阻塞型睡眠呼吸中止，如同間歇性低氧之狀態，會於呼吸道產生大量反應性氧衍生物、造成呼吸道發炎和產生高反應性的呼吸道疾病，然而其中之致病機轉仍有待釐清。肺迷走C纖維 (lung vagal C fibers) 為主要的肺迷走感覺神經接受器，極易接受化學介質的刺激。呼吸道過度敏感，是因肺感覺神經，特別是肺迷走C纖維的敏感化，使得對於相同程度的化學刺激物，卻引發更強烈的感覺神經與反射反應，此現象也被認為與高反應性的呼吸道疾病之形成有關。事實上，收集相關文獻發現，間歇性低氧暴露後能造成NADPH oxidase活化，產生過量的反應性氧衍生物，進一步造成能量調節的酵素AMP-activated protein kinase (AMPK) 活化，而AMPK可促使肺組織發炎。另外，越來越多證據顯示大量的反應性氧衍生物和發炎物質，例如cyclooxygenase代謝產物，能夠敏感化肺迷走C纖維，最後導致呼吸道過度敏感之形成。根據上述之推測，間性低氧模式能夠造成過量反應性氧衍生物之產生、發炎物質之釋放和肺迷走C纖維敏感化，然而彼此之間的因果關係與相關機轉，仍有待進一步釐清。
本論文第一部份的研究，主要探討反應性氧衍生物敏感的AMPK之發炎過程，於24小時間歇性低氧藉由肺迷走C纖維參與而引發大鼠呼吸道過度敏感之角色。我們利用清醒大鼠分別暴露於持續24小時空氣或持續24小時間歇性低氧，另在間歇性低氧暴露前預處理N-acetyl-L-cysteine (NAC；一種抗氧化劑)、Compound C (一種AMPK抑制劑)、ibuprofen （一種cyclooxygenase抑制劑）或它們的溶劑。在暴露結束後立即進行實驗，我們發現持續24小時間歇性低氧暴露的大鼠相較於空氣暴露的大鼠，經由頸靜脈注射辣椒素 (capsaicin)、苯基二鳥胺酸 (phenylbiguanide) 或α,β亞甲基三磷酸腺苷 (α,β-methylene-ATP) 所引發的肺迷走C纖維參與之呼吸暫停反應和肺迷走C纖維的神經放電反應皆明顯增強。而此增強的反應在間歇性低氧暴露結束後的6小時開始遞減，並在結束後的12小時消失。此外，24小時間歇性低氧暴露後，增強化學刺激物引發的肺迷走C纖維參與的呼吸暫停反應和肺迷走C纖維神經活性之反應，可被預處理NAC、Compound C或ibuprofen顯著地減弱，但預處理溶劑則無此效果。再者，在生化檢驗數據方面，持續24小時間歇性低氧暴露後，代表氧化壓力的脂質過氧化作用、代表AMPK活化的AMPK磷酸化和一種cyclooxygenase的代謝產物－PGE2，皆比空氣暴露組顯著的增加。經由持續24小時間歇性低氧暴露後，肺組織脂質過氧化的增加可以經由預處理NAC而消除，但預處理Compound C或ibuprofen則無影響。24小時間歇性低氧暴露後可增加肺組織AMPK磷酸化，此作用可經由預處理NAC或Compound C而完全消除，但預處理ibuprofen則無明顯的作用。最後，經由持續24小時間歇性低氧暴露後，肺泡灌洗液內PGE2的增加，可以經由上述三種抑制劑的前處理而減少。此外，當預處理這些抑制劑的溶劑對於間歇性低氧暴露後所造成上述的結果，皆無顯著的影響。以上這些結果顯示，24小時間歇性低氧暴露後，可導致肺迷走C纖維敏感化，進而增強化學刺激物引發的呼吸暫停反應和肺迷走C纖維放電反應；而此作用是因呼吸道的一連串發炎反應，包括反應性氧衍生物的增加、AMPK的活化和cyclooxygenase代謝產物的釋放所導致。
本論文第二部份的研究，主要探討14天間歇性低氧暴露後是否可擴大化學刺激物引發肺迷走C纖維的反射反應與神經活性，並探討反應性氧衍生物與NADPH oxidase在此呼吸道過度敏感所扮演之角色。清醒大鼠分別暴露於14天空氣、14天間歇性低氧，另在有或無間歇性低氧暴露前每天預處理MnTMPyP （一種superoxide anion驅除劑）、apocynin （一種NADPH oxidase的抑制劑）或是溶劑。於第14天間歇性低氧暴露結束後的16小時，麻醉的大鼠經由頸靜脈注射化學刺激物，辣椒素 (capsaicin)、腺苷酸 (adenosine) 或α,β亞甲基三磷酸腺苷 (α,β-methylene-ATP) 誘發的呼吸暫停反應相較於空氣暴露組更為增強。此增強的反應可以藉由雙側迷走神經截斷或神經周圍辣椒素處理法 （可選擇性阻斷肺迷走C纖維神經的傳導）而消除；另外，14天間歇性低氧暴露後引發的呼吸暫停反應增強，可以藉由每天間歇性低氧暴露前預處理MnTMPyP或apocynin而避免，然而每天預處理抑制劑的溶劑則無此影響。而在電生理實驗中可以看到，14天間歇性低氧暴露後16小時，大鼠麻醉後經由頸靜脈注射化學刺激物可導致肺迷走C纖維放電反應顯著增強，但此增強反應並沒有在7天間歇性低氧暴露後的大鼠觀察到。而若在14天間歇性低氧暴露前每天預處理MnTMPyP或apocynin，則可以有效地抑制經由間歇性低氧造成的肺迷走C纖維放電反應增強的情形。最後，生化檢驗數據的結果顯示，14天間歇性低氧暴露後，代表氧化壓力的脂質過氧化明顯增加，此外代表NADPH oxidase活化指標的細胞膜上p47phox的表現量也顯著的提高。而脂質過氧化增加可以經由預處理MnTMPyP或apocynin而減少；但是細胞膜上p47phox的表現量增加只可以藉由預處理apocynin而消除。綜合上述結果顯示，大鼠於14天間歇性低氧暴露後，可以導致肺迷走C纖維敏感化，進而造成化學刺激物引發的呼吸暫停反應和肺迷走C纖維放電反應增強，此敏感化現象主要是藉由NADPH oxidase活化產生反應性氧衍生物造成。
綜合兩個研究主題結果我們的結論為，間歇性低氧暴露後，經由頸靜脈注射化學刺激物，可導致肺迷走C纖維敏感化，進而擴大化學刺激物引發的呼吸暫停反應。此間歇性低氧引發的敏感化作用，可能是藉由呼吸道一連串發炎物質反應，包含：NADPH oxidase活化產生反應性氧衍生物、AMPK的活化和cyclooxygenase代謝產物的釋放。我們的發現，可進一步地了解阻塞型睡眠呼吸中止病患伴隨高反應性的呼吸道疾病的病理機轉和提供可能的治療方針。

