燙傷會誘使小腸黏膜屏蔽功能失常以至於造成多重器官衰竭，已有研究報告指出燙傷造成小腸及肺的傷害與iNOS的活化有關，iNOS及MMP-9的表現受到NF-κB活化的調控，而NF-κB的調控又受到上游MAPKs活化影響。此研究的目的在探求大白鼠燙模式下小腸及肺的ERKs活化情形。實驗中，我們將大白鼠進行體表面積30 ~ 35 %的燙傷並萃取其肺及小腸黏膜組織蛋白液，利用immunoblotting偵測ERKs和p38的磷酸化，EMSA偵測NF-κB的活化，RT-PCR偵測iNOS及MMP-9的表現並測量小腸及肺的通透性。實驗結果顯示燙傷會使小腸及肺的ERKs、p38、NF-κB、iNOS活化而小腸及肺的通透性也增加，但卻抑制MMP-9的表現，隨後在MEK1/2抑制劑PD98059及U0126的處理下，ERKs、NF-κB、MMP-9的活性受到抑制同時也減弱了小腸及肺的通透性，但iNOS的表現卻增加了。此外，有趣的是ERKs在小腸及肺有著不同的表現，並且ERKs和p38存在著兩個階段的活化情形。由實驗結果推斷NF-κB的活化可調控因燙傷導致組織器官的傷害，而NF-κB的活化又受到ERKs的調控，因此可推知燙傷所牽涉的訊息傳導路徑可能經過ERKs或p38、NF-κB、iNOS或MMP-9，最後造成組織器官的傷害。除此之外，由實驗結果推知ERKs在燙傷系統下扮演著傷害組織的角色，同時推斷MMP-9可能才是造成小腸及肺的傷害的主要原因。

Burn-induced intestinal barrier failure has been proposed to be a potential cause of subsequent multiple organ failure after burn. Studies have shown that the increased iNOS activity is closely related to intestinal and pulmonary damage in rats after burn. Expression of iNOS and MMP-9 is regulated by nuclear factor NF-κB activation, which is frequently a result of MAPKs pathway activation. This study was to investigate the role of ERKs in intestinal and pulmonary damage induced by burn in rats. In experiments, SD rats underwent 30 ~ 35 % TBSA burn. At various times after burn, intestinal mucosa and pulmonary proteins were assayed for ERKs and p38 phosphorylation by immunoblotting, nuclear extracts were assayed for NF-κB activation by EMSA, intestinal and pulmonary iNOS, MMP-9 expressions were evaluated by RT-PCR, the FITC-dextran permeability was determined to assess the intestinal barrier function and the pulmonary microvascular dysfunction was quantitated by measuring the extravasation of Evans blue dye. The results show that burn induced ERKs and p38 phosphorylation, the expression of iNOS, and NF-κB activation in intestinal mucosa and lung, but the expression of MMP-9 was attenuated. Treatment with MEK1/2 inhibitors, PD98059 (10 mg/kg i.p.) or U0126 (5 mg/kg i.p.) immediately after burn, attenuated the phosphorylation of intestinal mucosa and pulmonary ERKs, the activation of NF-κB, the increase in intestinal permeability, and pulmonary microvascular dysfunction. Interestingly, the expression of iNOS in intestinal mucosa and pulmonary tissues was induced by PD98059 administration, but the expression of MMP-9 in intestinal mucosa was attenuated by PD98059 administration. These results suggest that the tissue damage is regulated by NF-κB activation and the activation of NF-κB is primarily mediated by signal pathway of ERKs in burn-injured rats, so the signal transduction pathway may involve ERKs and p38, NF-κB, iNOS or MMP-9, then causes tissue damage. Further, burn-induced intestinal mucosa and pulmonary ERKs have different degree of activation. The p38 and ERKs phosphorylation showed a two-step activation in intestinal mucosa and pulmonary tissues after burn. Inhibition of intestinal and pulmonary ERKs in vivo afforded significant protection against burn-induced barrier failure. However, the data showed that iNOS may not play a major role in the burn-induced intestinal and pulmonary damage, and MMP-9 may have more affect on tissues damage.

