소음성난청 심현준 Hanyang Med Rev 2015;35: pissn X eissn 을지대학교의과대학서울을지병원이비인후과 Noise-Induced

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1 소음성난청 심현준 pissn X eissn 을지대학교의과대학서울을지병원이비인후과 Noise-Induced Hearing Loss Hyun Joon Shim Department of Otolaryngology, Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea Noise-induced hearing loss (NIHL) is the second most common cause of permanent hearing impairment after age-related hearing loss. NIHL is influenced by environmental and genetic factors and the effects of noise can be exacerbated by the administration of ototoxic drugs or exposure to chemicals. The pathophysiology of NIHL is classified as either mechanical injury or metabolic (or biochemical) injury. Exposure of cochleae to intense sounds has been found to disrupt the stereocilia on the hair cells by separating the tip links and to depolymerize actin filaments, resulting in a disturbance in signal transduction. Major mechanisms of metabolic injuries include accumulation of reactive oxygen species enhanced by oxidative stress, cochlear ischemia followed by reperfusion injury, and excitotoxicity to auditory neuron induced by excessive release of the cochlear afferent neurotransmitter, glutamate. Many studies involving therapeutic or preventive trial with antioxidants, JNK inhibitors, and NMDA antagonists have shown partial effectiveness. However, protection from noise before cochlear injury occurs is very important because damaged hair cells and auditory neurons in the mammalian cochleae are unable to regenerate. Key Words: Hearing Loss, Noise-Induced; Cochlea; Hair Cells, Auditory; Oxidative Stress; Apoptosis Correspondence to: Hyun Joon Shim 우 , 서울시노원구한글비석로 68, 을지병원이비인후과 Department of Otolaryngology, Eulji Medical Center, Eulji University School of Medicine, 68 Hangeulbiseok-ro, Nowongu, Seoul , Korea Tel: Fax: eardoc11@naver.com Received 25 February 2015 Revised 6 March 2015 Accepted 13 March 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 서론소음성난청은노화와관련된난청다음으로유병률이높은난청유형으로환경적요인과유전적소인의복합적인작용으로발생된다. 