Obstructive sleep apnea (OSA), manifested by airway exposure to intermittent hypoxia (IH), is associated with excess reactive oxygen species (ROS) production in airways, airway inflammation, and hyperreactive airway diseases; however, the cause-effect relationship for these events remains unclear. Lung vagal C fibers (LVCFs), a major type of lung vagal sensory receptors, are known to be sensitive to chemical stimuli. Airway hypersensitivity is characterized by augmented sensory and reflex responses to stimuli because of sensitization of lung afferents, particularly LVCFs, which have been implicated in the development of hyperreactive airway diseases. In fact, IH can cause excess ROS generation via activation of NADPH oxidase, which in turn activates AMP-activated protein kinase (AMPK), a critical regulator of energy, and these events ultimately may lead to promotion of lung inflammation. Accumulating evidence suggests that excess ROS and inflammatory mediators such as cyclooxygenase metabolites may sensitize LVCFs, which then leads to the development of airway hypersensitivity. Accordingly, an experimental model of IH that can induce a cascade of excess ROS, increased inflammatory mediators, and LVCF hypersensitivity is required to study the cause-effect relationship and the underlying mechanism.
Our first study investigated the inflammatory role of ROS-sensitive AMPK in IH-induced airway hypersensitivity mediated by LVCFs in rats. Conscious rats were exposed to room air (RA) or IH with or without treatment with N-acetyl-L-cysteine (NAC, an antioxidant), Compound C (an AMPK inhibitor), ibuprofen (a cyclooxygenase inhibitor), or their vehicles. Immediately after exposure, we found that intravenous capsaicin, phenylbiguanide, or α,β-methylene-ATP evoked augmented LVCF-mediated apneic responses and LVCF afferent responses in rats subjected to 24-h IH exposure in comparison with those in 24-h RA rats. The potentiating effect of IH on LVCF responses decreased at 6 h after and vanished at 12 h after the termination of IH exposure. The potentiating effect of 24-h IH on LVCF-mediated apneic and LVCF afferent responses to chemical stimulants was significantly attenuated by treatment with NAC, compound C, or ibuprofen, but not by their vehicles. Further biochemical analysis revealed that rats exposed to IH for 24 h displayed increased lung levels of lipid peroxidation (an index of oxidative stress), AMPK phosphorylation (an index of AMPK activation), and prostaglandin E2 (a cyclooxygenase metabolite), compared with those exposed to RA for 24 h. 24-h IH-induced increase in lipid peroxidation was considerably suppressed by treatment with NAC but not by compound C or ibuprofen. IH-induced increase in AMPK phosphorylation was totally abolished by NAC or compound C but not by ibuprofen. 24-h IH-induced increase in prostaglandin E2 was considerably prevented by any of these three inhibitor treatments. The vehicles of these inhibitors exerted no significant effect on the three IH-induced responses. These results suggest that 24-h IH exposure sensitizes LVCFs, leading to an exaggerated reflex and afferent responses to chemical stimulants in rats. Moreover, this 24-h IH-induced LVCF sensitization is mediated through a cascade of inflammatory responses in the airways involving increases in ROS, AMPK activation, and cyclooxygenase metabolite release.
Our second study investigated whether 14-day IH augments the reflex and afferent responses of LVCFs to chemical stimulants and the roles of ROS and NADPH oxidase in such airway hypersensitivity. Rats were exposed to room air (RA) or 14-day IH with/without daily treatment with MnTMPyP (a superoxide anion scavenger), apocynin (an NADPH oxidase inhibitor), or vehicle. At 16 h after their last exposure, intravenous capsaicin, adenosine, or α,β-methylene-ATP evoked an augmented apneic response in anesthetized rats with 14-day IH exposure, compared to anesthetized rats with 14-days RA exposure. The augmented apneic responses to these LVCF stimulants were abolished by bilateral vagotomy or perivagal capsaicin treatment, which block LVCFs neural conduction and were significantly suppressed by treatment with MnTMPyP or apocynin, but not vehicle. Electrophysiological studies revealed that 14-day IH exposure potentiated the responses of LVCFs to these stimulants. This effect was inhibited by treatment with MnTMPyP or apocynin treatment and was not seen in rats who received 7-days of IH exposure. Biochemical analysis indicated that 14-day IH exposure increased both lung lipid peroxidation, which is indicative of oxidative stress, and expression of the p47phox subunit in the membrane fraction of lung tissue, which is an index of NADPH oxidase activation. The former was prevented by treatment with either MnTMPyP or apocynin, while the later was prevented by treatment with apocynin only. These results suggest that 14-day IH exposure sensitizes LVCFs in rats, leading to an exaggerated reflex and afferent responses to stimulants and that this sensitization is mediated via ROS generated by NADPH oxidase.
In conclusion, IH exposure sensitizes LVCFs and augments reflex apneic responses to chemical stimulants of LVCFs. This sensitizing effect of IH appears to be mediated through a cascade of inflammatory responses involving action of ROS derived from NADPH oxidase, AMPK activation, and releases of cyclooxygenase metabolites in the airways. Our findings may provide novel information for better understanding of the pathogenic mechanisms of OSA-associated hyperreactive airway diseases and potential therapy.

目錄

中文摘要 i
英文摘要 iv
目錄 vii
圖目錄 xi
表目錄 xiii
壹、緒言 1
貮、文獻回顧及研究目的 4
一、本研究的重要性 4
二、間歇性低氧 5
三、間歇性低氧對生理之影響 6
四、肺迷走感覺神經-肺迷走C纖維 (Lung vagal C-fibers; LVCFs) 7
五、間歇性低氧暴露後引發反應性氧衍生物之產生 10
六、間歇性低氧暴露後引發的發炎物質 12
七、間歇性低氧暴露後引發肺迷走C纖維敏感化之可能機轉 15
八、研究目的 16
參、實驗材料與方法 18
一、第一部份實驗：間歇性低氧藉由反應性氧衍生物誘發肺迷走C纖維敏感化之機轉 18
1、間歇性低氧之暴露 18
2、動物麻醉和基本手術 18
3、呼吸參數之測量 19
4、迷走感覺神經周圍辣椒素處理法 (Perivagal Capsaicin Treatment, PCT) 19
5、單根神經分離與記錄 20
6、心房導管手術 21
7、肺組織脂質過氧化反應之測定 22
8、支氣管肺泡灌洗液 (Bronchoalveolar lavage fluid, BALF) 製備 22
9、酵素連結免疫吸附法 (Enzyme-linked immunosorbent assay, ELISA) 23
10、西方墨點法 (Western blot) 23
11、實驗藥物使用與製備 25
12、實驗設計與組別分配 26
13、數據分析與統計 28
二、第二部分實驗：14天間歇性低氧誘發反應性氧衍生物和造成肺迷走C纖維敏感化之機轉 29
1、間歇性低氧之暴露 29
2、動物麻醉和基本手術 29
3、呼吸參數之測量 30
4、迷走感覺神經周圍辣椒素處理法 (Perivagal Capsaicin Treatment, PCT) 30
5、單根神經分離與記錄 30
6、肺組織脂質過氧化反應之測定 30
7、西方墨點法 (Western blot) 30
8、實驗藥物使用與製備 32
9、實驗設計與組別分配 33
10、數據分析與統計 35
肆、實驗結果 36
一、第一部份實驗：間歇性低氧藉由反應性氧衍生物誘發肺迷走C纖維敏感化之機轉 36
1、基本生理參數 36
2、持續24小時間歇性低氧處理後，肺迷走C纖維在化學刺激物刺激呼吸暫停反應中的角色 36
3、持續24小時間歇性低氧處理後化學刺激物對於肺迷走C纖維反應的影響 37
4、反應性氧衍生物、AMPK和環氧合酶代謝產物在持續24小時間歇性低氧誘發呼吸暫停反應和肺迷走C纖維反應的角色 38
5、持續24小時間歇性低氧暴露後大鼠肺臟脂質過氧化、AMPK磷酸化和PGE2的表現 38
二、第二部分實驗：14天間歇性低氧誘發反應性氧衍生物和造成肺迷走C纖維敏感化之機轉 39
1、基本生理參數 39
2、14天間歇性低氧處理後，肺迷走C纖維在化學刺激物刺激呼吸暫停反應中的角色 40
3、14天間歇性低氧處理後化學刺激物對於肺迷走C纖維反應的影響 40
4、反應性氧衍生物和NADPH oxidase (NOX) 在14天間歇性低氧誘發呼吸暫停反應和肺迷走C纖維反應的角色 41
5、14天間歇性低氧暴露後大鼠肺臟脂質過氧化和p47phox在肺臟的表現 41
伍、討論 43
一、本研究的主要發現 43
二、間歇性低氧藉由反應性氧衍生物誘發肺迷走C纖維敏感化之機轉 45
三、14天間歇性低氧誘發反應性氧衍生物和造成肺迷走C纖維敏感化之機轉 48
四、本研究的生理意義及未來應用 50
五、結論 51
陸、圖表與說明 52
柒、參考文獻 74
捌、附錄 (研究成果) 95