Abstract in Chinese…………………………………1

Abstract in English…………………………………2

Introduction……………………………………………3

Materials and Methods………………………………8

Results…………………………………………………13

Discussion………………………………………………16

Figures…………………………………………………21

References……………………………………………34

1. Jones WG 2nd, Barber AE, Minei JP, Fahey TJ 3rd, Shires GT 3rd, Shires GT.Differential pathophysiology of bacterial translocation after thermal injury and sepsis. Ann Surg. 1991, 214:24-30.
2. Otamiri T, Sjodahl R, Tagesson C. An experimental model for studying reversible intestinal ischemia. Acta Chir Scand. 1987, 153:51-6.
3. Dressler DP, Barbee WK, Sprenger R. The effect of Hydron burn wound dressing on burned rat and rabbit ear wound healing. J Trauma. 1980, 20:1024-8.
4. Chen LW, Hsu CM, Wang JS, Chen JS, Chen SC. Specific inhibition of iNOS decreases the intestinal mucosal peroxynitrite level and improves the barrier function after thermal injury. Burns. 1998, 24:699-705.
5. Chen LW, Hsu CM, Cha MC, Chen JS, Chen SC. Changes in gut mucosal nitric oxide synthase (NOS) activity after thermal injury and its relation with barrier failure. Shock. 1999, 11:104-10.
6. Tavaf-Motamen H, Miner TJ, Starnes BW, Shea-Donohue T. Nitric oxide mediates acute lung injury by modulation of inflammation. J Surg Res. 1998, 78:137-42.
7. Baskaran H, Yarmush ML, Berthiaume F. Dynamics of tissue neutrophil sequestration after cutaneous burns in rats. J Surg Res. 2000, 93:88-96.
8. Fazal N, Shamim M, Khan SS, Gamelli RL, Sayeed MM. Neutrophil depletion in rats reduces burn-injury induced intestinal bacterial translocation. Crit Care Med. 2000, 28:1550-5.
9. Ward PA, Till GO. Pathophysiologic events related to thermal injury of skin. J Trauma. 1990, 30:75-9.
10. Chen LW, Hsu CM, Wang JS, Chen HL, Chen JS. Inhibition of inducible nitric oxide synthase (iNOS) prevents lung neutrophil deposition and damage in burned rats. Shock. 2001, 15:151-6.
11. Stuehr DJ, Griffith OW. Mammalian nitric oxide synthases. Adv Enzymol Relat Areas Mol Biol. 1992, 65:287-346. Review.
12. Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994, 78:915-8. Review.
13. Nathan C. Inducible nitric oxide synthase: what difference does it make? J Clin Invest. 1997, 100:2417-23. Review.
14. Lowenstein CJ, Dinerman JL, Snyder SH. Nitric oxide: a physiologic messenger. Ann Intern Med. 1994, 120:227-37. Review.
15. Schmidt HH, Walter U. NO at work. Cell. 1994, 78:919-25. Review.
16. Michel T, Feron O. Nitric oxide synthases: which, where, how, and why? J Clin Invest. 1997, 100:2146-52. Review.
17. Morris SM Jr, Billiar TR. New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol. 1994, 266:829-39. Review.
18. Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997, 9:180-6. Review.
19. Tibble LA, Woodgett JR. The stress-activated protein kinase pathways. Cell Mol Life Sci. 1999, 55:1230–1254.
20. Ivanov V, Ronai Z. p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF- B activity and Fas expression. Oncogene. 2000,19:3003–3012.
21. Whitmarsh A, Davis R. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med. 1996, 74:589–607.
22. Clerk A, Sugden PH. Cell stress-induced phosphorylation of ATF2 and c-Jun transcription factors in rat ventricular myocytes. Biochem J. 1997; 325:801–810.
23. Wang XZ, Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase. Science. 1996, 272:1347–1349.
24. Cohen P. The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol. 1997, 7:353–361.
25. Chakraborti S, Chakraborti T. Oxidant-mediated activation of mitogen-activated protein kinases and nuclear transcription factors in the cardiovascular system: a brief overview. Cell Signal 1998; 10: 675-683.
26. Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 2000, 351:289-305.
27. Sachsenmaier C, Radler-Pohl A, Zinck R, Nordheim A, Herrlich P, Rahmsdorf HJ. Involvement of growth factor receptors in the mammalian UVC response. Cell 1994, 78:963-972.
28. Schieven GL, Mittler RS, Nadler SG, Kirihara JM, Bolen JB, Kanner SB, Ledbetter JA. ZAP-70 tyrosine kinase, CD45, and T cell receptor involvement in UV- and H2O2-induced T cell signal transduction. J Biol Chem 1994, 269: 20718-20726.
29. Guyton KZ, Gorospe M, Wang X, Mock YD, Kokkonen GC, Liu Y, Roth GS, Holbrook NJ. Age-related changes in activation of mitogen-activated protein kinase cascades by oxidative stress. J Investig Dermatol Symp Proc 1998, 3: 23-27.
30. Burdon RH. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med 1995, 18:775-794.