문헌에따르면전인구의약 1.7% 가소음성난청에의한장애를가지고있는것으로알려져있다 [1]. 미국의통계에따르면약 1,000만명의소음성난청환자가있으며약 3,000만명이소음에노출되고있다고한다 [2]. 그러나산업현장뿐아니라일상생활에서노출되는생활소음도꾸준히축적될경우소음성난청을유발할수있기때문에정확한유병률을산정하는것은불가능하다. 소음성난청은난청이외에이명, 이충만감, 청각과민등의증상을수반하기도한다. 소음성난청을예방하기위한약제들에대한연구가꾸준히이루어지고있고인간에게적용된예도있지만근본적 으로포유류의유모세포는일단손상을받아사멸하고나면재생이불가능하기때문에그치료에는한계가있다. 또한개인에따라소음에대한민감도가다르다는것은알려져있지만그민감한정도를미리검사할수있는도구는아직없는실정이다. 그러므로소음성난청을예방하기위해서는소음에노출되지않도록노력하고반드시소음에노출되어야되는현장에서는소음차폐를위한최선의노력을다하는것이가장중요하다. 특히산업현장이나총기류를다루는군대에서소음성난청에대한교육과적절한보호장구의착용은필수적이며이를위한제도적장치와사회적관심이필요하다. 최근들어주변소음이 80 db A에이를수있는교통수단내에서개인용음향기기의빈번한사용은또다른유형의위험인자로부각되고있다 Hanyang University College of Medicine Institute of Medical Science

2 심현준 소음성난청 분류소음성난청은일시역치변동 (temporary threshold shift), 영구역치변동 (permanent threshold shift), 그리고음향외상 (acoustic trauma) 으로분류할수있다. 일시적으로난청이발생하였다가회복되는일시역치변동의경우중등도크기의소음에노출되었다가 3-6 khz 대역의난청을나타내고회복은수분에서수일에걸쳐일어나는청력소실을말한다. 이러한일시역치변동상태에서추가적인소음노출이없음에도회복되지않고난청이지속되는경우영구역치변동이라고진단하게된다. 음향외상은영구역치변동의특별한형태로일시적이지만강력한소음에의해고막또는이소골등중이구조와난원창막, 정원창막또는 Corti기등내이구조물이기계적손상을받음으로써발생하고, 더흔한유형의영구역치변동은강도는약하지만오랜기간소음에지속적으로폭로되어와우내외유모세포와내유모세포등의미세구조물이서서히파괴됨으로써초래된다. 그러나아직일시역치변동과영구역치변동의연관성은명확히밝혀져있지않다. 지속적이고반복적인일시역치변동이영구역치변동으로진행될것이라고추정할수있겠지만두가지조직병리사이에는기본적인차이가있기때문에서로다른발생기전에의해발생된다고생각되기도한다. Nordmann 등은 chinchilla의조직병리소견에서영구역치변동의경우유모세포의결손과해당신경말단의변성등전형적인와우손상의소견을발견할수있는반면일시역치변동의경우손상받은주파수대역의기둥세포 (pillar cell) 가휘는현상만발견되었다고하였고지지세포들의액틴 (actin) 이부분중합해체반응 (partial depolymerization) 되었다가회복되는것으로추정된다 [3]. 또다른연구에서일시역치변동은유모세포 stereocilia의잔뿌리가짧아지고부러지는현상이발견되고 48시간에걸쳐위에서아래로재생되는것을관찰할수있는반면 [4], 손상이더강력할경우달팽이관 (cochlear duct) 구조에균열이발생하면서내림프가코르티 (Corti) 기내부로유입되고외림프와섞이면서유모세포의결손을유발하게되며이러한경우영구역치변동이발생하는것으로생각된다. 그외에도일시역치변동의발생기전은덮개막 (tectorial membrane) 이 stereocilia tip에서떨어졌다가다시붙으면서회복되거나내유모세포 / 청신경시냅스의 excitotoxicity가회복되는경우로설명하기도한다 [5]. 소음성난청의청각학적특성소음성난청의대략적인특성은첫째, 외유모세포에서시작되는유모세포손상그리고이러한병리소견과동반되는감각신경성난청, 둘째, 90 db A 이상의소음에하루 8시간이상지속적으로노출된병력셋째, 소음노출후첫 5-10년동안점차적으로청력이떨어져야하며넷째, 3-8 khz 주파수대역에서 2 khz 이하보다먼저난 청이발생하여야하며다섯째, 어음분별력이난청의정도에합당하여야하고여섯째, 소음폭로가중단되면난청도진행하지않아야한다는점이다 [6]. Davis 등의고전적인연구에의하면 1-20분정도의짧은기간의소음으로일시역치변동을유발시키면 4 khz 소음의경우에는 4 khz 의 1/2-1 octave 위에난청이집중되는반면 0.5 khz noise는 500-8,000 Hz 범위에넓게난청이초래하는것으로나타났다 [7]. 