圖目錄

圖一、間歇性低氧處理之氧氣濃度變化 53
圖二、右側頸部迷走神經的單根神經分離與記錄示意圖 54
圖三、實驗裝置及各項生理參數測量之示意圖 55
圖四、兩隻分別持續暴露24小時空氣 (RA) 或間歇性低氧 (IH) 之大鼠對於三種化學刺激物引發的呼吸暫停反應 57
圖五、肺迷走C纖維在間歇性低氧後三種化學刺激物誘發大鼠呼吸暫停反應所扮演的角色 58
圖六、兩隻分別持續暴露24小時空氣 (RA) 或間歇性低氧 (IH) 之大鼠對於三種化學刺激物引發的肺迷走C纖維反應 59
圖七、持續24小時間歇性低氧對肺迷走C纖維敏感化的影響 60
圖八、反應性氧衍生物、AMPK和環氧合酶代謝產物在持續24小時間歇性低氧暴露後三種化學刺激物誘發呼吸暫停反應和肺迷走C纖維反應的角色 61
圖九、持續24小時間歇性低氧暴露後大鼠肺臟脂質過氧化、AMPK磷酸化和PGE2的表現量 62
圖十、兩隻空氣 (RA) 或14天間歇性低氧暴露之大鼠對於三種化學刺激物引發的呼吸暫停反應 64
圖十一、肺迷走C纖維在14天間歇性低氧後三種化學刺激物誘發大鼠呼吸暫停反應所扮演的角色 66
圖十二、兩隻分別暴露空氣 (RA) 或14天間歇性低氧之大鼠對於三種化學刺激物誘發的肺迷走C纖維反應 67
圖十三、14天間歇性低氧對肺迷走C纖維敏感化的影響 68
圖十四、反應性氧衍生物和NADPH oxidase (NOX) 在14天間歇性低氧暴露後三種化學刺激物誘發呼吸暫停反應的角色 69
圖十五、反應性氧衍生物和NADPH oxidase (NOX) 在14天間歇性低氧處理後三種化學刺激物誘發肺迷走C纖維反應的角色 70
圖十六、大鼠肺臟脂質過氧化和p47phox的表現量 71

表目錄

表一、14天空氣或間歇性低氧暴露前與暴露後大鼠的體重變化 72
表二、肺迷走C纖維在不同組別的基礎神經反應 73

Aboubakr, S.E., Taylor, A., Ford, R., Siddiqi, S., Badr, M.S., 2001. Long-term facilitation in obstructive sleep apnea patients during NREM sleep. J Appl Physiol 91, 2751-2757.

Abramov, A.Y., Scorziello, A., Duchen, M.R., 2007. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27, 1129-1138.

Al-Delaimy, W.K., Manson, J.E., Willett, W.C., Stampfer, M.J., Hu, F.B., 2002. Snoring as a risk factor for type II diabetes mellitus: a prospective study. Am J Epidemiol 155, 387-393.

Alexander, A., Cai, S.L., Kim, J., Nanez, A., Sahin, M., MacLean, K.H., Inoki, K., Guan, K.L., Shen, J., Person, M.D., Kusewitt, D., Mills, G.B., Kastan, M.B., Walker, C.L., 2010. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A 107, 4153-4158.

Alonso-Fernandez, A., Garcia-Rio, F., Arias, M.A., Hernanz, A., de la Pena, M., Pierola, J., Barcelo, A., Lopez-Collazo, E., Agusti, A., 2009. Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial. Thorax 64, 581-586.

Barnes, P.J., 1996. Neuroeffector mechanisms: the interface between inflammation and neuronal responses. J Allergy Clin Immunol 98, 73-83.

Bautista, T.G., Xing, T., Fong, A.Y., Pilowsky, P.M., 2012. Recurrent laryngeal nerve activity exhibits a 5-HT-mediated long-term facilitation and enhanced response to hypoxia following acute intermittent hypoxia in rat. J Appl Physiol 112, 1144-1156.

Bazan, N.G., Palacios-Pelaez, R., Lukiw, W.J., 2002. Hypoxia signaling to genes: significance in Alzheimer's disease. Mol Neurobiol 26, 283-298.

Bedard, K., Krause, K.H., 2007. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87, 245-313.

Beg, Z.H., Allmann, D.W., Gibson, D.M., 1973. Modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity with cAMP and wth protein fractions of rat liver cytosol. Biochem Biophys Res Commun 54, 1362-1369.

Bergren, D.R., Peterson, D.F., 1993. Identification of vagal sensory receptors in the rat lung: are there subtypes of slowly adapting receptors? J Physiol 464, 681-698.

Birring, S.S., Parker, D., Brightling, C.E., Bradding, P., Wardlaw, A.J., Pavord, I.D., 2004. Induced sputum inflammatory mediator concentrations in chronic cough. Am J Respir Crit Care Med 169, 15-19.

Bonekat, H.W., Hardin, K.A., 2003. Severe upper airway obstruction during sleep. Clin Rev Allergy Immunol 25, 191-210.

Bradley, T.D., Floras, J.S., 2009. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 373, 82-93.

Brandes, R.P., 2003. A radical adventure: the quest for specific functions and inhibitors of vascular NAPDH oxidases. Circ Res 92, 583-585.

Brzecka, A., Pawelec-Winiarz, M., Piesiak, P., Nowak, E., Jankowska, R., 2011. Suppression of chronic nocturnal cough during continuous positive airway pressure (CPAP) treatment in a patient with asthma and obstructive sleep apnea syndrome. Pneumonol Alergol Pol 79, 121-126.

Burki, N.K., Lee, L.Y., 2010. Mechanisms of dyspnea. Chest 138, 1196-1201.

Canning, B.J., Mori, N., Mazzone, S.B., 2006. Vagal afferent nerves regulating the cough reflex. Respir Physiol Neurobiol 152, 223-242.

Carling, D., Thornton, C., Woods, A., Sanders, M.J., 2012. AMP-activated protein kinase: new regulation, new roles? Biochem J 445, 11-27.

Carlson, C.A., Kim, K.H., 1973. Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation. J Biol Chem 248, 378-380.

Carpagnano, G.E., Lacedonia, D., Foschino-Barbaro, M.P., 2011. Non-invasive study of airways inflammation in sleep apnea patients. Sleep Med Rev 15, 317-326.

Carpagnano, G.E., Spanevello, A., Sabato, R., Depalo, A., Turchiarelli, V., Foschino Barbaro, M.P., 2008. Exhaled pH, exhaled nitric oxide, and induced sputum cellularity in obese patients with obstructive sleep apnea syndrome. Transl Res 151, 45-50.

Carr, M.J., Lee, L.Y., 2006. Plasticity of peripheral mechanisms of cough. Respir Physiol Neurobiol 152, 298-311.

Carr, M.J., Undem, B.J., 2001. Inflammation-induced plasticity of the afferent innervation of the airways. Environ Health Perspect 109 Suppl 4, 567-571.

Carr, M.J., Undem, B.J., 2003. Bronchopulmonary afferent nerves. Respirology 8, 291-301.

Chakraborti, S., Gurtner, G.H., Michael, J.R., 1989. Oxidant-mediated activation of phospholipase A2 in pulmonary endothelium. Am J Physiol 257, L430-437.