31. Chen W, Martindale JL, Holbrook NJ, Liu Y. Tumor promoter arsenite activates extracellular signal-regulated kinase through a signaling pathway mediated by epidermal growth factor receptor and Shc. Mol Cell Biol 1998, 18: 5178-5188.
32. Knebel A, Rahmsdorf HJ, Ullrich A, Herrlich P. Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J 1996, 15:5314-5325.
33. Lee SR, Kwon KS, Kim SR, Rhee SG. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J Biol Chem 1998, 273:15366-15372.
34. Meves A, Stock SN, Beyerle A, Pittelkow MR, Peus D. H2O2 mediates oxidative stress-induced epidermal growth factor receptor phosphorylation. Toxicol Lett 2001, 122:205-214.
35. Guyton KZ, Gorospe M, Kensler TW, Holbrook NJ. Mitogen-activated protein kinase (MAPK) activation by butylated hydroxytoluene hydroperoxide: implications for cellular survival and tumor promotion. Cancer Res 1996, 56: 3480-3485.
36. Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Tanaka M, Shiojima I, Hiroi Y, Yazaki Y. Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. J Clin Invest 1997, 100:1813-1821.
37. Wang X, Martindale JL, Liu Y, Holbrook NJ. The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J 1998, 333:291-300.
38. Petrache I, Choi ME, Otterbein LE, Chin BY, Mantell LL, Horowitz S, Choi AM. Mitogen-activated protein kinase pathway mediates hyperoxia-induced apoptosis in cultured macrophage cells. Am J Physiol 1999, 277:589-595.
39. Brand A, Gil S, Seger R, Yavin E. Lipid constituents in oligodendroglial cells alter susceptibility to H2O2-induced apoptotic cell death via ERK activation. J Neurochem 2001, 76:910-918.
40. Ishikawa Y, Kitamura M. Anti-apoptotic effect of quercetin: intervention in the JNK- and ERK-mediated apoptotic pathways. Kidney Int 2000, 58:1078-1087.
41. Dollery CM, McEwan JR, and Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995, 77:863–868.
42. Bendeck, M. P., Zempo, N., Clowes, A. W., Galardy, R. E., and Reidy, M. A. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ. Res. 1994, 75:539-545
43. Webb, K. E., Henney, A. M., Anglin, S., Humphries, S. E., and Mcewan, J. R. Expression of matrix metalloproteinases and their inhibitor TIMP-1 in the rat carotid artery after balloon injury. Arterioscler. Thromb. Vasc. Biol. 1997, 17:1837-1844
44. Zempo, N., Kenagy, R. D., Au, Y. P. T., Bendeck, M., Clowes, M. M., Reidy, M. A., and Clowes, A. W. Matrix metalloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery. J. Vasc. Surg. 1994, 20:209-217
45. Galis, Z. S., Sukhova, G. K., Lark, M. W., and Libby, P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest. 1994, 94:2493-2503
46. Brown, D. L., Hibbs, M. S., Kearney, M., Loushin, C., and Isner, J. M. Identification of 92-kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina. Circulation 1995, 91: 2125-2131
47. Brown, D. L., Hibbs, M. S., Kearney, M., and Isner, J. M. Differential expression of 92-kDa gelatinase in primary atherosclerotic versus restenotic coronary lesions. Am. J. Cardiol. 1997, 79:878-882
48. Okada, Y., Gonoji, Y., Naka, K., Tomita, K., Nakanishi, I., Iwata, K., Yamashita, K., and Hayakawa, T. Matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) from HT 1080 human fibrosarcoma cells. Purification and activation of the precursor and enzymic properties. J. Biol. Chem. 1992, 267:21712-21719
49. Senior, R. M., Griffin, G. L., Fliszar, C. J., Shapiro, S. D., Goldberg, G. I., and Welgus, H. G. Human 92- and 72-kilodalton type IV collagenases are elastases. J. Biol. Chem. 1991, 1991:7870-7875
50. Galis, Z. S., Muszynski, M., Sukhova, G. K., Simon-Morrissey, E., Unemori, E. N., Lark, W. W., Amento, E., and Libby, P. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ. Res. 1994, 75:181-189
51. Fabunmi, R. P., Baker, A. H., Murray, E. J., Booth, R. F. G., and Newby, A. C. Divergent regulation by growth factors and cytokines of 95 kDa and 72 kDa gelatinases and tissue inhibitors or metalloproteinases-1, -2, and -3 in rabbit aortic smooth muscle cells. Biochem. J. 1996, 315:335-342
52. Cho A, Graves J, Reidy MA. Mitogen-activated protein kinases mediate matrix metalloproteinase-9 expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000, 20:2527-32.
53. Gurjar MV, Deleon J, Sharma RV, Bhalla RC. Role of reactive oxygen species in IL-1 beta-stimulated sustained ERK activation and MMP-9 induction. Am J Physiol Heart Circ Physiol. 2001, 281:2568-74.
54. Wang X, Mori T, Jung JC, Fini ME, Lo EH. Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase. J Neurotrauma. 2002, 19:615-25.

