1958b; Misrahy et al., 1958a). Although the dramatic change in oxygen that they observed in this acute experiment could not be replicated in certain later experiments by others (Nuttall et al., 1981), it will be seen below that the general concept of a sound-induced hypoxia is well established. A reduction of the oxygen tension in endolymph strongly implicates cochlear microvessels as a target of sound energy. Perlman and Kimura (1962), by direct observation of cochlear microvessels in the living cochlea, observed halted flow in some capillaries during very intense sound stimulation. Hawkins (1971) was among the first to note the fine features of vascular morphology that are influenced by high-level sound exposure. [Figure - 1]A (from Hawkins, 1971; [Figure - 5] shows the effect of an 8-hour wideband noise exposure at 118-120 dB SPL on the capillary of the basilar membrane. Red blood cells are trapped by apparently swollen capillary endothelial cells. Sound-induced pathology of the capillaries in the lateral wall was also found [Figure - 1]B, from Hawkins, 1973; [Figure - 5]. "Intervascular strands", which are remnants of capillaries, widened pericapillary spaces, and avascular channels, from which capillaries had disappeared, were observed. These microvascular changes were similar to those described by Kuwabara and Cogan (1966) in the retina. Little research has been done since this work on the process and mechanism of devascularisation of the cochlear lateral wall and the basilar membrane, but similar capillary changes are seen after ototoxic drug administration (Hawkins, 1973).
Characterisation and quantification of cochlear vascular changes, following sound exposures, is one approach to determine whether there is a cochlear ischaemia. Axelsson et al. (1981) and colleagues (Vertes and Axelsson, 1981) conducted many of the most systematic studies aimed at quantifying the morphological variables of the capillaries of the lateral wall. These measurements include red blood cell density and many other parameters related to rheology. In general, their quantitative analysis of capillary morphology showed only minor effects of sound, but statistically significant changes were seen in a later study using a similar approach (Dengerink et al., 1984).
Microsphere-measured CBF, Oxygen Tension and the Endocochlear Potential:
A considerable effort has been expended to determine the actual changes in blood flow during and following sound exposures. The measurement of CBF is technically difficult, however. Radioactive and nonradioactive microspheres are the only methods yet applied to measure the absolute CBF value. Angelborg et al. (1979) were the first to accomplish such measurements and initial studies showed no effect of 100 dB SPL noise on cochlear blood flow in the anaesthetised rabbit. There was, also, no CBF change in response to 120 dB SPL exposure in conscious rabbits (Hultcrantz, 1979). Prazma and colleagues found either no effect of loud sound (Prazma et al., 1987) or an increase in CBF (Prazma et al., 1983; Prazma et al., 1988). However, another study using the microsphere method did show significant reduction in CBF (Hillerdal et al., 1987). These contrasting results are possibly accounted for by the difficulties of the microsphere method which, besides being primarily useful only as a single time point measurement, results in a very small yield of countable microspheres trapped in the cochlea. Whatever the problems that lead to this variability of results, investigators were driven to find alternative methods to measure CBF. Laser Doppler flowmetry emerged as a technique of choice for inner ear studies (see below).
The 2-deoxyglucose (2-DG) accumulation has been tried for the cochlea as a single time point measurement of CBF (Ryan et al., 1982). The 2DG method is an indirect measure of flow, but the Ryan et al. (1982) study suggests that CBF can increase during moderate sound exposures. Moderate sound-evoked CBF increase appears to have been corroborated by a later study using the laser Doppler flowmetry technology (Scheibe et al., 1993).
CBF is but one measure of the metabolic homeostatic condition of the cochlea. Hypoxia results from an imbalance between oxygen delivery and oxygen usage. Thus, the intracochlear oxygen tension is an important parameter to study. As mentioned above, (Misrahy et al., 1958a, b) observed a striking decrease of endocochlear oxygen tension during a sound exposure of 130-135 dB SPL. Although some support for these early data was published (Maass et al., 1976), the dramatic finding (an abrupt decline of >50%) has not been repeated in later studies (Nuttall et al., 1981; Thorne and Nuttall, 1989). [Figure - 2] presents composite data from two different studies of the decline in endolymphatic oxygen tension during sound exposure in the anesthetized guinea pig. The decline is not dramatic, i.e., occurring in seconds during a single, short sound exposure. The total fall in pO2 over a one hour exposure amounted to only about 25% [Figure 2A] for a one hour exposure to 110 dB SPL high-pass noise (Thorne and Nuttall, 1989). In a more recent study, a fall of perilymphatic pO2 amounted to about 25%,
180 minutes after a 30 min exposure to 106 dB SPL broadband noise [Figure - 2]B (Lamm and Arnold, 1998). There are technical difficulties associated with the microelectrode measurements of pO2, as sound may alter the physiochemical analysis properties of an electrode leading to an erroneous oxygen tension reading (Nuttall et al., 1981). Sound also changes the endocochlear potential and oxygen electrodes can be sensitive to the potential shift (Lubbers, 1966). On the whole, the oxygen tension experiments point to declining oxygen availability during a loud sound exposure. Although relatively small, the percentage pO2 change is a cumulative deficit and it is not known how significant this deficit is in the cochlea where energy needs are high. Moreover, recovery from the deficit could lead to reperfusion injury from the generation of oxygen-free radicals (see below).