Chan, C.S., Woolcock, A.J., Sullivan, C.E., 1988. Nocturnal asthma: role of snoring and obstructive sleep apnea. Am Rev Respir Dis 137, 1502-1504.

Chan, K., Ing, A., Birring, S.S., 2015. Cough in obstructive sleep apnoea. Pulm Pharmacol Ther 35, 129-131.

Chan, K.K., Ing, A.J., Laks, L., Cossa, G., Rogers, P., Birring, S.S., 2010. Chronic cough in patients with sleep-disordered breathing. Eur Respir J 35, 368-372.

Chang, M.Y., Ho, F.M., Wang, J.S., Kang, H.C., Chang, Y., Ye, Z.X., Lin, W.W., 2010. AICAR induces cyclooxygenase-2 expression through AMP-activated protein kinase-transforming growth factor-beta-activated kinase 1-p38 mitogen-activated protein kinase signaling pathway. Biochem Pharmacol 80, 1210-1220.

Chen, C.C., Sun, Y.T., Chen, J.J., Chiu, K.T., 2000. TNF-alpha-induced cyclooxygenase-2 expression in human lung epithelial cells: involvement of the phospholipase C-gamma 2, protein kinase C-alpha, tyrosine kinase, NF-kappa B-inducing kinase, and I-kappa B kinase 1/2 pathway. J Immunol 165, 2719-2728.

Choi, S.L., Kim, S.J., Lee, K.T., Kim, J., Mu, J., Birnbaum, M.J., Soo Kim, S., Ha, J., 2001. The regulation of AMP-activated protein kinase by H(2)O(2). Biochem Biophys Res Commun 287, 92-97.

Ciftci, T.U., Ciftci, B., Guven, S.F., Kokturk, O., Turktas, H., 2005. Effect of nasal continuous positive airway pressure in uncontrolled nocturnal asthmatic patients with obstructive sleep apnea syndrome. Respir Med 99, 529-534.

Coleridge, H.M., Coleridge, J.C., 1977. Impulse activity in afferent vagal C-fibres with endings in the intrapulmonary airways of dogs. Respir Physiol 29, 125-142.

Coleridge, H.M., Coleridge, J.C., Luck, J.C., 1965. Pulmonary afferent fibres of small diameter stimulated by capsaicin and by hyperinflation of the lungs. J Physiol 179, 248-262.

Coleridge, J.C., Coleridge, H.M., 1984. Afferent vagal C fibre innervation of the lungs and airways and its functional significance. Rev Physiol Biochem Pharmacol 99, 1-110.

Dannhardt, G., Kiefer, W., 2001. Cyclooxygenase inhibitors--current status and future prospects. Eur J Med Chem 36, 109-126.

De Backer, W., 2013. Obstructive sleep apnea/hypopnea syndrome. Panminerva Med 55, 191-195.

Droge, W., 2002. Free radicals in the physiological control of cell function. Physiol Rev 82, 47-95.

Du, J.H., Xu, N., Song, Y., Xu, M., Lu, Z.Z., Han, C., Zhang, Y.Y., 2005. AICAR stimulates IL-6 production via p38 MAPK in cardiac fibroblasts in adult mice: a possible role for AMPK. Biochem Biophys Res Commun 337, 1139-1144.

Dyugovskaya, L., Lavie, P., Lavie, L., 2002. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 165, 934-939.

Edge, D., Bradford, A., O'Halloran, K.D., 2012. Chronic intermittent hypoxia increases apnoea index in sleeping rats. Adv Exp Med Biol 758, 359-363.

Eliopoulos, A.G., Dumitru, C.D., Wang, C.C., Cho, J., Tsichlis, P.N., 2002. Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J 21, 4831-4840.

Emamian, F., Khazaie, H., Tahmasian, M., Leschziner, G.D., Morrell, M.J., Hsiung, G.Y., Rosenzweig, I., Sepehry, A.A., 2016. The Association Between Obstructive Sleep Apnea and Alzheimer's Disease: A Meta-Analysis Perspective. Front Aging Neurosci 8, 78.

Emerling, B.M., Weinberg, F., Snyder, C., Burgess, Z., Mutlu, G.M., Viollet, B., Budinger, G.R., Chandel, N.S., 2009. Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio. Free Radic Biol Med 46, 1386-1391.

Evans, A.M., Hardie, D.G., Peers, C., Wyatt, C.N., Viollet, B., Kumar, P., Dallas, M.L., Ross, F., Ikematsu, N., Jordan, H.L., Barr, B.L., Rafferty, J.N., Ogunbayo, O., 2009. Ion channel regulation by AMPK: the route of hypoxia-response coupling in thecarotid body and pulmonary artery. Ann N Y Acad Sci 1177, 89-100.

Fletcher, B.L., Dillard, C.J., Tappel, A.L., 1973. Measurement of fluorescent lipid peroxidation products in biological systems and tissues. Anal Biochem 52, 1-9.

Fletcher, E.C., Lesske, J., Behm, R., Miller, C.C., 3rd, Stauss, H., Unger, T., 1992. Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 72, 1978-1984.

Fortuna, A.M., Miralda, R., Calaf, N., Gonzalez, M., Casan, P., Mayos, M., 2011. Airway and alveolar nitric oxide measurements in obstructive sleep apnea syndrome. Respir Med 105, 630-636.

Fridovich, I., 1998. Oxygen toxicity: a radical explanation. J Exp Biol 201, 1203-1209.

Garvey, J.F., Pengo, M.F., Drakatos, P., Kent, B.D., 2015. Epidemiological aspects of obstructive sleep apnea. J Thorac Dis 7, 920-929.

Giuliano, F., Warner, T.D., 2002. Origins of prostaglandin E2: involvements of cyclooxygenase (COX)-1 and COX-2 in human and rat systems. J Pharmacol Exp Ther 303, 1001-1006.

Gloire, G., Legrand-Poels, S., Piette, J., 2006. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72, 1493-1505.

Goldbart, A.D., Krishna, J., Li, R.C., Serpero, L.D., Gozal, D., 2006. Inflammatory mediators in exhaled breath condensate of children with obstructive sleep apnea syndrome. Chest 130, 143-148.

Griendling, K.K., Minieri, C.A., Ollerenshaw, J.D., Alexander, R.W., 1994. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 74, 1141-1148.

Gu, Q., Ruan, T., Hong, J.L., Burki, N., Lee, L.Y., 2003. Hypersensitivity of pulmonary C fibers induced by adenosine in anesthetized rats. J Appl Physiol 95, 1315-1324.

Guardiola, J., Yu, J., Hasan, N., Fletcher, E.C., 2004. Evening and morning blood gases in patients with obstructive sleep apnea. Sleep Med 5, 489-493.

Hardie, D.G., 2007. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8, 774-785.

Hardie, D.G., Ross, F.A., Hawley, S.A., 2012. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13, 251-262.

Harijith, A., Ebenezer, D.L., Natarajan, V., 2014. Reactive oxygen species at the crossroads of inflammasome and inflammation. Front Physiol 5, 352.

Harris, R.C., McKanna, J.A., Akai, Y., Jacobson, H.R., Dubois, R.N., Breyer, M.D., 1994. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 94, 2504-2510.

Hawley, S.A., Pan, D.A., Mustard, K.J., Ross, L., Bain, J., Edelman, A.M., Frenguelli, B.G., Hardie, D.G., 2005. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2, 9-19.

Herrero-Martin, G., Hoyer-Hansen, M., Garcia-Garcia, C., Fumarola, C., Farkas, T., Lopez-Rivas, A., Jaattela, M., 2009. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J 28, 677-685.