55. Nakano, H., Shindo, M., Sakon, S., Nishinaka, S., Mihara, M., Yagita, H., and Okumura, K. Differential regulation of Ikappa B kinase α and βby two upstream kinases, NF-kappaB inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc. Natl. Acad. Sci. 1998, 9:3537-3542.
56. Von Knethen, A., Callsen,, D., and Brune, B. NF-kappaB and AP-1 activation by nitric oxide attenuated apoptotic cell death in RAW 264.7 macrophages. Mol. Biol. Cell. 1999,10:361-372.
57. Romashkova, J. A., and Makarov, S. S. NF-kappaB is a target of AKT in anti-apoptotic PDGF signaling. Nature 1999,401:86-90.
58. Baeuerle,P.A. and Baltimore,D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science, 1988, 242:540–546.
59. Baeuerle,P.A. and Baltimore,D. NF-kappa B: ten years after. Cell, 1996, 87: 13–20.
60. Telek G, Feher J, Jakab F, Claude R. Acute pancreatitis: recent advances in understanding its pathophysiology. Orv Hetil. 2000, 141:267-78. Review.
61. Chen F, Castranova V, Shi X, Demers LM. New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem. 1999, 45:7-17. Review.
62. Manna SK, Mukhopadhyay A, Aggarwal BB. IFN-alpha suppresses activation of nuclear transcription factors NF-kappa B and activator protein 1 and potentiates TNF-induced apoptosis. J Immunol. 2000, 165:4927-34.
63. Martel-Pelletier J, Mineau F, Jovanovic D, Di Battista JA, Pelletier JP. Mitogen-activated protein kinase and nuclear factor kappaB together regulate interleukin-17-induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated proten kinase (MAPKAPK). Arthritis Rheum. 1999, 42:2399-409.
64. Aesim Cho, Jonathan Graves, Michael A. Reidy. Mitogen-activated protein kinases mediate matrix metalloproteinase-9 expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000, 20:2527-32.
65. Schmeling DJ, Caty MG, Oldham KT, Guice KS, Hinshaw DB. Evidence for neutrophil-related acute lung injury after intestinal ischemia-reperfusion.Surgery. 1989, 106:195-201; discussion 201-2.
66. Cuzzocrea S, Zingarelli B, Sautebin L, Rizzo A, Crisafulli C, Campo GM, Costantino G, Calapai G, Nava F, Di Rosa M, Caputi AP. Multiple organ failure following zymosan-induced peritonitis is mediated by nitric oxide. Shock. 1997, 8:268-75.
67. Hansbrough JF, Wikstrom T, Braide M, Tenenhaus M, Rennekampff OH, Kiessig V, Bjursten LM. Neutrophil activation and tissue neutrophil sequestration in a rat model of thermal injury. J Surg Res. 1996, 61:17-22.
68. Li X, Xiang J, Liao Z. Statistical analysis of 4,547 burn patients and the mortality in different periods. Zhonghua Zheng Xing Shao Shang Wai Ke Za Zhi. 1995, 11:335-8.
69. Arbak S, Ercan F, Hurdag CG, Karabulut O, Gurbuz V, Corak A, Alican I. Acute lung injury following thermal insult to the skin: a light and transmission electron microscopial study. Acta Histochem. 1999, 101:255-62.
70. Turnage RH, Guice KS, Oldham KT. Pulmonary microvascular injury following intestinal reperfusion. New Horiz. 1994, 2:463-75. Review.
71. Meyer J, Traber L D, Nelson S, Lentz C W, Nakazawa H, Herndon D N, Noda H, Traber D L. Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis. J Appl Physiol 1992, 73:324-328.
72. Unno N, Wang H, Menconi M J, Tytgat S H, Larkin V, Smith M, Morin M J, Chavez A, Hodin R A, et al. Inhibition of inducible nitric oxide synthase ameliorates endotoxin- induced gut mucosal barrier dysfunction in rats [see comments]. Gastroenterology 1997,113:1246-1257.
73. Clerk, A, Fuller SJ, Michael A, and Sugden PH. Stimulation of "stress-regulated" mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses. J Biol Chem 1998, 273: 7228-7234
74. Nakano, A, Baines CP, Kim SO, Pelech SL, Downey JM, Cohen MV, and Critz SD. Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart: evidence for involvement of p38 MAPK. Circ Res 2000,86:144-151.