The dependence of the endocochlear potential on oxygen metabolism suggests that the sound generated deficiency might lead to a fall in the endocochlear potential (EP). There are a number of studies that show a fall in EP for very loud sounds (e.g., over 125 dB SPL) (e.g., Wang et al.; 1990, Syka et al., 1981), while sound levels lower than 125 dB, but above 115 dB, seem to increase EP (Salt and Konishi, 1979; Wang et al., 1992). Lower sound levels, but those which decrease blood flow (see below) and intracochlear pO2, appear to have no effect on EP (Salt et al., 1981; Ma et al., 1995).
Since changes in EP can occur as a result of altered electrical resistance (Fex, 1959; Gifford and Guinan, 1987) of the organ of Corti, the interpretation of the increase (and decreases) is difficult. The lack of EP change for levels of sound that may reduce blood flow and pO2 is a paradox and might indicate an ability of O2 dependent ion pumps in the stria vascularis to function adequately, but at the cost of increased production of reactive oxygen by-products as discussed below.
Laser Doppler Flowmetry
The LDF technique was introduced for the study of CBF by Goodwin et al. (1984). The method has the important advantage of "real time" continuous determination of capillary blood flux 1 . It also has the ability to measure "regional" CBF, as the laser light is somewhat confined to the portion of the cochlea toward which the laser probe is aimed. It is sometimes stated in LDF reports that the technique "measures" blood flow from a volume of tissue 1 mm in diameter (Nilsson et al., 1980), but this remains a controversial issue, especially for the cochlea. The exact volume of cochlear tissue contributing to the Doppler velocity signal has not been determined, although some investigators have made attempts to define the measured volume by placing opaque objects between the probe and the bony wall of the cochlea (Scheibe et al., 1990). These and other technical issues are addressed by Miller and Nuttall (1990) and by others in a book edited by Shepherd and Oberg (1990).
A substantial literature has now accumulated on studies of CBF using the LDF method. It is a very efficient approach to determine whether a vasoactive pharmacological agent can induce changes in blood flow (see for example, Ohlsen et al., 1991). When used for examining the effects of loud sound, caution must be exercised because of the sound-induced artefact in the flow reading of the instrument. The nature of the artefact is reviewed by Miller and Nuttall (1990).
Thorne et al. (1987) showed that noise (highpass 10-40 kHz, 110 dB SPL) causes a gradual fall in CBF. Over the time period of 1 hour, the flow decreased by 25% in the mean response of a group of 13 guinea pigs relative to control levels prior to sound exposure. This result has been confirmed by subsequent studies (Scheibe et al., 1993). [Figure - 3]A illustrates the general trend toward CBF decline seen in the Thorne et al. study compared with recent measurements by Lamm and Arnold (1998) [Figure - 3]B. These results appear to be consistent with the general findings of the above-mentioned histological studies and with the direct observations of decreased flow velocity of red blood cells in the cochlea (Quirk et al., 1991). One must be careful, however, to compare the level of the sound exposure among the studies because increases or decreases in flow might occur for "ranges" of sound level (Nuttall, 1986; Miller and Nuttall, 1990). At the highest range (>110 dB SPL) acute damage could occur. The intravital microscope observations of red blood cell stasis are an example of this. In a midrange of sound exposure (100-110 dB SPL), the slowly accumulative effect of decreased blood flow would represent the ischaemia that is the hypothesis of this review paper. A lower level of sound could drive CBF based on the metabolic need of the cochlea. Scheibe et al. (1993) have reported an increase in CBF for relatively low sound levels, apparently confirming earlier studies which suggested such flow increases through the use of other methodologies (i.e., the above-mentioned 2-DG method and the autoradiographic method based on accumulation of iodoantipyrine [Ryan et al., 1988]).