Hill, S.J., May, L.T., Kellam, B., Woolard, J., 2014. Allosteric interactions at adenosine A(1) and A(3) receptors: new insights into the role of small molecules and receptor dimerization. Br J Pharmacol 171, 1102-1113.

Hirst, J.J., Teixeira, F.J., Zakar, T., Olson, D.M., 1995. Prostaglandin endoperoxide-H synthase-1 and -2 messenger ribonucleic acid levels in human amnion with spontaneous labor onset. J Clin Endocrinol Metab 80, 517-523.

Ho, C.Y., Gu, Q., Hong, J.L., Lee, L.Y., 2000. Prostaglandin E(2) enhances chemical and mechanical sensitivities of pulmonary C fibers in the rat. Am J Respir Crit Care Med 162, 528-533.

Ho, C.Y., Gu, Q., Lin, Y.S., Lee, L.Y., 2001. Sensitivity of vagal afferent endings to chemical irritants in the rat lung. Respir Physiol 127, 113-124.

Ho, C.Y., Lee, L.Y., 1998. Ozone enhances excitabilities of pulmonary C fibers to chemical and mechanical stimuli in anesthetized rats. J Appl Physiol 85, 1509-1515.

Ho, K.W., Ward, N.J., Calkins, D.J., 2012. TRPV1: a stress response protein in the central nervous system. Am J Neurodegener Dis 1, 1-14.

Hopps, E., Caimi, G., 2015. Obstructive Sleep Apnea Syndrome: Links Betwen Pathophysiology and Cardiovascular Complications. Clin Invest Med 38, E362-370.

Irrcher, I., Ljubicic, V., Hood, D.A., 2009. Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells. Am J Physiol Cell Physiol 296, C116-123.

Janvier, A., Khairy, M., Kokkotis, A., Cormier, C., Messmer, D., Barrington, K.J., 2004. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol 24, 763-768.

Julien, J.Y., Martin, J.G., Ernst, P., Olivenstein, R., Hamid, Q., Lemiere, C., Pepe, C., Naor, N., Olha, A., Kimoff, R.J., 2009. Prevalence of obstructive sleep apnea-hypopnea in severe versus moderate asthma. J Allergy Clin Immunol 124, 371-376.

Kapsimalis, F., Basta, M., Varouchakis, G., Gourgoulianis, K., Vgontzas, A., Kryger, M., 2008. Cytokines and pathological sleep. Sleep Med 9, 603-614.

Karamanli, H., Ozol, D., Ugur, K.S., Yildirim, Z., Armutcu, F., Bozkurt, B., Yigitoglu, R., 2014. Influence of CPAP treatment on airway and systemic inflammation in OSAS patients. Sleep Breath 18, 251-256.

Kargman, S., Charleson, S., Cartwright, M., Frank, J., Riendeau, D., Mancini, J., Evans, J., O'Neill, G., 1996. Characterization of Prostaglandin G/H Synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts. Gastroenterology 111, 445-454.

Karla, W., Shams, H., Orr, J.A., Scheid, P., 1992. Effects of the thromboxane A2 mimetic, U46,619, on pulmonary vagal afferents in the cat. Respir Physiol 87, 383-396.

Kent, B.D., Garvey, J.F., Ryan, S., Nolan, G., Dodd, J.D., McNicholas, W.T., 2013. Severity of obstructive sleep apnoea predicts coronary artery plaque burden: a coronary computed tomographic angiography study. Eur Respir J 42, 1263-1270.

Kerksick, C., Willoughby, D., 2005. The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J Int Soc Sports Nutr 2, 38-44.

Kim, H.S., Moon, S., Paik, J.H., Shin, D.W., Kim, L.S., Park, C.S., Ha, J., Kang, J.H., 2015. Activation of the 5'-AMP-Activated Protein Kinase in the Cerebral Cortex of Young Senescence-Accelerated P8 Mice and Association with GSK3beta- and PP2A-Dependent Inhibition of p-tau(3)(9)(6) Expression. J Alzheimers Dis 46, 249-259.

Kinkead, R., Bach, K.B., Johnson, S.M., Hodgeman, B.A., Mitchell, G.S., 2001. Plasticity in respiratory motor control: intermittent hypoxia and hypercapnia activate opposing serotonergic and noradrenergic modulatory systems. Comp Biochem Physiol A Mol Integr Physiol 130, 207-218.

Ko, H.K., Lee, H.F., Lin, A.H., Liu, M.H., Liu, C.I., Lee, T.S., Kou, Y.R., 2015. Regulation of Cigarette Smoke Induction of IL-8 in Macrophages by AMP-activated Protein Kinase Signaling. J Cell Physiol 230, 1781-1793.

Ko, J.W., Lim, S.Y., Chung, K.C., Lim, J.W., Kim, H., 2014. Reactive oxygen species mediate IL-8 expression in Down syndrome candidate region-1-overexpressed cells. Int J Biochem Cell Biol 55, 164-170.

Kolarova, H., Bino, L., Pejchalova, K., Kubala, L., 2010. The expression of NADPH oxidases and production of reactive oxygen species by human lung adenocarcinoma epithelial cell line A549. Folia Biol 56, 211-217.

Kou, Y.R., Kwong, K., Lee, L.Y., 2011. Airway inflammation and hypersensitivity induced by chronic smoking. Respir Physiol Neurobiol 178, 395-405.

Kou, Y.R., Wang, C.Y., Lai, C.J., 1995. Role of vagal afferents in the acute ventilatory responses to inhaled wood smoke in rats. J Appl Physiol 78, 2070-2078.

Kuo, T.B., Yuan, Z.F., Lin, Y.S., Lin, Y.N., Li, W.S., Yang, C.C., Lai, C.J., 2011. Reactive oxygen species are the cause of the enhanced cardiorespiratory response induced by intermittent hypoxia in conscious rats. Respir Physiol Neurobiol 175, 70-79.

Kwong, K., Lee, L.Y., 2002. PGE(2) sensitizes cultured pulmonary vagal sensory neurons to chemical and electrical stimuli. J Appl Physiol 93, 1419-1428.

Lai, C.J., Kou, Y.R., 1998. Stimulation of vagal pulmonary C fibers by inhaled wood smoke in rats. J Appl Physiol 84, 30-36.

Lai, C.J., Yang, C.C., Hsu, Y.Y., Lin, Y.N., Kuo, T.B., 2006. Enhanced sympathetic outflow and decreased baroreflex sensitivity are associated with intermittent hypoxia-induced systemic hypertension in conscious rats. J Appl Physiol 100, 1974-1982.

Lavie, L., 2003. Obstructive sleep apnoea syndrome--an oxidative stress disorder. Sleep Med Rev 7, 35-51.

Lavie, L., 2012. Oxidative stress inflammation and endothelial dysfunction in obstructive sleep apnea. Front Biosci (Elite Ed) 4, 1391-1403.

Lavie, L., Vishnevsky, A., Lavie, P., 2004. Evidence for lipid peroxidation in obstructive sleep apnea. Sleep 27, 123-128.

Lee, D.S., Badr, M.S., Mateika, J.H., 2009. Progressive augmentation and ventilatory long-term facilitation are enhanced in sleep apnoea patients and are mitigated by antioxidant administration. J Physiol 587, 5451-5467.

Lee, J.Y., Choi, A.Y., Oh, Y.T., Choe, W., Yeo, E.J., Ha, J., Kang, I., 2012. AMP-activated protein kinase mediates T cell activation-induced expression of FasL and COX-2 via protein kinase C theta-dependent pathway in human Jurkat T leukemia cells. Cell Signal 24, 1195-1207.

Lee, L.Y., 2009. Respiratory sensations evoked by activation of bronchopulmonary C-fibers. Respir Physiol Neurobiol 167, 26-35.