대규모역학연구에서광역대소음이 4 khz notch를만드는것은널리알려져있는사실이다. 4 khz notch에대해서는여러가지가설이있지만청각학적측면에서볼때소리가귓바퀴와외이도를통과하면서그공명주파수와일치하는 3 khz에중심주파수를가지는 bandpass noise로변환되어와우를자극하게되는데이때가장큰자극을받는부위는 3 khz보다 1/2 octave 높은 4 khz 부위이기때문으로생각한다 [8]. 소음성난청은이독성약물을동시에투여하거나이독성화학물질에동시에노출되는경우그손상이배가되며각각의원인에의해발생하는난청의합보다초과하게된다. 대표적인이독성약물에는 aminoglycoside와 cisplatin과같은백금 (platinum) 계항암제가있다. 소음성난청의효과를배가시킬수있는화학물질로는산업현장에서생성되는톨루엔, 헥센, 메칠수은, 아세틸납, 플라스틱제조공정에서나오는 trimethyltin chloride 와 styrene, 고무제조공정에서나오는 polyurethane 등이있고일산화탄소나시안화수소와같은대기오염물질등도마찬가지역할을할수있다. 소음에특성에따른손상을보면일시적인큰소음과그이후이어지는지속적인소음은두가지소음손상의단순한합보다더많은손상을야기시킨다는보고가있다 [9]. 산업현장에서착암기등에의해유발되는수완진동증후군 (hand-arm vibration syndrome) 과소음성난청간에도동반상승효과를보이는것으로밝혀졌다 [10]. 병태생리 1. 와우세포의병리소견외유모세포는와우내에서가장취약한세포로소음에가장먼저손상받게되는것으로알려져있다. 소음은먼저 stereocilia의골절과뒤틀림을유발함으로써덮개막과의연결에문제가생겨 shearing force의전달을떨어뜨리고, stereocilia 사이의 tip link가깨어지게되면 mechanotransduction에문제가유발된다. Chinchilla의경우 40 또는 50 db까지청력감소가오면외유모세포는완전소실되지만내유모세표와나선신경절세포 (spiral ganglion cell) 는외유모세포가완전유실되는시점부터유실되기시작한다 [11]. 이것은외유모세포가스스로늘었다줄었다하면서기저막을끌어당겨만들어내는능동적와우증폭과정 (active cochlear amplification) 이 db 이득을만들어내는사실에부합되는소견이다. Wang 등 85

3 Hyun Joon Shim Noise-Induced Hearing Loss 의연구에서 spiral ligament fibrocyte 의소실과소음노출량과의상관관계가매우높은것으로나타났는데, 이것은내림프에서들어온 K + 이온이 Henson cell과 Claudius cell을거쳐 spiral ligament fibrocyte를통하여혈관조 (stria vascularis) 로들어가재활용되는이른바 K + cycling과소음손상이관련되어있음을시사하는결과이다 [12]. 소음은감각세포뿐아니라지지세포에도영향을미치는데강력한소음은코르티기의지주역할을하고있는기둥세포들을기저막에서떨어져나오게하여기저부가첨부보다 200배더딱딱한기저막의임피던스분포에영향을주어소리에대한민감도와주파수분별력을떨어뜨리게된다. 유모세포의결손은소음노출후 30일간계속지속되고 [13], 외유모세포의결손부위는수일내로기저부방향으로진행하면서세포괴사 (necrosis) 와세포자멸사 (apoptosis) 두가지세포사멸의병리형태를모두보이게된다 [14]. 2. 와우혈류의변화음향외상과같은매우큰강도의소음의경우에는혈관계의작용이일어나기전에심한기계적손상에의해세포가대부분사멸하게되지만오랜기간지속되는소음노출은와우혈류량의변화를유발하고이변화가세포의사멸에역할을하게된다. 소음에의한와우혈류량의변화가와우세포들의사멸에영향을주는지반대로와우세포들의사멸에의해와우혈류량이떨어지는지분명하지는않지만소음에의해달팽이관혈류가감소하는현상은 Laser- Doppler로확인되었다 [15]. 또한소음손상에 CO를동시에노출시켜산소농도를떨어뜨리는경우외유모세포유실과난청이더욱심해지는현상은와우혈류량의감소가미치는영향을보여주는근거가된다 [16]. 와우혈류량은소음의매우초기에는다소증가하였다가시간이흐르면서떨어져한동안코르티기의허혈을가져오고그이후다시재관류 (reperfusion) 가일어나는일련의과정을겪게되는데허혈과재관류모두활성산소 (reactive oxygen species, ROS) 를다량생성함으로써세포사멸을유발하게된다 [17]. 