Permeability and Endothelial cell injury
Given the severe capillary changes seen following intense sound, it would not be surprising that the usual function of the vascular endothelium, to partition the plasma from the interstitial space, is compromised. Permeability studies indicate the accumulation of highmolecular-weight horseradish peroxidase in the stria vascularis following intense sound (Hukee and Duvall, 1985). Of note, increased vascular permeability is a hallmark of ischaemia/reperfusion injury mechanisms in the brain (Chan, 1996). Unfortunately the mechanism of the permeability changes in the cochlea is unknown, but one may speculate that endothelial cells or their intercellular junctions in strial vessels are damaged by reactive oxygen species (ROS) generated during hypoxia or following ischaemia (see below for a further discussion of ROS).
It should be noted that there are other aspects and consequences of endothelial cell injury. One cause of increased microvascular permeability in ischaemia/reperfusion injury is from leukocytes, which become activated and adhere to the luminal wall (Granger et al., 1989). Thus far, this subject has not been systematically studied in the cochlea. Hultcrantz and Nuttall (1988; unpublished observations) tentatively observed leukocyte adhesion in a preliminary study of local mechanical injury of strial capillaries, but their observations did not include the venules. Nuttall (1987), in a study of normal flow velocity of red blood cells in the lateral wall of the cochlea, observed a particular mechanical vulnerability of the strial capillaries. Surgical manipulations to expose the soft tissue of the third cochlear turn in the guinea pig sometimes caused flow in the strial capillaries to halt, whereas nearby spiral ligament capillaries were not affected. The surgically damaged vessels (the capillaries) were filled with nonmoving red blood cells (Nuttall, 1987; unpublished observations). The mechanism of the mechanical damage is not known, but it could be related to the damage from extremely loud sounds.
Strategies to enhance CBF for protection against noise
A number of the experimental and clinical approaches to protection against noise-induced hearing loss involve mechanisms related to CBF and the oxygenation of the cochlea. These are such diverse procedures as sympathectomy, hyperbaric oxygen treatment and carbogen respiration. It is not within the scope of this review to address the literature concerning these and other approaches comprehensively, but is useful to consider a few examples and their relative success. Strategies in relation to ROS are covered in the next section.
Carbogen (95% O2:5% CO2) respiration is a relatively noninvasive treatment method. Carbogen can be freely respired by subjects or administered by artificial ventilation. Brown et al. (1982) showed that guinea pigs exposed to 120 dB SPL broad-band noise while breathing carbogen showed a reduction in hair cell loss and permanent threshold shift. This work was repeated using a variety of respiratory gases by Hatch et al. (1991), who found that the protective effect was achieved only if the carbogen or 100% oxygen was given during the sound exposure.
Kallanin et al. (1991) found the CBF changes induced by carbogen in anaesthetised guinea pigs were significant only when the guinea pigs received artificial respiration. Apparently, the partial pressure of CO2, which may cause vasodilation in the cochlea, may not be achieved by freely breathing carbogen. One conclusion to be drawn is that the excess oxygen available when respiring carbogen or elevated oxygen mixtures (not blood flow) is sufficient to protect the cochlea. This is consistent with the concept that oxygen therapy moderates the effect of an ischaemia from loud sound exposure. [Figure - 4] shows the considerable reduction of permanent threshold shift that was seen by Hatch et al. (1991). The enrichment of the blood with oxygen would compensate for low flow. Measurements of intracochlear oxygen during respiration with oxygen-enriched mixtures supports this concept by showing that perilymphatic and endolymphatic pO2 levels are increased during the oxygen respiration (Prazma, 1982). Moreover, Lamm et al. (1998) conclude, in a survey of the clinical literature, that hyperbaric oxygen treatment is effective, even following acoustic trauma.