Lee, L.Y., Kwong, K., Lin, Y.S., Gu, Q., 2002. Hypersensitivity of bronchopulmonary C-fibers induced by airway mucosal inflammation: cellular mechanisms. Pulm Pharmacol Ther 15, 199-204.

Lee, L.Y., Morton, R.F., 1995. Pulmonary chemoreflex sensitivity is enhanced by prostaglandin E2 in anesthetized rats. J Appl Physiol 79, 1679-1686.

Lee, L.Y., Pisarri, T.E., 2001. Afferent properties and reflex functions of bronchopulmonary C-fibers. Respir Physiol 125, 47-65.

Lee, L.Y., Shuei Lin, Y., Gu, Q., Chung, E., Ho, C.Y., 2003. Functional morphology and physiological properties of bronchopulmonary C-fiber afferents. Anat Rec A Discov Mol Cell Evol Biol 270, 17-24.

Lee, L.Y., Widdicombe, J.G., 2001. Modulation of airway sensitivity to inhaled irritants: role of inflammatory mediators. Environ Health Perspect 109 Suppl 4, 585-589.

Lee, M.G., Kollarik, M., Chuaychoo, B., Undem, B.J., 2004. Ionotropic and metabotropic receptor mediated airway sensory nerve activation. Pulm Pharmacol Ther 17, 355-360.

Lemes, E.V., Aiko, S., Orbem, C.B., Formentin, C., Bassi, M., Colombari, E., Zoccal, D.B., 2016. Long-term facilitation of expiratory and sympathetic activities following acute intermittent hypoxia in rats. Acta Physiol 217, 254-266.

Li, C., Keaney, J.F., Jr., 2010. AMP-activated protein kinase: a stress-responsive kinase with implications for cardiovascular disease. Curr Opin Pharmacol 10, 111-115.

Li, G., Wang, J., Ye, J., Zhang, Y., Zhang, Y., 2015. PPARalpha Protein Expression Was Increased by Four Weeks of Intermittent Hypoxic Training via AMPKalpha2-Dependent Manner in Mouse Skeletal Muscle. PLoS One 10, e0122593.

Li, R.C., Row, B.W., Gozal, E., Kheirandish, L., Fan, Q., Brittian, K.R., Guo, S.Z., Sachleben, L.R., Jr., Gozal, D., 2003. Cyclooxygenase 2 and intermittent hypoxia-induced spatial deficits in the rat. Am J Respir Crit Care Med 168, 469-475.

Liang, Y., Huang, B., Song, E., Bai, B., Wang, Y., 2014. Constitutive activation of AMPK alpha1 in vascular endothelium promotes high-fat diet-induced fatty liver injury: role of COX-2 induction. Br J Pharmacol 171, 498-508.

Lieu, T., Undem, B.J., 2011. Neuroplasticity in vagal afferent neurons involved in cough. Pulm Pharmacol Ther 24, 276-279.

Lim, C.T., Kola, B., Korbonits, M., 2010. AMPK as a mediator of hormonal signalling. J Mol Endocrinol 44, 87-97.

Lin, C.C., Lin, C.Y., 1995. Obstructive sleep apnea syndrome and bronchial hyperreactivity. Lung 173, 117-126.

Lin, R.L., Lin, Y.J., Xu, F., Lee, L.Y., 2015. Hemorrhagic hypotension-induced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 308, R605-613.

Lin, Y.J., Lin, Y.S., Lai, C.J., Yuan, Z.F., Ruan, T., Kou, Y.R., 2013. Perivagal antagonist treatment in rats selectively blocks the reflex and afferent responses of vagal lung C fibers to intravenous agonists. J Appl Physiol 114, 361-370.

Lin, Y.S., Hsu, C.C., Bien, M.Y., Hsu, H.C., Weng, H.T., Kou, Y.R., 2010. Activations of TRPA1 and P2X receptors are important in ROS-mediated stimulation of capsaicin-sensitive lung vagal afferents by cigarette smoke in rats. J Appl Physiol 108, 1293-1303.

Lin, Y.S., Lin, R.L., Bien, M.Y., Ho, C.Y., Kou, Y.R., 2009. Sensitization of capsaicin-sensitive lung vagal afferents by anandamide in rats: role of transient receptor potential vanilloid 1 receptors. J Appl Physiol 106, 1142-1152.

Lu, Y., Wahl, L.M., 2005. Oxidative stress augments the production of matrix metalloproteinase-1, cyclooxygenase-2, and prostaglandin E2 through enhancement of NF-kappa B activity in lipopolysaccharide-activated human primary monocytes. J Immunol 175, 5423-5429.

Lurie, A., 2011. Inflammation, oxidative stress, and procoagulant and thrombotic activity in adults with obstructive sleep apnea. Adv Cardiol 46, 43-66.

MacFarlane, P.M., Satriotomo, I., Windelborn, J.A., Mitchell, G.S., 2009. NADPH oxidase activity is necessary for acute intermittent hypoxia-induced phrenic long-term facilitation. J Physiol 587, 1931-1942.

Maeder, M.T., Schoch, O.D., Rickli, H., 2016. A clinical approach to obstructive sleep apnea as a risk factor for cardiovascular disease. Vasc Health Risk Manag 12, 85-103.

Marcus, N.J., Li, Y.L., Bird, C.E., Schultz, H.D., Morgan, B.J., 2010. Chronic intermittent hypoxia augments chemoreflex control of sympathetic activity: role of the angiotensin II type 1 receptor. Respir Physiol Neurobiol 171, 36-45.

Marin, J.M., Carrizo, S.J., Vicente, E., Agusti, A.G., 2005. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 365, 1046-1053.

Matyas, S., Pucovsky, V., Bauer, V., 2002. Effects of various reactive oxygen species on the guinea pig trachea and its epithelium. Jpn J Pharmacol 88, 270-278.

McAdam, B.F., Mardini, I.A., Habib, A., Burke, A., Lawson, J.A., Kapoor, S., FitzGerald, G.A., 2000. Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation. J Clin Invest 105, 1473-1482.

McBride, A., Ghilagaber, S., Nikolaev, A., Hardie, D.G., 2009. The glycogen-binding domain on the AMPK beta subunit allows the kinase to act as a glycogen sensor. Cell Metab 9, 23-34.

McCann, S.K., Roulston, C.L., 2013. NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives. Brain Sci 3, 561-598.

McGuire, M., Zhang, Y., White, D.P., Ling, L., 2003. Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats. J Appl Physiol 95, 1499-1508.

Mejza, F., Kania, A., Nastalek, P., Nizankowska-Jedrzejczyk, A., Nizankowska-Mogilnicka, E., 2016. Systemic prostacyclin and thromboxane production in obstructive sleep apnea. Adv Med Sci 61, 154-159.

Mittal, M., Gu, X.Q., Pak, O., Pamenter, M.E., Haag, D., Fuchs, D.B., Schermuly, R.T., Ghofrani, H.A., Brandes, R.P., Seeger, W., Grimminger, F., Haddad, G.G., Weissmann, N., 2012. Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med 52, 1033-1042.

Miyamoto, T., Ogino, N., Yamamoto, S., Hayaishi, O., 1976. Purification of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. J Biol Chem 251, 2629-2636.

Nanduri, J., Vaddi, D.R., Khan, S.A., Wang, N., Makarenko, V., Semenza, G.L., Prabhakar, N.R., 2015. HIF-1alpha activation by intermittent hypoxia requires NADPH oxidase stimulation by xanthine oxidase. PLoS One 10, e0119762.

Nichols, N.L., Satriotomo, I., Harrigan, D.J., Mitchell, G.S., 2015. Acute intermittent hypoxia induced phrenic long-term facilitation despite increased SOD1 expression in a rat model of ALS. Exp Neurol 273, 138-150.

