家塵蟎(house dust mite)為造成人類過敏性疾病主要過敏原之ㄧ。呼吸道上表皮細胞暴露過敏原時會分泌趨化因子(chemokines)，吸引發炎細胞，如嗜酸性球(eosinophil)和嗜中性球(neutrophil)聚集於肺部組織。受過敏原致敏化之嗜酸性球亦會產生大量的活性氧化物種(reactive oxygen species; ROS)、腫瘤壞死因子 (tumor necrosis factor a; TNFa)及顆粒性蛋白，進而破壞呼吸道上皮細胞，造成氧化性傷害(oxidative damage)。受損之呼吸道表皮細胞會釋放許多細胞介質(mediator)，包括生長因子(growth factors)、細胞週期蛋白依賴性激酶抑制因子(cyclin-dependent kinase inhibitors)及基質金屬蛋白酵素(matrix metalloproteinases; MMP)等，將會促使呼吸道變形(airway remodeling)現象產生，造成呼吸道狹窄和肺功能衰退。本研究針對家塵蟎及其致敏化之嗜酸性球，是否會對呼吸道表皮細胞導致氧化性傷害，以及是否影響呼吸道變形之相關基因表現進行探討。此外，已知硫醇氧化還原蛋白(thioredoxin; TRX)為氧化還原蛋白，可清除體內或外來之ROS，並參與細胞發炎、生長等機制。因而，本研究進一步探討，當呼吸道表皮細胞大量表現TRX時是否可調節家塵蟎對於呼吸道傷害之情形，及其對變形基因表現之影響。
將正常人類呼吸道表皮細胞(BEAS-2B cells)單獨暴露於0.5 ug/ml重組家塵蟎抗原(recombinant Dermatophagoides pteronyssinus 1; rDer p1) 24小時。結果顯示rDer p1可刺激BEAS-2B細胞分泌白介素-6 (interleukin-6; IL-6; 202.7 ± 22.2 pg/10(6) cells)及一氧化氮(nitric oxide; NO; 5.7 ± 0.1 uM )。進而將BEAS-2B細胞與經rDer p1致敏化嗜酸性球共養24小時後，可促使BEAS-2B細胞分泌更多IL-6 (687.0 ± 41.1 pg/10(6) cells)及NO (6.0 ± 0.1 uM)。此外，rDer p1致敏化嗜酸性球2小時會導致嗜酸性球產生大量的ROS，若將致敏化嗜酸性球與BEAS-2B細胞共養24小時後，會促使嗜酸性球持續產生ROS。BEAS-2B細胞與經rDer p 1致敏化之嗜酸性球共養或以其培養液培養24小時後，發現BEAS-2B細胞培養液中TNF□濃度均高於BEAS-2B細胞(16.04 ± 0.75, 14.86 ± 1.25和4.92 ± 0.17 pg/10(6) cells)。研究結果亦發現，rDer p1致敏化嗜酸性球之培養液會促使BEAS-2B細胞走向細胞凋亡(apoptosis)。推測rDer p1致敏化嗜酸性球可能藉由釋放mediator，如TNFa，導致BEAS-2B細胞走向apoptosis。此外，以西方墨點法分析發現BEAS-2B細胞與rDer p1致敏化嗜酸性球共養或將其暴露於致敏化嗜酸性球之培養液，均可活化BEAS-2B細胞中細胞凋亡信號調控激酶(apoptosis signal-regulating kinase1; ASK1)及其下游p38 mitogen-activated protein kinases (MAPK)分子。由此推測呼吸道表皮細胞藉由活化ASK1-p38 MAPK途徑導致細胞走向apoptosis。另一方面將TRX大量表現於BEAS-2B細胞中，則可抑制ASK1-p38 MAPK活化，進而降低rDer p1致敏化嗜酸性球對於BEAS-2B細胞所造成之apoptosis情形。研究結果亦發現，受rDer p1致敏化嗜酸性球傷害的BEAS-2B細胞會促使呼吸道變形基因，如：transformating growth factor (TGF)-b1、epidermal growth factor receptor (EGFR)及cyclin dependent kinase inhibitor (p21waf)之表現。BEAS-2B細胞大量表現TRX可降低rDer p1致敏化嗜酸性球對於BEAS-2B細胞中上述呼吸道變形基因之表現。此外，TRX大量表現時亦會促使表皮細胞中MMP9表現量上升。TGF-b1抗體可降低致敏化嗜酸性球活化呼吸道表皮細胞中MMP9表現，故推測致敏化嗜酸性球促使MMP9表現主要是藉由TGF-b1之表現。綜合以上結果，經rDer p1致敏化之嗜酸性球會釋放ROS及mediator，對呼吸道表皮細胞產生氧化傷害，導致apoptosis。呼吸道表皮細胞大量表現TRX可降低致敏化嗜酸性球所造成之氧化傷害及抑制細胞凋亡分子活化，並且調控呼吸道變形之表現。據此得知TRX可應用於過敏相關疾病之治療。

House dust mite (HDM) is a common allergen of allergic disorders. After exposure to allergens, bronchial epithelial cells release chemokines to recruit inflammatory cells, such as eosinophils and neutrophils, and cause inflammatory cells accumulate in the lung. Activated eosinophils cause oxidative stress and damage in human bronchial epithelial cells through release of reactive oxygen species (ROS), tumor necrosis factor (TNFa) and granular proteins. The damaged epithelial cells secrete mediators, such as growth factors, cyclin-dependent kinase inhibitors and matrix metalloproteinase (MMP), contributing to the occurrence of airway remodeling. That would cause airway narrow and decline respiratory function. This study aimed to explore whether HDM and/or its activated eosinophils would cause oxidative stress and interfere with gene expression of remodeling factors in bronchial epithelial cells. Moreover, thioredoxin (TRX) is a redox (reduction/oxidation)-active protein to scavenge ROS, which mediates cell inflammation, growth, and etc. This study was further to investigate how TRX regulated damage and gene expression upon the interaction between human bronchial epithelial cells and HDM-stimulated eosinophils.