Cochlear blood vessels are innervated by sympathetic neurons originating in the cervical sympathetic chain of ganglia (Spoendlin and Lichtensteiger, 1966). These nerves are thought to control the tonic level of blood flow (Laurikainen et al., 1997). Excessive sympathetic activity during loud sound exposure, as in a stress response, would cause vasoconstriction and enhance any ischaemic condition. Whereas Hultcrantz (1979) could not demonstrate any effect of sympathectomy on microsphere-measured CBF after noise exposure in rabbits. Borg (1982b), in contrast, showed that there was about a 10 dB protective effect for changes in auditory brainstem response on the sympathectomized side. The Borg study was done in rats exposed for one month to 100 dB SPL (linear weighting) wide-band noise. The protection did not extend to hypertensive rats (Borg, 1982a). The Borg results are supported by Hildesheimer et al. (1991), who found a lessened temporary threshold shift of the cochlear compound action potential (CAP). However, as in the microsphere study, an autoradiographic study of 2-DG uptake did not show altered uptake on the sympathectomized side during sound exposure (Meyer zum Gottesberge et al., 1987). These data suggest a protective effect for sympathectomy, but that blood flow control might not be involved. It is known that a portion of the sympathetic fibres is not associated with blood vessel (Spoendlin and Lichtensteiger, 1966), and perhaps these have some bearing on the protection. Nevertheless, it is instructive to note that hyperactive sympathetic fibres might contribute to a 10-20% reduction in blood flow based on studies that have investigated the effect of electrically stimulating the superior cervical ganglion (e.g., Ren et al., 1993b) or the inferior cervical (stellate) ganglion (e.g., Ren et al., 1993a).
Loud sound damage and reactive oxygen species.
The strong experimental evidence, that cochlear oxygen levels and blood flow decline during sound exposure, supports the general concept of ischaemia and reperfusion as an important pathophysiological process in sound-induced hearing loss. It is well known from studies of stroke that reactive oxygen species are a major source of cellular damage (Juurlink and Sweeney, 1997). For the cochlea, there has been accumulating evidence that ROS are involved in sound-induced damage. Seidman et al. (1991, 1993) were among the first to investigate ROS damage mechanisms in the cochlea. Animals that received prior treatment with superoxide dismutase (SOD) or allopurinol were compared with controls. SOD is a scavenger of superoxide radicals, while allopurinol reduces the formation of ROS by inhibiting xanthine oxidase. In the treated animals the levels of cochlear microphonic and CAP were partially preserved, following acute ischaemia from clamping the arterial supply to the cochlea. Since the CM is largely related to sound-evoked changes in the membrane potentials of outer hair cells (OHCs), the data suggest that ROS were present during sound exposure and possibly had effects on outer hair cells. These drugs also provided protection from threshold shift caused by 60 hours of 90 dB SPL broad-band noise exposure (Seidman et al., 1993).
In all studies published thus far, one cannot draw the conclusion that the ROS directly and primarily react with the OHCs because changes in CM or CAP can be the complex result of the little-understood alterations in the mechanoelectric feedback mechanisms of the organ of Corti. The feedback mechanisms are part of the "cochlear amplifier", and the changes could also be secondary to an altered endocochlear potential. The latter possibility is especially interesting because of the observation that ROS (in the form of superoxide anion radicals) have been histochemically labeled on the marginal surface of the stria vascularis (Yamane et al., 1995). There is much that needs to be learned about the targets of ROS in the cochlea and experimental models of the pathophysiology of damage are yet to be fully exploited. For example, Ren et al. (1995) found subtle changes in the cubic distortion product otoacoustic emission following whole-cochlea ischaemia in the gerbil. It should be possible to use whole cochlea ischaemia and otoacoustic emissions as a quantitative approach to study the efficacy of various treatments. The relative role of EP in organ of Corti pathology also needs to be sorted out in future studies.
That ROS can damage the function of the cochlea has been tested using the perilymphatic perfusion method (Clerici and Yang, 1996) and, additionally, direct ROS damage to isolated hair cells has been observed (Clerici et al., 1995; Ikeda et al., 1993). Furthermore, as for the brain,
ROS appear to be involved in "excitotoxic" processes whereby excess excitatory neurotransmitter is released to cause damage to dendrites of neurons (Puel et al., 1995). This type of damage, at least from direct ischaemia in other tissues, can be prevented by ROS scavengers (e.g., Miyamoto et al., 1989).
The strongest evidence available concerning the ROS and noise damage mechanisms comes from studies of the role of glutathione in the cochlea. Glutathione (GSH) is known to have an important function as an antioxidant in cellular systems. ROS are strongly generated by mitochondria (Chance et al., 1979). Glutathione is the most abundant cytoplasmic antioxidant in mammalian cells and it reacts directly with hydrogen peroxide to form water. The reaction is catalyzed by glutathione peroxidase. Glutathione depletion had been noted to increase the ototoxicity of kanamycin (Hoffman et al., 1988) and glutathione supplementation in dietary depleted guinea pigs reduced ototoxic hearing loss (Lautermann et al., 1995). In the cochlea, GSH is found to have a preferential distribution in the stria vascularis and the spiral ligament (Usami et al., 1996). Vascular endothelial cells also have high levels of GSH. Organ of Corti cells have less. GSH S-transferase has been found to have considerable overlap with the patterns of GSH labeling (el Barbary et al., 1993; Hjeller et al., 1998), giving confidence that GSH is biochemically used at its locations of high concentration. Presumably, the high concentration of GSH in the lateral wall is required to counteract a high production of ROS. Whether the relatively smaller amount of GSH in the organ of Corti contributes to a more effective targeting of ROS to hair cells is not known.