75. Roulston, A, Reinard C, Amiri P, and Williams LT. Early activation of c-Jun N-terminal kinase and p38 kinase regulate cell survival in response to tumor necrosis factor- . J Biol Chem 1998, 273:10232-10239.
76. Rouse, J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, and Nebreda AR. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 1994, 78:1027-1037.
77. Bogoyevitch, M., Gillespie-Brown, J., Ketterman, A., Fuller, S., Ben-Levy, R., Ashworth, A., Marshall, C., and Sugden, P. Stimulation of the Stress-Activated Mitogen-Activated Protein Kinase Subfamilies in Perfused Heart. Circ. Res. 1996, 79:162-173
78. Nakano, A., Baines, C. P., Kim, S. O., Pelech, S. L., Downey, J. M., Cohen, M. V., and Critz, S. D. Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart: evidence for involvement of p38 MAPK. Circ. Res. 2000, 86: 144-151
79. Saurin, A. T., Martin, J. L., Heads, R. J., Foley, C., Mockridge, J. W., Wright, M. J., Wang, Y., and Marber, M. S. The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. FASEB J. 2000, 14:2237-2246
80. Nagarkatti, D, and Sha'afi RI. Role of p38 MAP kinase in myocardial stress. J Mol Cell Cardiol 1998, 30:1651-1664.
81. Yin, T, Sandhu G, Wolfgang CD, Burrier A, Webb RL, Rigel DF, Hai T, and Whelan J. Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem 1997, 272:19943-19950.
82. Ping, P, and Murphy E. Role of p38 mitogen-activated protein kinases in preconditioning: a detrimental factor or a protective kinase? Circ Res 2000, 86: 921-922.
83. Winzen, R., Kracht, M., Ritter, B., Wilhelm, A., Chen, C.-Y. A., Shyu, A.-B., Müller, M., Gaestel, M., Resch, K., and Holtmann, H. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. EMBO J. 1999, 18:4969-4980.
84. Bhat, N. R., Zhang, P., Lee, J. C., and Hogan, E. L. Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J. Neurosci. 1998, 18:1633-1641.
85. Lowenstein, C. J., Alley, E. W., Raval, P., Snowman, A. M., Snyder, S. H., Russell, S. W., and Murphy, W. J. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc. Natl Acad. Sci. U. S. A. 1993, 90:9730-9734.
86. Xie, Q. W., Whisnant, R., and Nathan, C. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J. Exp. Med. 1993, 177:1779-1784.
87. Eberhardt, W., Kunz, D., Hummel, R., and Pfeilschifter, J. Molecular cloning of the rat inducible nitric oxide synthase gene promoter. Biochem. Biophys. Res. Commun. 1996, 223:752-756.
88. Chen, C.-C., and Wang, J.-K. p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages Mol. Pharmacol. 1999, 55: 481-488.
89. Jiang B, Brecher P, Cohen RA. Persistent activation of nuclear factor-kappaB by interleukin-1beta and subsequent inducible NO synthase expression requires extracellular signal-regulated kinase. Arterioscler Thromb Vasc Biol. 2001, 21:1915-20.
90. MacMicking J, Xie QW and Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol 1997, 15:323-350.
91. Barancik, M, Htun P, Strohm C, Kilian S, and Schaper W. Inhibition of the cardiac p38-MAPK pathway by SB-203580 delays ischemic cell death. J Cardiovasc Pharmacol 2000, 35:474-483.
92. Ma, XL, Kumar S, Gao F, Louden CS, Lopez BL, Christopher TA, Wang C, Lee JC, Feuerstein GZ, and Yue T-L. Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation 1999, 99:1685-1691.
93. Maulik, N, Watanabe M, Zu Y-O, Huang C-K, Cordis GA, Schley JA, and Das DK. Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts. FEBS Lett 1996, 396:233-237.
94. Narayan R. Bhat, Douglas L. Feinstei, Qin Shen, and Aruna N. Bhat. p38 MAPK-mediated Transcriptional Activation of Inducible Nitric-oxide Synthase in Glial Cells. J. Biol. Chem.2002, 277:29584-29592,