This study cultured normal human bronchial epithelial (BEAS-2B) cells exposed 0.5□ug/ml recombinant Dermatophagoides pteronyssinus 1 (rDer p1) for 24 hr. rDer p1 induced interleukin-6 (IL-6; 202.7 ± 22.2 pg/106 cells) and nitric oxide (NO; 5.7 ± 0.1□uM) release in the medium of BEAS-2B cells. BEAS-2B cells co-cultured with human primary eosinophils or eosinophil cell line (differentiated HL-60/clone 15; EOS/HL-60) for 24 hr. The release of IL-6 (687.0 ± 41.1 pg/106 cells) and NO (6.0 ± 0.1□uM) were obviously increased. Moreover, rDer p1 induced eosinophils to generate great amount of ROS in 2 hr, and the generation of ROS was sustained when co-cultured with BEAS-2B cells for 24 hr. BEAS-2B cells cultured with rDer p1-stimulated eosinophils (16.04 ± 0.75 pg/106 cells) or conditioned medium from rDer p1-stimulated EOS/HL-60 cells (14.86 ± 1.25 pg/10(6) cells) for 24 hr secreted TNFa□higher than BEAS-2B cells (4.92 ± 0.17 pg/10(6) cells). BEAS-2B cells underwent apoptosis when they were treated with conditioned medium for 24 hr. Accordingly, rDer p1-stimulated eosinophils caused bronchial epithelial cells damage through mediator TNFa□release. Western blot analysis showed that BEAS-2B cells cultured with rDer p1-stimulated eosinophils conditioned medium were both activated apoptosis signal-regulating kinase 1 (ASK1) and p38 mitogen-activated protein kinases (MAPK). It suggested that rDer p1-stimulated eosinophils caused BEAS-2B cells undergoing apoptosis through activation of ASK1-p38 MAPK pathway. On the other hand, TRX-over-expressing cells inactivated ASK1-p38 MAPK pathway and reduced the degree of apoptosis when cells were treated with conditioned medium. The damaged BEAS-2B cells caused by rDer p1-activated eosinophils induced gene expression of remodeling factors, such as transformating growth factor-b1 (TGF-b1), epidermal growth factor receptor (EGFR) and cyclin dependent kinase inhibitor (p21waf). TRX over-expression in BEAS-2B cells attenuated the expression of aforementioned remodeling factors. The results of this study also showed that over-expression of TRX elevated MMP9 expression. TGF-b1 antibody reduced expression of MMP9 protein, which suggested that up-regulation of MMP9 protein in BEAS-2B cells cultured with rDer p1-stimulated eosinophils was mainly through TGF-b1 activation. In summary, rDer p1-stimulated eosinophils released ROS and mediators to cause bronchial epithelial cells oxidative stress and undergo apoptosis. This study found that TRX over-expression in bronchial epithelial cells repressed oxidative stress and attenuate activation of apoptosis-related molecules. Additionally, TRX mediated gene expression of remodeling factors in bronchial epithelial cells exposed to rDer p1-stimulated eosinophils. TRX may play a potential role in the treatment of allergic diseases.