또한소음에노출되었을때마그네슘을투여하여와우혈류량을증가시킴으로써소음성난청을감소시킬수있다는연구결과도발표되었다 [18; in guinea pig, 19; in human]. 3. 소음에의한와우손상기전소음노출에의한와우의손상기전은크게기계적 (mechanical) 손상과대사성 (metabolic) 손상으로설명되는데소음성난청의종류에따라그비중은차이가있는것으로보인다. 대개음향외상의경우에는기계적손상이주로작용하게되는데, 155 db psp로 30 분간 chinchilla에게소음을노출시킨경우코르티기가기저막에서탈출하고, 유모세포들은코르티기에서떨어지고, 외유모세포의일열과이열사이에균열이생기면서독성이강한내림프가코르티기내측을들어와세포내삼투압변화와세포사멸을일으키는것이 관찰되었다 [20]. 일시역치변동의경우에는 stereocilia에국한된회복가능한기계적손상이중요기전으로생각된다. 그러나상당한시간동안소음에노출되면서발생한영구역치변동의경우기계적인손상이손상의방아쇠역할을하고거기에이어지는대사성손상이세포사멸을결정하는것으로보인다. 대사성손상은첫째, 미토콘드리아에서 ROS나 reactive nitrogen species (RNS) 같은자유라디칼 (free radical) 의과다생성으로인한손상이다. 과다생성된 ROS는세포막에축적되어세포막을 lipid peroxidation 시키면서 4-hydroxy-2-noneal (4-HNE) 같은 phospholipids membrane peroxidation product 가 DNA와세포막에직접손상을일으키면서세포괴사를일으키거나세포자멸사를유발한다 [21]. 정상반응에서 98% 의 O 2 는미토콘드리아에서소비되어 ATP를만들어내고나머지 2% 는소모되지않고미토콘드리아또는그밖에서 superoxide (O 2- ) 나 hydrogen peroxide (H 2O 2) 로변하게되는데소음노출과같은병적인상태에서는와우의대사를매우빠르게하여몇배나많은양의 ROS가미토콘드리아에서생성되게된다. 소음손상에의해와우혈류량이줄어들면서미토콘드리아대사에필요한 O 2 는부족하게되지만 ROS는오히려증가되는결과를초래한다. 와우혈류량감소로코르티기의허혈이오게되고뒤에따라오는재관류 (reperfusion) 는또다른 ROS 증가의원인으로작용할수있다 [22]. 또한세포손상으로세포밖으로나오게되는물질중 Fe 성분은 Fenton reaction을통하여 H 2O 2 를 highly reactive and toxic hydroxyl radical (OH*) 로변화시킨다. 여러연구에서소음노출후 ROS가유모세포내에서지속적으로증가하는것이관찰되었다 [14,23]. Cochlea에 O 2 를 O 2* - 로전환시켜자유라디칼을증가시키는 paraquat를주입하여인위적으로 ROS 유발세포손상을일으켜그양상을소음손상과비교하였는데외유모세포의사멸이진행되는동안내유모세포는잘유지되고있는점 [24,25]. 그리고고음역대손상이먼저발생한다는점에서소음손상과매우유사한병리소견을보였다 [24]. 이는소음손상에서발생하는기계적손상없이대사성손상만으로도거의흡사한병리소견이나타난다는것을의미하며소음성난청발생에서특히 ROS 와관련되는대사성손상이중심적인역할을수행한다는것을의미한다고볼수있다. 둘째로는소음의기계적손상에의해외유모세포사이에균열이생기거나코르티기골격의어느부위에균열이생긴후내림프가코르티기내부로유입되면서외림프와섞이게되어세포내삼투압변화가일어나면서세포가사멸하게되는기전이다. 셋째로는내유모세포 / 나선신경세포시냅스에서발생하는 excitotoxicity이다. 내유모세포에서소리신호가전기신호로바뀌어활동전위가 I형나선신경세포, 구심성신경로를통하여중추청각계로전달되는일련의과정에서내유모세포 / 나선신경세포시냅스에는글루탐산염 (glutamate) 이신경전달물질로이용된다. 그런데크고지속적인소리자극이들어오는경우시냅스에과도한글 86

심현준 소음성난청 Fig. 1. Stress-activated MAPK signaling modules. The JNK and p38 MAPK are activated by dual phosphorylation on Thr and Tyr caused by members of the MAPKK group of protein kinases.