95. Weinbrenner, C, Liu G-S, Cohen MV, and Downey JM. Phosphorylation of tyrosine 182 of p38 mitogen-activated protein kinase correlates with the protection of preconditioning in the rabbit heart. J Mol Cell Cardiol 1997, 29:2383-2391.
96. Dana, A, Skarli M, Papakrivopoulou J, and Yellon DM. Adenosine A1 receptor induced delayed preconditioning in rabbits: induction of p38 mitogen-activated protein kinase activation and HSP27 phosphorylation via a tyrosine kinase- and protein kinase C-dependent mechanism. Circ Res 2000, 86:989-997.
97. Zhao, T, Hines DS, Krottapalli K, Emani VR, Xi L, and Kukreja RC. Adenosine induced delayed "pharmacological preconditioning" involves p38 MAP kinase signaling in mouse heart (Abstract). Circulation 100, Suppl 1999, 2966.
98. Armstrong SC, Delacey M, Ganote CE. Phosphorylation state of hsp27 and p38 MAPK during preconditioning and protein phosphatase inhibitor protection of rabbit cardiomyocytes. J Mol Cell Cardiol. 1999, 31:555–567.
99. Mackay K, Mochly-Rosen D. An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J Biol Chem. 1999, 274:6272–6279
100. Maulik N, Yoshida T, Zu Y-L, Sato M, Banerjee A, Das DK. Ischemic preconditioning triggers tyrosine kinase signaling: a potential role for MAPKAP kinase 2. Am J Physiol. 1998, 275:1857–1864.
101. Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res. 1994, 75:539–545.
102. Zempo N, Kenagy RD, Au YPT, Bendeck M, Clowes MM, Reidy MA, Clowes AW. Matrix metalloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery. J Vasc Surg. 1994, 20:209–217.
103. Gum R, Wang H, Lengyel E, Juarez J, Boyd D. Regulation of 92 kDa type IV collagenase expression by the jun amino terminal kinase- and the extracellular signal-regulated kinase-dependent signaling cascades. Oncogene. 1997, 14: 1481–1493.
104. Simon C, Goepfert H, Boyd D. Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. Cancer Res. 1998, 58:1135–1139.
105. Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998, 273:18623–18632.
106. Himelstein BP, Lee EJ, Sato H, Seiki M, Muschel RJ. Tumor cell contact mediated transcriptional activation of the fibroblast matrix metalloproteinase-9 gene: involvement of multiple transcription factors including Ets and an alternating purine-pyrimidine repeat. Clin Exp Metastasis. 1998, 16:169–177.
107. Martindale JL, Holbrook NJ.vCellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol. 2002, 192:1-15. Review.
108. Kim YM, Lee BS, Yi KY, Paik SG. Upstream NF-kappaB site is required for the maximal expression of mouse inducible nitric oxide synthase gene in interferon-gamma plus lipopolysaccharide-induced RAW 264.7 macrophages. Biochem Biophys Res Commun. 1997, 236:655-60.
109. Yamamoto A, Okagawa T, Kotani A, Uchiyama T, Shimura T, Tabata S, Kondo S, Muranishi S. Effects of different absorption enhancers on the permeation of ebiratide, an ACTH analogue, across intestinal membranes. J Pharm Pharmacol. 1997, 49:1057-61.
110. Yang GH, Jarvis BB, Chung YJ, Pestka JJ. Apoptosis induction by the satratoxins and other trichothecene mycotoxins: relationship to ERK, p38 MAPK, and SAPK/JNK activation. Toxicol Appl Pharmacol. 2000, 164:149-60.
111. Mackay K, Mochly-Rosen D. An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J Biol Chem. 1999, 274:6272-9.
112. Wang D, Yu X, and Brecher P. Nitric oxide and N-acetylcysteine inhibit the activation og mitogen-activated protein kinases by angiotensin Ⅱ in rat cardiac fibroblasts. J Biol Chem. 1998, 273:33027-33034.
113. Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Unemori EN, Lark MW, Amento E, and Libby P. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res. 1994, 75:181-189