1. Adam E, Hansen KK, Astudillo Fernandez O, Coulon L, Bex F, Duhant X, Jaumotte E, Hollenberg MD, Jacquet A. (2006) The house dust mite allergen Der p 1, unlike Der p 3, stimulates the expression of interleukin-8 in human airway epithelial cells via a proteinase-activated receptor-2-independent mechanism. J. Biol. Chem. 281(11):6910-6923.
2. Andreadis AA, Hazen SL, Comhair SA, Erzurum SC. (2003) Oxidative and nitrosative events in asthma. Free Radic. Biol. Med. 35(3):213-225.
3. Anna E, Kossakowska DR, Edwards CP, Melissa CZ, Dianlin G, Stetan JU, Thomas G, Leah AM, Anna JW. (1999) Interleukin-6 regulation of matrix metalloproteinase (MMP-2) and tissue inhibitor of metalloproteinase (TIMP-1) expression in malignant non-Hodgkin’s lymphomas. Blood 94(6):2080-2089.
4. Alison AH, Clare MU, Sara JM, Daniel SF, Georgina X, Erin EM, Sorina G, Norma PG, Channing Y, Stuart HO, Craig G. (2004) A critical role for eosinophils in allergic airway remodeling. Science 203(5691):1776-1779.
5. Beasley R. (2002). The burden of asthma with specific reference to the United States. J. Allergy Clin. Immunol. 109(5 Suppl):S482-S489.
6. Bellido T, O'Brien CA, Roberson PK, Manolagas SC. (1998) Transcriptional activation of the p21(WAF1,CIP1,SDI1) gene by interleukin-6 type cytokines. A prerequisite for their pro-differentiating and anti-apoptotic effects on human osteoblastic cells. J. Biol. Chem. 273(33):21137-21144.
7. Berkova N, Lair-Fulleringer S, Féménia F, Huet D, Wagner MC, Gorna K, Tournier F, Ibrahim-Granet O, Guillot J, Chermette R, Boireau P, Latgé JP. (2006) Aspergillus fumigatus conidia inhibit tumour necrosis factor (TNF)□ or staurosporine-induced apoptosis in epithelial cells. Int. Immunol. 18(1):139-150.
8. Blobe GC, Schiemann WP, Lodish HF. (2000) Role of transforming growth factor beta in human disease. N. Engl. J. Med. 342:1350-1358.
9. Bove PF, Wesley UV, Greul AK, Hristova M, Dostmann WR, van der Vliet A. (2007) Nitric oxide promotes airway epithelial wound repair through enhanced activation of MMP-9. Am. J. Respir. Cell Mol. Biol. 36(2):138-46.
10. Broide DH. (2008) Immunologic and inflammatory mechanisms that drive asthma progression to remodeling. J. Allergy Clin. Immunol. 121(3):560-70.