4 심현준 소음성난청 Fig. 1. Stress-activated MAPK signaling modules. The JNK and p38 MAPK are activated by dual phosphorylation on Thr and Tyr caused by members of the MAPKK group of protein kinases. The MAPKK are activated, in turn, by phosphorylation mediated by a group of MAP- KKK. Stress-activated MAPK signaling modules can be created through the sequential actions of a MAPKKK, a MAPKK, and a MAPK. Ref. 30 with permission from Cell Press. 루탐산염이분비되고 dendrite 의후시냅스세포막의투과성을변화시켜이온채널로작용하는수용체 (α-amino-3-hydroxy-5-methylisoxazonle-4-proprionic acid [AMPA] receptor, N-methyl-Daspartic acid [NMDA] receptor) 들을통해다량의양이온이유입된다. 다량의양이온유입은후시냅스세포막의지속적인탈분극을유도하고, 삼투압불균형에따른 Cl-와물의수동적인유입으로세포부종이일어나다가결국세포막이터져버리는세포괴사가일어나게된다 [26,27]. 청신경세포의사멸이내유모세포소실에의한이차적인현상인지내유모세포말단의글루탐산염의과다한분비에의한 excitotoxicity에의한것인지아직확실하지는않지만소음손상에의해시냅스와청신경내부에부종이관찰되는것은 excitotoxicity 를소음에의한청신경사멸의중대한기전으로볼수있는근거가된다 [28]. 4. 손상받은와우세포의사멸과정소음에의한손상이후회복되지못하면세포는사멸의과정을겪게되는데세포괴사와세포자멸사두가지과정모두관여된다. 세포괴사는외부자극에의한수동적메커니즘으로세포막안으로 Ca 2+ 가유입되면서물이수동적으로따라들어와세포가팽창하다가터지면서일어나는과정인반면, 세포자멸사는 gene-directed self-destruction mechanism 이다. 세포는지속적인외부자극에대해세포를생존시키거나자멸시키는두가지방향을모색하다가자멸쪽으로방향이정해지면여기에관련되는유전자에의해세포자멸이유도된다. 세포자멸사에서유전자에의해유도된 cell death signal은궁극적으로세포내부에서 caspase라는효소를활성화시켜핵분열, 세포의수축, 염색질 (chromatin) 응축, 세포막의수포화를일으키는데초기에는세포막자체는유지되다가결국 DNA 가수분해가되면서세포가 apoptotic body들로쪼개져서대식세포에서처리되는과정을겪게된다 [21,29]. 세포괴사의경우터져나온세포내부의독성물질들에의해인근세포들에도염증이나손상을일으킬수있는반면세포자멸사는그렇지않은특성을가진다. 세포자멸사는 oxidative stress, hypoxia, radiation, cytokine 등의의해 mitogene-activated protein kinase (MAPK, 예를들면 c- Jun NH 2-terminal kinase [JNK], p38) 의활성화로시작되는데이는 MAPKK kinase, MAPK kinase, MAPK로이어지는연속적인인산화과정에의한 kinase signaling cascade의결과이다 [21,29,30]. MAPK가 cell death signal을가진전사인자 (transcription factor) 인 c-jun, c-fos, ATF-2, EIK-1 등을만들어내면이어서 pro-apoptotic protein (Bax, Bim, Bak) 가전사된다 (Fig. 1)[21,30]. 그러면세포내에서는 caspase들이활성화되는데 caspae-3 활성화가최종공통과정이고, 외부자극제 (stimulus ligand) 가세포막에있는 death receptor (Fas/CD95, TNFRI/ CD120a) 와결합하여활성화된 caspase 8 가 caspase 3 를활성화시키는외인성과정과세포내의미토 콘드리아막전위가떨어지면서 cytochrome c 를분비하여 Adaf-1, caspase 9, caspase 3 를차례로활성화시키는내인성과정이있다 (Fig. 2)[30]. Cell survival signal 은 neurotrophic stimuli 에의해서 도생길수있고 ROS 등의스트레스에의해보상적으로생기기도 하며 neurotrophic factor (nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, 4) 들의감소가 MAPK 를활성화시켜세포자멸사를유도할수도있다. 