Nieto, F.J., Young, T.B., Lind, B.K., Shahar, E., Samet, J.M., Redline, S., D'Agostino, R.B., Newman, A.B., Lebowitz, M.D., Pickering, T.G., 2000. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 283, 1829-1836.

Nisbet, R.E., Graves, A.S., Kleinhenz, D.J., Rupnow, H.L., Reed, A.L., Fan, T.H., Mitchell, P.O., Sutliff, R.L., Hart, C.M., 2009. The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice. Am J Respir Cell Mol Biol 40, 601-609.

Noble, M.I., 2015. Abraham Guz memorial: Still unresolved hypotheses: Lung reflexes and perceptions of breathing. Respir Physiol Neurobiol 217, 46-53.

North, R.A., 2002. Molecular physiology of P2X receptors. Physiol Rev 82, 1013-1067.

O'Sullivan, M.G., Huggins, E.M., Jr., Meade, E.A., DeWitt, D.L., McCall, C.E., 1992. Lipopolysaccharide induces prostaglandin H synthase-2 in alveolar macrophages. Biochem Biophys Res Commun 187, 1123-1127.

Ohga, E., Tomita, T., Wada, H., Yamamoto, H., Nagase, T., Ouchi, Y., 2003. Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol 94, 179-184.

Olson, E.B., Jr., Bohne, C.J., Dwinell, M.R., Podolsky, A., Vidruk, E.H., Fuller, D.D., Powell, F.L., Mitchel, G.S., 2001. Ventilatory long-term facilitation in unanesthetized rats. J Appl Physiol 91, 709-716.

Paintal, A.S., 1969. Mechanism of stimulation of type J pulmonary receptors. J Physiol 203, 511-532.

Paintal, A.S., 1973. Vagal sensory receptors and their reflex effects. Physiol Rev 53, 159-227.

Pan, J.T., Gala, R.R., 1985. Central nervous system regions involved in the estrogen-induced afternoon prolactin surge. II. Implantation studies. Endocrinology 117, 388-395.

Passali, D., Corallo, G., Yaremchuk, S., Longini, M., Proietti, F., Passali, G.C., Bellussi, L., 2015. Oxidative stress in patients with obstructive sleep apnoea syndrome. Acta Otorhinolaryngol Ital 35, 420-425.

Pavlinac, I., Pecotic, R., Dogas, Z., Valic, M., 2011. Role of 5-HT(1)(A) receptors in induction and preservation of phrenic long-term facilitation in rats. Respir Physiol Neurobiol 175, 146-152.

Peebles, R.S., Jr., Dworski, R., Collins, R.D., Jarzecka, K., Mitchell, D.B., Graham, B.S., Sheller, J.R., 2000. Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice. Am J Respir Crit Care Med 162, 676-681.

Peng, Y.J., Nanduri, J., Yuan, G., Wang, N., Deneris, E., Pendyala, S., Natarajan, V., Kumar, G.K., Prabhakar, N.R., 2009. NADPH oxidase is required for the sensory plasticity of the carotid body by chronic intermittent hypoxia. J Neurosci 29, 4903-4910.

Peng, Y.J., Overholt, J.L., Kline, D., Kumar, G.K., Prabhakar, N.R., 2003. Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci U S A 100, 10073-10078.

Peng, Y.J., Rennison, J., Prabhakar, N.R., 2004. Intermittent hypoxia augments carotid body and ventilatory response to hypoxia in neonatal rat pups. J Appl Physiol 97, 2020-2025.

Perng, D.W., Chang, T.M., Wang, J.Y., Lee, C.C., Lu, S.H., Shyue, S.K., Lee, T.S., Kou, Y.R., 2013. Inflammatory role of AMP-activated protein kinase signaling in an experimental model of toxic smoke inhalation injury. Crit Care Med 41, 120-132.

Petrosyan, M., Perraki, E., Simoes, D., Koutsourelakis, I., Vagiakis, E., Roussos, C., Gratziou, C., 2008. Exhaled breath markers in patients with obstructive sleep apnoea. Sleep Breath 12, 207-215.

Potter, W.B., O'Riordan, K.J., Barnett, D., Osting, S.M., Wagoner, M., Burger, C., Roopra, A., 2010. Metabolic regulation of neuronal plasticity by the energy sensor AMPK. PLoS One 5, e8996.

Powell, F.L., Milsom, W.K., Mitchell, G.S., 1998. Time domains of the hypoxic ventilatory response. Respir Physiol 112, 123-134.

Prabhakar, N.R., 2001. Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol 90, 1986-1994.

Prabhakar, N.R., 2011. Sensory plasticity of the carotid body: role of reactive oxygen species and physiological significance. Respir Physiol Neurobiol 178, 375-380.

Prabhakar, N.R., Kline, D.D., 2002. Ventilatory changes during intermittent hypoxia: importance of pattern and duration. High Alt Med Biol 3, 195-204.

Qiao, Y.X., Xiao, Y., 2015. Asthma and Obstructive Sleep Apnea. Chin Med J 128, 2798-2804.

Rajan, P., Greenberg, H., 2015. Obstructive sleep apnea as a risk factor for type 2 diabetes mellitus. Nat Sci Sleep 7, 113-125.

Ramamurthy, S., Ronnett, G., 2012. AMP-Activated Protein Kinase (AMPK) and Energy-Sensing in the Brain. Exp Neurobiol 21, 52-60.

Rangan, U., Bulkley, G.B., 1993. Prospects for treatment of free radical-mediated tissue injury. Br Med Bull 49, 700-718.

Rathore, R., Zheng, Y.M., Niu, C.F., Liu, Q.H., Korde, A., Ho, Y.S., Wang, Y.X., 2008. Hypoxia activates NADPH oxidase to increase [ROS]i and [Ca2+]i through the mitochondrial ROS-PKCepsilon signaling axis in pulmonary artery smooth muscle cells. Free Radic Biol Med 45, 1223-1231.

Rey, S., Del Rio, R., Alcayaga, J., Iturriaga, R., 2004. Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia. J Physiol 560, 577-586.

Rossi, F., Zatti, M., 1964. Biochemical aspects of phagocytosis in polymorphonuclear leucocytes. NADH and NADPH oxidation by the granules of resting and phagocytizing cells. Experientia 20, 21-23.

Ruan, T., Lin, Y.J., Hsu, T.H., Lu, S.H., Jow, G.M., Kou, Y.R., 2014. Sensitization by pulmonary reactive oxygen species of rat vagal lung C-fibers: the roles of the TRPV1, TRPA1, and P2X receptors. PLoS One 9, e91763.

Ruan, T., Lin, Y.S., Lin, K.S., Kou, Y.R., 2005. Sensory transduction of pulmonary reactive oxygen species by capsaicin-sensitive vagal lung afferent fibres in rats. J Physiol 565, 563-578.

Ruderman, N., Prentki, M., 2004. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 3, 340-351.

Ryan, S., Taylor, C.T., McNicholas, W.T., 2005. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 112, 2660-2667.

Sabato, R., Guido, P., Salerno, F.G., Resta, O., Spanevello, A., Barbaro, M.P., 2006. Airway inflammation in patients affected by obstructive sleep apnea. Monaldi Arch Chest Dis 65, 102-105.

Samad, T.A., Moore, K.A., Sapirstein, A., Billet, S., Allchorne, A., Poole, S., Bonventre, J.V., Woolf, C.J., 2001. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410, 471-475.

Sardo, L., Palange, P., Di Mario, F., Barbano, B., Gigante, A., Mordenti, M., Steffanina, A., Bonini, M., Amoroso, A., Vaccaro, F., Cianci, R., 2015. Intrarenal hemodynamic and oxidative stress in patients with obstructive sleep apnea syndrome. Sleep Breath 19, 1205-1212.