11. Brown A, Farmer K, MacDonald L, Kalsheker N, Pritchard D, Haslett C, Lamb J, Sallenave JM. (2003) House dust mite Der p 1 downregulates defenses of the lung by inactivating elastase inhibitors. Am. J. Respir. Cell Mol. Biol. 29(3 pt 1):381-389.
12. Burke-Gaffney A, Callister ME, Nakamura H. (2005) Thioredoxin: friend or foe in human disease? Trends Pharmacol. Sci. 26(8):398-404.
13. Chen Y, Cai J, Jones DP. (2006) Mitochondrial thioredoxin in regulation of oxidant-induced cell death. FEBS Lett. 580(28-29):6596-602.
14. Chiappara G, Gagliardo R, Siena A, Bonsignore MR, Bousquet J, Bonsignore G, Vignola AM. (2001) Airway remodeling in the pathogenesis of asthma. Curr. Opin. Allergy Clin. Immunol. 1(1):85-93.
15. Cohn L, Elias JA, Chupp GL. (2004) Asthma: mechanisms of disease persistence and progression. Annu. Rev. Immunol. 22(1):789-815.
16. Coward WR, Sagara H, Wilson SJ, Holgate ST, Church MK. (2004) Allergen activates peripheral blood eosinophil nuclear factor-kappaB to generate granulocyte macrophage-colony stimulating factor, tumour necrosis factor-□ and interleukin-8. Clin. Exp. Allergy 34(7):1071-1078.
17. de Halleux S, Stura E, VanderElst L, Carlier V, Jacquemin M, Saint-Remy JM. (2006) Three-dimensional structure and IgE-binding properties of mature fully active Der p 1, a clinically relevant major allergen. J. Allergy Clin. Immunol. 117(3):571-576.
18. Davies DE, Wicks J, Powell RM, Puddicombe SM, Holgate ST. (2003) Airway remodeling in asthma: new insights. J. Allergy Clin. Immunol. 111(2):215-225.
19. Dworski, R. (2000) Oxidant stress in asthma. Thorax 55(suppl 2):S51-53.
20. Fan TC, Chang HT, Chen IW, Wang HY, Chang MD. (2007) A heparan sulfate-facilitated and raft-dependent macropinocytosis of eosinophil cationic protein. Traffic 8(12):1778-1795.
21. Fedorov IA, Wilson SJ, Davies DE, Holgate ST. (2005) Epithelial stress and structural remodeling in childhood asthma. Thorax 60(5):389-394.
22. Gartel AL, Tyner AL. (2002) The role of the cyclin dependent kinase inhibitor p21 in apoptosis. Mol. Cancer Ther. 1(8):639-649.
23. Ghaemmaghami AM, Shakib F. (2002) Human T cells that have been conditioned by the proteolytic activity of the major dust mite allergen Der p 1 trigger enhanced immunoglobulin E synthesis by B cells. Clin. Exp. Allergy 32(5):728-732.
24. Giembycz MA, Lindsay MA. (1999) Pharmacology of the eosinophil. Pharmacol. Rev. 51(2):213-340.
25. Hamada Y, Miyata S, Nii-Kono T, Kitazawa R, Kitazawa S, Higo S, Fukunaga M, Ueyama S, Nakamura H, Yodoi J, Fukagawa M, Kasuga M. (2007) Overexpression of thioredoxin1 in transgenic mice suppresses development of diabetic nephropathy. Nephrol. Dial. Transplant. 22(6):1547-1557.
26. Hamilton LM, Torres-Lozano C, Puddicombe SM, Richter A, Kimber I, Dearman RJ, Vrugt B, Aalbers R, Holgate ST, Djukanović R, Wilson SJ, Davies DE. (2003) The role of the epidermal growth factor receptor in sustaining neutrophil inflammation in severe asthma. Clin. Exp. Allergy 33(2):233-40.
27. Hoshino M, Nakamura Y, Sim JJ. (1998) Expression of growth factors and remodelling of the airway wall in bronchial asthma. Thorax 53(1):21-27.