소음노출후 caspase-8 와 caspase-9 가발현되고 pro-apoptotic protein 이증가하는것은세포자멸사가소음손상에의한세포사 멸과정의일부라는명백한증거이다 [31,32]. Hu 등의연구에의하면 1 시간의소음노출후불과 5 분만에외유모세포의세포자멸사가관 찰되고 30 분이지나게되면서병변이기저부방향으로확장되는데 세포자멸사와세포괴사두가지병리소견이함께관찰되었다고하 였다 [14]. 또한소음의정도에따라유전자발현에의해생성되는 Bcl-2 family protein 의종류에따라일시역치변동과영구역치변동 이결정될가능성도제기되었다. Vincente-Torres 등은일시역치변 동에서는 anti-apoptotic protein (Bcl-2FP, Bcl-x) 이외유모세포에서 발현되는반면영구역치변동을유발하는강력한소음에서는 proapoptotic protein (Bak, Bad) 이발현되는것을관찰하였다 [32]. 5. 중추청각로의변화 유모세포의결손과청신경섬유의퇴화는중추청각로에도이어 지는 axonal degeneration 을일으킨다. Chinchilla 에서와우핵 (cochlear nucleus) 의손상은주로복측와우핵 (ventral cochlear nu- 87

Hyun Joon Shim Noise-Induced Hearing Loss Fig. 2. Role of the JNK signaling pathway in stress-induced apoptosis. The caspase apoptotic machinery is illustrated in a simplified cartoon.

5 Hyun Joon Shim Noise-Induced Hearing Loss Fig. 2. Role of the JNK signaling pathway in stress-induced apoptosis. The caspase apoptotic machinery is illustrated in a simplified cartoon. Effector caspases, including caspase-3, are activated by initiator caspases that are activated by cell surface death receptors (caspase-8) and by the mitochondrial pathway (caspase-9). JNK is not required for death receptor signaling, but is required for caspase-9 activation by the mitochondrial pathway. Potential targets of JNK include members of the Bcl2 group of apoptotic regulatory proteins. Ref. 30 with permission from Cell Press. cleus) 에서일어나는데이부분에서는유모세포결손위치와부합하는 totnotoy를보이는반면경미한배측와우핵 (dorsal cochlear nucleus) 의손상은 totnotoy와무관한특성을보였다 [33,34]. 중추청각신경로각부위의역치변화를비교한연구에서하구 (inferior colliculus) 의신경이와우핵의경우보다더큰역치변화를보였다 [35]. 또한청신경과와우핵과는달리하구와청각피질 (auditory cortex) 에서는소음노출전보다 evoked potential 이증가하는현상이발견되었으며이것은손상받은주파수영역인근에서일어나는탈억제메커니즘에의해설명될수있다 [36,37]. 소음손상 2-30일후에하구에서글루탐산염 decarboxylase 의감소가측정되는것도같은원인으로추정된다 [38]. 소음성난청의조기진단 Psychophysical tuning curves라든가 frequency discrimination tasks와같은음향심리검사로미세한청력의변화를측정할수있지만시간이오래걸리고검사방법이까다로워임상적으로적용하기는어렵다. 임상에서적용할수있는검사도구로는이음향방사 (otoacoustic emission) 검사가가장유력하다. 