Saria, A., Martling, C.R., Yan, Z., Theodorsson-Norheim, E., Gamse, R., Lundberg, J.M., 1988. Release of multiple tachykinins from capsaicin-sensitive sensory nerves in the lung by bradykinin, histamine, dimethylphenyl piperazinium, and vagal nerve stimulation. Am Rev Respir Dis 137, 1330-1335.

Sariman, N., Levent, E., Cubuk, R., Yurtlu, S., Benli Aksungar, F., 2011. Bronchial hyperreactivity and airway wall thickening in obstructive sleep apnea patients. Sleep Breath 15, 341-350.

Scheinfeldt, L.B., Tishkoff, S.A., 2010. Living the high life: high-altitude adaptation. Genome Biol 11, 133-135.

Schulz, R., Mahmoudi, S., Hattar, K., Sibelius, U., Olschewski, H., Mayer, K., Seeger, W., Grimminger, F., 2000. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 162, 566-570.

Schulz, R., Murzabekova, G., Egemnazarov, B., Kraut, S., Eisele, H.J., Dumitrascu, R., Heitmann, J., Seimetz, M., Witzenrath, M., Ghofrani, H.A., Schermuly, R.T., Grimminger, F., Seeger, W., Weissmann, N., 2014. Arterial hypertension in a murine model of sleep apnea: role of NADPH oxidase 2. J Hypertens 32, 300-305.

Shah, M.H., Liu, G.S., Thompson, E.W., Dusting, G.J., Peshavariya, H.M., 2015. Differential effects of superoxide dismutase and superoxide dismutase/catalase mimetics on human breast cancer cells. Breast Cancer Res Treat 150, 523-534.

Shen, M.Y., Luo, Y.L., Yang, C.H., Ruan, T., Lai, C.J., 2012. Hypersensitivity of lung vagal C fibers induced by acute intermittent hypoxia in rats: role of reactive oxygen species and TRPA1. Am J Physiol Regul Integr Comp Physiol 303, R1175-1185.

Simmons, D.L., Botting, R.M., Hla, T., 2004. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56, 387-437.

Smutzer, G., Devassy, R.K., 2016. Integrating TRPV1 Receptor Function with Capsaicin Psychophysics. Adv Pharmacol Sci 2016, 1512457.

Smyth, E.M., Grosser, T., Wang, M., Yu, Y., FitzGerald, G.A., 2009. Prostanoids in health and disease. J Lipid Res 50 Suppl, S423-428.

Steinberg, G.R., Kemp, B.E., 2009. AMPK in Health and Disease. Physiol Rev 89, 1025-1078.

Sundar, K.M., Daly, S.E., Pearce, M.J., Alward, W.T., 2010. Chronic cough and obstructive sleep apnea in a community-based pulmonary practice. Cough 6, 2-7.

Tang, C.H., Chiu, Y.C., Tan, T.W., Yang, R.S., Fu, W.M., 2007. Adiponectin enhances IL-6 production in human synovial fibroblast via an AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway. J Immunol 179, 5483-5492.

Tang, G.J., Wang, H.Y., Wang, J.Y., Lee, C.C., Tseng, H.W., Wu, Y.L., Shyue, S.K., Lee, T.S., Kou, Y.R., 2011. Novel role of AMP-activated protein kinase signaling in cigarette smoke induction of IL-8 in human lung epithelial cells and lung inflammation in mice. Free Radic Biol Med 50, 1492-1502.

Taylor-Clark, T., Undem, B.J., 2006. Transduction mechanisms in airway sensory nerves. J Appl Physiol 101, 950-959.

Taylor-Clark, T.E., Undem, B.J., 2011. Sensing pulmonary oxidative stress by lung vagal afferents. Respir Physiol Neurobiol 178, 406-413.

Teodorescu, M., Polomis, D.A., Teodorescu, M.C., Gangnon, R.E., Peterson, A.G., Consens, F.B., Chervin, R.D., Jarjour, N.N., 2012. Association of obstructive sleep apnea risk or diagnosis with daytime asthma in adults. J Asthma 49, 620-628.

Thompson, A.J., Lummis, S.C., 2006. 5-HT3 receptors. Curr Pharm Des 12, 3615-3630.

Tirmenstein, M.A., Pierce, C.A., Leraas, T.L., Fariss, M.W., 1998. A fluorescence plate reader assay for monitoring the susceptibility of biological samples to lipid peroxidation. Anal Biochem 265, 246-252.

Touyz, R.M., 2008. Apocynin, NADPH oxidase, and vascular cells: a complex matter. Hypertension 51, 172-174.

Tsai, T.L., Chang, S.Y., Ho, C.Y., Kou, Y.R., 2006. Neural and hydroxyl radical mechanisms underlying laryngeal airway hyperreactivity induced by laryngeal acid-pepsin insult in anesthetized rats. J Appl Physiol 101, 328-338.

Tsai, T.L., Chang, S.Y., Ho, C.Y., Kou, Y.R., 2009. Role of ATP in the ROS-mediated laryngeal airway hyperreactivity induced by laryngeal acid-pepsin insult in anesthetized rats. J Appl Physiol 106, 1584-1592.

Tsuzaki, M., Guyton, G., Garrett, W., Archambault, J.M., Herzog, W., Almekinders, L., Bynum, D., Yang, X., Banes, A.J., 2003. IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells. J Orthop Res 21, 256-264.

Vogtel, M., Michels, A., 2010. Role of intermittent hypoxia in the treatment of bronchial asthma and chronic obstructive pulmonary disease. Curr Opin Allergy Clin Immunol 10, 206-213.

Widdicombe, J., 2001. Airway receptors. Respir Physiol 125, 3-15.

Widdicombe, J.G., 2003. Overview of neural pathways in allergy and asthma. Pulm Pharmacol Ther 16, 23-30.

Wyatt, C.N., Mustard, K.J., Pearson, S.A., Dallas, M.L., Atkinson, L., Kumar, P., Peers, C., Hardie, D.G., Evans, A.M., 2007. AMP-activated protein kinase mediates carotid body excitation by hypoxia. J Biol Chem 282, 8092-8098.

Xue, B., Kahn, B.B., 2006. AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues. J Physiol 574, 73-83.

Yaggi, H.K., Concato, J., Kernan, W.N., Lichtman, J.H., Brass, L.M., Mohsenin, V., 2005. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 353, 2034-2041.

Young, L.H., 2008. AMP-activated protein kinase conducts the ischemic stress response orchestra. Circulation 117, 832-840.

Yuan, C., Sidhu, R.S., Kuklev, D.V., Kado, Y., Wada, M., Song, I., Smith, W.L., 2009. Cyclooxygenase Allosterism, Fatty Acid-mediated Cross-talk between Monomers of Cyclooxygenase Homodimers. J Biol Chem 284, 10046-10055.

Yuan, G., Khan, S.A., Luo, W., Nanduri, J., Semenza, G.L., Prabhakar, N.R., 2011. Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia. J Cell Physiol 226, 2925-2933.

Yuan, L., Wu, J., Liu, J., Li, G., Liang, D., 2015. Intermittent Hypoxia-Induced Parvalbumin-Immunoreactive Interneurons Loss and Neurobehavioral Impairment is Mediated by NADPH-Oxidase-2. Neurochem Res 40, 1232-1242.

Zhang, G., Lee, L.Y., 2007. Prostaglandin E2 enhances the sensitizing effect of hyperthermia on pulmonary C-fibers in rats. Respir Physiol Neurobiol 156, 241-249.

Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., Musi, N., Hirshman, M.F., Goodyear, L.J., Moller, D.E., 2001. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108, 1167-1174.

Zmijewski, J.W., Banerjee, S., Bae, H., Friggeri, A., Lazarowski, E.R., Abraham, E., 2010. Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J Biol Chem 285, 33154-33164.