28. Hirota K, Murata M, Itoh T, Yodoi J, Fukuda K. (2001) Redox-sensitive transactivation of epidermal growth factor receptor by tumor necrosis factor confers the NF-kappa B activation. 13;276(28):25953-25958.
29. Ichiki H, Hoshino T, Kinoshita T, Imaoka H, Kato S, Inoue H, Nakamura H, Yodoi J, Young HA, Aizawa H. (2005) Thioredoxin suppresses airway hyperresponsiveness and airway inflammation in asthma. Biochem. Biophys. Res. Commun. 334(4):1141-1148.
30. Imaoka H, Hoshino T, Takei S, Sakazaki Y, Kinoshita T, Okamoto M, Kawayama T, Yodoi J, Kato S, Iwanaga T, Aizawa H. (2007) Effects of thioredoxin on established airway remodeling in a chronic antigen exposure asthma model. Biochem. Biophys. Res. Commun. 360(3):525-530.
31. James AL, Pare PD, Hogg JC. (1989) The mechanics of airway narrowing in asthma. Am. Rev. Respir. Dis. 139(1):242-246.
32. Kaimul AM, Nakamura H, Tanito M, Yamada K, Utsumi H, Yodoi J. (2005) Thioredoxin-1 suppresses lung injury and apoptosis induced by diesel exhaust particles (DEP) by scavenging reactive oxygen species and by inhibiting DEP-induced downregulation of Akt. Free Radic. Biol. Med. 39(12):1549-1559.
33. Kalsheker NA, Deam S, Chambers L, Sreedharan S, Brocklehurst K, Lomas DA. (1996) The house dust mite allergen Der p1 aatalytically inactivates [alpha]1-antitrypsin by specific reactive centre loop cleavage: a mechanism that promotes airway inflammation and asthma. Biochem. Biophys. Res. Commun. 221(1):59-61.
34. Kerr JF, Wyllie AH, Currie, AR. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26(4):239-257.
35. Kharitonov SA, Barnes PJ. (2006) Exhaled biomarkers. Chest 130(5):1541-1546.
36. Kim HS, Luo L, Pflugfelder SC, Li DQ. (2005) Doxycycline inhibits TGF-beta1-induced MMP-9 via Smad and MAPK pathways in human corneal epithelial cells. Invest. Ophthalmol. Vis. Sci. 46(3):840-848.
37. King C, Brennan S, Thompson PJ, Stewart GA. (1998) Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium. J. Immunol. 161(7):3645-3651.
38. Lai CL, Shyur SD, Wu CY, Chang CL, Chu SH. (2002) Specific IgE to 5 different major house dust mites among asthmatic children. Acta. Paediatr. Taiwan. 43(5):265-270.
39. Lee YC, Chuang CY, Lee PK, Harper RW, Buckpitt AB, Wu R, Oslund K. (2008) TRX-ASK1-JNK signaling regulation of cell density-dependent cytotoxicity in cigarette smoking-exposed human bronchial epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 294(5):L921-931.
40. Lillig CH, Holmgren A. (2007) Thioredoxin and related molecules-from biology to health and disease. Antioxid. Redox. Signal 9(1):25-47.
41. Li GX, Hirabayashi Y, Yoon BI, Kawasaki Y, Tsuboi I, Kodama Y, Kurokawa Y, Yodoi J, Kanno J, Inoue T. (2006) Thioredoxin overexpression in mice, model of attenuation of oxidative stress, prevents benzene-induced hemato-lymphoid toxicity and thymic lymphoma. Exp. Hematol. 34(12):1687-1697.
42. Lundahl J, Sehmi R, Hayes L, Howie K, Denburg JA. (2000) Selective upregulation of a functional beta7 integrin on differentiating eosinophils. Allergy 55(9):865-872.
43. Massagué J. (2000) How cells read TGF-beta signals. Nat. Rev. Mol. Cell Biol. 1(3):169-178.
44. Masutani H, Ueda S, Yodoi J. (2005) The thioredoxin system in retroviral infection and apoptosis. Cell Death Differ. 12(S1):991-998.