소음에가장민감하게먼저반응하는세포가외유세포이므로이세포에서나오는반사를이용하는이음향방사검사는일반적으로순음청력검사보다먼저소음성난청에변화를보이는것으로알려져있다. 또한검사 가비교적간단하고, 비침습적이며객관적청력검사라는장점때문에임상적으로널리사용되고있다 [39]. 외유모세포는소음에가장민감하게손상받는세포이기도하지만소음에대한생체방어기전으로알려진원심성신경로를주로받아들이는세포이기도하다. 반대측귀에소리자극을주고동측의 OAE의감소를측정하는방법은 medial olivocochlear reflex를측정하는대표적이방법이다. 소음에지속적으로노출된경우에는피로현상으로반대측음자극에의한동측 OAE 감소현상이잘나타나지않는특성을이용하여와우의초기손상을예측할수있다는해석도있으며또한 medial olivocochlear reflex의정도로소음에대한개인간의민감도의차이를예측할수있다는해석도있다 [40,41]. 소음성난청의예방 1. 자연방어기전소음에대한자연방어기전으로중이강내등골근반사와 superior olivary complex 에서기원하는원심성신경이외유모세포에작용하는 medial olivary reflex 등두가지반사작용이있다. Medial orivary reflex는 II형나선신경절세포 / 외유모세포시냅스내로 GABA와 acetylcholine를분비시키고외유모세포내로 Ca 2+ 내입을감소시켜큰소리에대한감수성을떨어뜨린다 [42]. 대사성손상 88

6 심현준 소음성난청 에대하여도자연방어기전이발생하는데 natural ROS scavenger 라고일컫는 glutathione과 γ-glutamy cysteine synthetase, 그리고 anti-apoptotic protein인 heat shock protein, bcl-2 들이이코르티기에서발현되는것이관찰된다 [43,44]. 2. 조건화적은강도의소음에지속적으로노출시키게되면나중에큰소음이들어왔을때손상이덜하다는개념이다. 원래 preconditioning은뇌허혈에대하여활발하게연구되던주제로약한자극을지속적으로주면 HSP70, NF-кB, CREB 등이증가되고 JN, Bim 등이감소되면서 cell death보다는 cell survival에유리한분자생물학적환경이조성된다는원리를가지고있다 [45]. 지속적인소음노출이 hypothalamic-pituitary-adrenal axis에영향을주어혈중 glucocorticoid 농도를올리고와우의 glucocorticoid 수용체를상향조절함으로써큰소음에의한손상을줄일수있다는이론도있다 [46]. 또다른이론으로는적은강도의소음으로원심성신경로를단련시킴으로써큰소음에대한손상을줄일수있다는주장도있다. 그러나윤리적인문제로인간을대상으로한연구에서는한계가있다. 3. 약물동물실험들을통하여여러가지약제들을소음과같이투여하였을때역치변동을줄이는예방적효과가있음이밝혀졌다. 대표적인약제들로 1) 미토콘드리아의기능을유지시켜줄수있는 acetyl-l-carnitine, 2) 항산화제로서 glutathione (GSH), superoxide dismutase, N-acethyl L-cysteine (L-NAC), methionine, ebselen, salicylate [47], 3) RNS 길항제인 L-N ω -Nitroarginine methyl ester (L-NAME) [48], 4) NMDA 수용체길항제로서 excitotoxicity에의한손상을막을수있는 carbamathione, caroverine [49], 5) 세포자멸사의주요경로인 JNK 길항제인 CEP D-JNKI-1 등이있고 [50], 그밖에 magnesium, caspase inhibitor, transforming growth factor β1 inhibitor [51] 등에대한연구가이루어져있다. 하지만대부분의연구들은소음과약제를동시에투여하여약제의예방적효과를본것이지소음성난청발생이후치료적인효과를본연구는극히드물다. Yamashita 등은기니피그를이용한실험에서소음노출후 ROS 축적이서서히증가하여 7일에서 10일경절정에달하고항산화제를소음노출 3일이내에투여하기시작하였을때는역치변동을줄일수있어 3일을 time window 로제시하였다 [23]. 이연구는소음노출직후에국한되지만항산화제에의한예방효과가아닌치료효과를보여주는것으로평가할수있다. 이밖에도다른약제로소음노출의매우직후부터약제를투여하여일부소음성난청을일부경감시킨연구들은있으나치료제라고하기에는한계가많은것으로보인다. 