[Figure - 5] shows the permanent threshold shift observed (at three weeks post sound exposure) by Yamasoba et al. (1998) in guinea pigs subjected to two GSH-manipulating treatments as compared with control animals. All animals received 102 dB SPL broad-band noise for 3 hours/day for five consecutive days. The controls received an injection of saline every day. One experimental group (filled squares in [Figure - 5] received daily injections of Lbuthionine-[S,R]-sulfoximine (BSO) which is an inhibitor of GSH g-glutamylcysteine synthetase, the rate-limiting enzyme of GSH synthesis. Studies by others of cochlear levels of GSH following BSO administration have found small GSH reductions (Hoffman et al., 1988). The other animal group received daily injections of 2-oxothiazolidine-4-carboxylate (OTC) (filled triangles). Animals treated with BSO had statistically significant increases in the permanent threshold shift (PTS) of their ABR response to frequencies above 8 kHz.
The relative protection afforded by OTC seen in [Figure - 5] reached statistical significance at only one frequency (12 kHz). This is perhaps not unexpected in the experimental protocol of the study because OTC manipulations do not result in proportional changes of GSH (Meister, 1991). OTC is converted to cysteine in cells and the cysteine is in turn available for GSH synthesis. The fact that a trend toward reduced PTS is seen suggests several possibilities: 1) that GSH is depleted in sound exposure, 2) that cysteine, the substrate for GSH, is depleted, or 3) adaptive regulatory mechanisms of GSH production are affected by the sound. Although which actually occurs is not known, this study and similar findings by Jacono et al. (1998) show that sound does influence the GSH production and that this effect follows a particular temporal course. The GSH level in the lateral wall of the sound exposed guinea pig cochlea was significantly elevated within the time frame of two to four hours following a five hour sound exposure (Yamasoba et al., 1998a).
In addition to GSH, other evidence is available pointing to ROS damage mechanisms during sound exposures. For example, iron, an important redox intermediate that is known to promote the production of ROS and increase aminoglycoside ototoxicity (Conlon and Smith, 1998), has also been shown to influence the degree of noise induced hearing loss (Yamasoba et al., 1997). ROS blockers and scavengers can also protect against carbon monoxide toxicity to the cochlea, a possible hypoxic challenge (Fechter et al., 1997). Moreover, other natural mechanisms of free radical scavenging may be active in the cochlea; e.g., the type of melanin in the lateral wall appears to be correlated with the level of sound-induced damage (Barrenas, 1997) and melanin may act to reduce ROS (Jimbow, 1995).
| Conclusion|| |
Sound exposure at levels that cause permanent hearing loss also reduces cochlear blood flow and intracochlear oxygen. The resulting hypoxia can be pretreated by oxygen respiration or antioxidant protocols to decrease threshold shift and hair cell loss. ROS have been histochemically demonstrated in the cochlea following sound exposure and manipulations of endogenous antioxidants or related enzymes can protect the cochlea. The accumulated experimental evidence points to sound-induced microvascular pathology (or hypoxia that is functionally relevant) as an important component of noise induced hearing loss via ischaemia/reperfusion-induced ROS production.
Although the hypothesis of this paper is supported by the above work, further research is needed. It must be shown that "restoration" of CBF during sound exposure reduces ROS production in the cochlea and noise-induced damage and, conversely, that deficient CBF enhances ROS production and noise damage. The origin and cellular targets of ROS must be defined along with the specific biochemical pathways through which sound has its effect. The ischaemia/reperfusion hypothesis has implications for prevention and treatment of noise-induced hearing loss. In addition to rationales that improve CBF, blocking or scavenging ROS, by dietary, systemic drug protocols, and topical drug applications to the cochlea, should be feasible. To the extent that ROS production and tissue damage is reversible following ischaemia/reperfusion, post sound exposure treatments must also be discovered.
| Acknowledgement|| |
This work was supported by NIH NIDCD R01 DC 00105. The author is indebted to Prof. Joseph Hawkins for the original photomicrographs used in [Figure - 1].
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Alfred L Nuttall
Oregon Hearing Research Centre, NRC04, Department of Otolaryngology/Head & Neck Surgery, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97201-3098
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]