45. McWhinnie R, Pechkovsky DV, Zhou D, Lane D, Halayko AJ, Knight DA, Bai TR. (2007) Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells. Am. J. Physiol. Lung Cell Mol. Physiol. 292(1):L278-286.
46. Miike S, Kita H. (2003) Human eosinophils are activated by cysteine proteases and release inflammatory mediators. J. Allergy Clin. Immunol. 111(4):704-713.
47. Minshall EM, Leung DY, Martin RJ, Song YL, Cameron L, Ernst P, Hamid Q. (1997) Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am. J. Respir. Cell Mol. Biol. 17(3):326-333.
48. Murillo MM, del Castillo G, Sánchez A, Fernández M, Fabregat I. (2005) Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes. Oncogene 24(28):4580-4587.
49. Munoz NM, Leff AR. (2006) Highly purified selective isolation of eosinophils from human peripheral blood by negative immunomagnetic selection. Nat. Protoc. 1(6):2613-2620.
50. Ohbayashi H, Shimokata K. (2005) Matrix metalloproteinase-9 and airway remodeling in asthma. Curr. Drug Targets Inflamm. Allergy 4(2):177-81.
51. Pascual RM, Peters SP. (2005) Airway remodeling contributes to the progressive loss of lung function in asthma: An overview. J. Allergy Clin. Immunol. 116(3):477-486.
52. Pégorier S, Wagner LA, Gleich GJ, Pretolani M. (2006) Eosinophil-derived cationic proteins activate the synthesis of remodeling factors by airway epithelial cells. J. Immunol. 177(7):4861-4869.
53. Pichavant M, Charbonnier AS, Taront S, Brichet A, Wallaert B, Pestel J, Tonnel AB, Gosset P. (2005) Asthmatic bronchial epithelium activated by the proteolytic allergen Der p1 increases selective dendritic cell recruitment. J. Allergy Clin. Immunol. 115(4):771-778.
54. Rahman I, Biswas SK, Kode A. (2006) Oxidant and antioxidant balance in the airways and airway diseases. Eur. J. Pharmacol. 533(1-3):222-39.
55. Redington AE, Springall DR, Meng QH, Tuck AB, Holgate ST, Polak JM, Howarth PH. (1997) Immunoreactive endothelin in bronchial biopsy specimens: Increased expression in asthma and modulation by corticosteroid therapy. J. Allergy Clin. Immunol. 100(4):544-552.
56. Rothenberg ME, Hogan SP. (2006) The Eosinophil. Annu. Rev. Immunol. 24(1):147-174.
57. Sanders SP, Zweier JL, Harrison SJ, Trush MA, Rembish SJ, Liu MC. (1995) Spontaneous oxygen radical production at sites of antigen challenge in allergic subjects. Am. J. Respir. Crit. Care Med. 151(6):1725-1733.
58. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17(9):2596-2606.
59. Schulz O, Sewell HF, Shakib F. (1998) Proteolytic cleavage of CD25, the alpha subunit of the human T cell interleukin 2 receptor, by Der p 1, a major mite allergen with cysteine protease activity. J. Exp. Med. 187(2):271-275.
60. Seomum Y, Kim JT, Joo CK. (2008) MMP-14 mediated MMP-9 expression is involved in TGF-beta1-inudced keratinocyte migration. J.Cell Biochem. J. Cell Biochem. 104(3):934-941.
61. Sharma S, Lackie PM, Holgate ST. (2003) Uneasy breather: the implications of dust mite allergens. Clin. Exp. Allergy 33(2):163-165.
62. Sheng G, Bernabe KQ, Guo J, Warner BW. (2006) Epidermal growth factor receptor-mediated proliferation of enterocytes requires p21waf1/cip1 expression. Gastroenterology 131(1):153-164.
63. Slungaard A, Vercellotti GM, Walker G, Nelson RD, Jacob HS. (1990) Tumor necrosis factor alpha/cachectin stimulates eosinophil oxidant production and toxicity towards human endothelium. J. Exp. Med. 171(6):2025-2041.