인간을대상으로한임상실험으로마그네슘, L-NAC, Ebselen 을군인들에게복용시키고총기류훈련을시 킨후소음성난청의유병률과정도를조사한이중맹검실험들이 있었고일부의미있는효과를보이는것으로나타났다 [19,52]. 4. 기타 그밖에저출력레이저요법 (low level laser therapy) 을이용하여 실험동물에서산화성손상와세포자멸사를억제하여소음성난 청을예방할수있었다는보고가있으며 [53], 내측올리브와우각 반사 (medial olivocochlear reflex) 를강화하여소음손상을줄이려 는시도가있다 [54]. 결론 소음성난청은환경적요인과유전적소인에의해발생하는매우 흔한난청유형이다. 소음은와우내부구조에기계적손상과대사 성손상을일으키게되고 ROS, 와우혈류감소, 내림프액의유입, 시 냅스내의 excitotoxicity 등으로요약되는대사성손상과정을거치 면서와우내세포들을사멸시키게된다. 외유모세포는가장취약 하고먼저손상되는세포이고외유모세포의소실이모두일어난후 내유모세포와나선신경절세포의손상도동반된다. 소음은감각 세포뿐아니라지지세포와 spiral ligament fibrocyte 에도손상을 일으키게되고와우내구성세포들의손상으로인하여주파수분 별력의악화와청력역치의상승을초래하게된다. 소음에의한와 우의손상을예방하거나치료하기위한방법에대한연구가활발 히진행되고있지만아직임상에적용할수있는단계는아니며현 재로서는소음성난청이발생하기전에소음을차단하는것이최 선의방법이다. REFERENCES 1. Phaneuf R, Hetu R. An epidemiological perspective of the causes of hearing loss among industrial workers. J Otolaryngol 1990;19: Brink LL, Talbott EO, Burks JA, Palmer CV. Changes over time in audiometric thresholds in a group of automobile stamping and assembly workers with a hearing conservation program. AIHA J (Fairfax, Va) 2002;63: Nordmann AS, Bohne BA, Harding GW. Histopathological differences between temporary and permanent threshold shift. Hear Res 2000;139: Liberman MC, Dodds LW. Acute ultrastructural changes in acoustic trauma: serial-section reconstruction of stereocilia and cuticular plates. Hear Res 1987;26: Zheng XY, Henderson D, Hu BH, McFadden SL. Recovery of structure and function of inner ear afferent synapses following kainic acid excitotoxicity. Hear Res 1997;105: Lonsbury-Martin BL, Martin GK. Noise-induced hearing loss. In Flint PW, Haughey BH, Lund VJ, Niparko JK, Richardson MA, Robbins KT et al. eds. Cummings Otolaryngology Head & Neck surgery. 5th ed. Philadelphia: Mosby Elsevier; 2010:

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소음성난청과약국경영 (2) 저자김성철영남대학교임상약학대학원겸임교수약학정보원학술자문위원 개요 소음성난청은노화와관련된난청다음으로유병률이높은난청유형으로환경적요인과유전적소인의복합적인작용으로발생된다. 우리나라의통계는없지만많은문헌에따르면전인구의약 1.7% 가소음성난청에의한장애를가

소음성난청과약국경영 (2) 저자김성철영남대학교임상약학대학원겸임교수약학정보원학술자문위원 개요 소음성난청은노화와관련된난청다음으로유병률이높은난청유형으로환경적요인과유전적소인의복합적인작용으로발생된다. 우리나라의통계는없지만많은문헌에따르면전인구의약 1.7% 가소음성난청에의한장애를가지고있는것으로알려져있다. 그러나산업현장뿐아니라일상생활에서노출되는생활소음도꾸준히축적될경우소음성난청을유발할수있기때문에정확한유병률을산정하는것은불가능하다.