64. Stacey MA, Sun G, Vassalli G, Marini M, Bellini A, Mattoli S. (1997) The allergen Der p1 induces NF-kB activation through interference with IkB[alpha] function in asthmatic bronchial epithelial cells. Biochem. Biophys. Res. Commun. 236(2):522-526.
65. Sun HL, Chou MC, Lue KH. (2000) The relationship of air pollution of ED visits for asthma differ between children and adults. Am. J. Emerg. Med. 24(6):709-713.
66. Tesfaigzi Y. (2006) Roles of apoptosis in airway epithelia. Am. J. Respir. Cell Mol. Biol. 34(5):537-547.
67. Trautmann A, Schmid-Grendelmeier P, Krüger K, Crameri R, Akdis M, Akkaya A, Bröcker EB, Blaser K, Akdis CA. (2002) T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma. J. Allergy Clin. Immunol. 109(2):329-337.
68. Tripathi P, Tripathi P, Kashyap L, Singh V. (2007) The role of nitric oxide in inflammatory reactions. FEMS. Immunol. Med. Microbiol. 51(3):443-452.
69. Ueno M, Masutani H, Arai RJ, Yamauchi A, Hirota K, Sakai T, Inamoto T, Yamaoka Y, Yodoi J, Nikaido T. (1999) Thioredoxin-dependent redox regulation of p53-mediated p21 activation. J. Biol. Chem. 274(50):35809-35815.
70. Vignola AM, Chanez P, Chiappara G, Merendino A, Pace E, Rizzo A, la Rocca AM, Bellia V, Bonsignore G, Bousquet J. (1997) Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med. 156(2):591-599.
71. Walsh GM. (2001) Eosinophil-epithelial cell interactions: a special relationship? Clin. Exp. Allergy 31(3):351-354.
72. Wan H, Winton HL, Soeller C, Taylor GW, Gruenert DC, Thompson PJ, Cannell MB, Stewart GA, Garrod DR, Robinson C. (2001) The transmembrane protein occludin of epithelial tight junctions is a functional target for serine peptidases from faecal pellets of Dermatophagoides pteronyssinus. Clin. Exp. Allergy 31(2):279-294.
73. Wong CK, Ho CY, Ko FW, Chan CH, Ho AS, Hui DS, Lam CW. (2001) Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-□, IL-4, IL-10 and IL-13) in patients with allergic asthma. Clin. Exp. Allergy 125(2):177-183.
74. Wong CK, Li ML, Wang CB, Ip WK, Tian YP, Lam CW. (2006) House dust mite allergen Der p1 elevates the release of inflammatory cytokines and expression of adhesion molecules in co-culture of human eosinophils and bronchial epithelial cells. Int. Immunol. 18(8):1327-1335.
75. Yamada T, Iwasaki Y, Nagata K, Fushiki S, Nakamura H, Marunaka Y, Yodoi J. (2007) Thioredoxin-1 protects against hyperoxia-induced apoptosis in cells of the alveolar walls. Pulm. Pharmacol. Ther. 20(6):650-659
76. Yamasaki M, Kang HR, Homer RJ, Chapoval SP, Cho SJ, Lee BJ, Elias JA, Lee CG. (2008) P21 regulates TGF-beta1-induced pulmonary responses via a TNF-alpha-signaling pathway. Am. J. Respir. Cell Mol. Biol. 38(3):346-353.
77. Yang KD. (2000) Childhood asthma: aspects of global environment, genetics and management. Chang Gung Med. J. 23(11):641-661.
78. Yoon HK, Cho HY, Kleeberger SR. (2007) Protective role of matrix metalloproteinase-9 in ozone-induced airway inflammation. Environ. Health Perspect. 115(11):1557-1563.
79. Yoshida S, Katoh T, Tetsuka T, Uno K, Matsui N, Okamoto T. (1999) Involvement of thioredoxin in rheumatoid arthritis: its costimulatory roles in the TNF-{alpha}-induced production of IL-6 and IL-8 from cultured synovial fibroblasts. J. Immunol. 163(1):351-358.