Previous studies have shown that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a unique role in many physiological stress processes. The present study investigated the role of Nrf2 in the regulation of traumatic brain injury (TBI)-induced acute lung injury (ALI). Wild-type Nrf2 (+/+) and Nrf2 (−/−)-deficient mice were subjected to a moderately severe weight-drop impact head injury. Pulmonary capillary permeability (PCP), wet/dry weight ratio, apoptosis, inflammatory cytokines and antioxidant/detoxifying enzymes were measured at 24 h after TBI. Mice lacking Nrf2 were found to be more susceptible to TBI-induced ALI, as characterized by the higher increase in PCP, wet/dry weight ratio and alveolar cells apoptosis after TBI. This exacerbation of lung injury in Nrf2-deficient mice was associated with increased pulmonary mRNA and protein expression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6); and with decreased pulmonary mRNA expression and enzymatic activities of antioxidant and detoxifying enzymes including NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase α1 (GST-α1)—as compared with their wild-type Nrf2 (+/+) counterparts after TBI. The results of the present study suggest that Nrf2 reduces TBI-induced acute lung injury, possibly by decreasing pulmonary inflammation and inducing antioxidant and detoxifying enzymes.
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References
1.
Dettbarn CL, Davidson LJ. Pulmonary complications in the patient with acute head injury: neurogenic pulmonary edema. Heart Lung18: 583–589, 1989.
2.
Holland MC, Mackersie RC, Morabito D, Campbell AR, Kivett VA, Patel R, Erickson VR, Pittet JF. The development of acute lung injury is associated with worse neurologic outcome in patients with severe traumatic brain injury. J Trauma55:106–111, 2003.
3.
Kalsotra A, Zhao J, Anakk S, Dash PK, Strobel HW. Brain trauma leads to enhanced lung inflammation and injury: evidence for role of P4504Fs in resolution. J Cereb Blood Flow Metab27:963–974, 2007.
4.
Shohami E, Gati I, Beit-Yannai E, Trembovler V, Kohen R. Closed head injury in the rat induces whole body oxidative stress: overall reducing antioxidant profile. J Neurotrauma16:365–376, 1999.
5.
Chen XL, Kunsch C. Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases. Curr Pham Des10:879–891, 2004.
6.
Owuor ED, Kong AN. Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol64:765–770, 2002.
7.
Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol37:139–143, 2004.
8.
Osburn WO, Wakabayashi N, Misra V, Nilles T, Biswal S, Trush MA, Kensler TW. Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion. Arch Biochem Biophys454:7–15, 2006.
9.
Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA. Nrf2, a multi-organ protector? FASEB J19:1061–1066, 2005.
10.
Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY, Kleeberger SR. Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol26:175–182, 2002.
11.
Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest114:1248–1259, 2004.
12.
Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med202:47–59, 2005.
13.
Chan K, Kan YW. Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci U S A96:12731–12736, 1999.
14.
Cho HY, Reddy SP, Yamamoto M, Kleeberger SR. The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J18:1258–1260, 2004.
15.
Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, Biswal S. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest116: 984–995, 2006.
16.
Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol294:478–488, 2008.
17.
Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun236:313–322, 1997.
18.
Hall ED. High-dose glucocorticoid treatment improves neurological recovery in head-injured mice. J Neurosurg62:882–887, 1985.
19.
Kupina NC, Nath R, Bernath EE, Inoue J, Mitsuyoshi A, Yuen PW, Wang KK, Hall ED. The novel calpain inhibitor SJA6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury. J Neurotrauma18:1229–1240, 2001.
20.
Mikrogianakis A, Shaye RE, Griffin P, Kawesa S, Lockwood J, Gendron NH, Gaboury I, Merali Z, Mackenzie AE, Hutchison JS. Hypoxia alters the expression of inhibitor of apoptosis proteins after brain trauma in the mouse. J Neurotrauma24:338–353, 2007.
21.
Wagner EM, Karagulova G, Jenkins J, Bishai J, McClintock J. Changes in lung permeability after pulmonary artery obstruction. J Appl Physiol100:1224–1229, 2006.
22.
Lv R, Zhou W, Chu C, Xu J. Mechanism of the effect of hydroxyethyl starch on reducing pulmonary capillary permeability in a rat model of sepsis. Ann Clin Lab Sci35:174–183, 2005.
23.
Benson AM, Hunkeler MJ, Talalay P. Increase of NAD(P)H: quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. Proc Natl Acad U S A77:5216–5220, 1980.
24.
Kelly VP, Ellis EM, Manson MM, Chanas SA, Moffat GJ, McLeod R, Judah DJ, Neal GE, Hayes JD. Chemoprevention of aflatoxin B1 hepatocarcinogenesis by coumarin, a natural benzopyrone that is a potent inducer of aflatoxin B1-aldehyde reductase, the glutathione S-transferase A5 and P1 subunits, and NAD(P)H:quinone oxidoreductase in rat liver. Cancer Res60:957–969, 2000.
25.
Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med342:1334–1349, 2000.
26.
Kawkitinarong K, Linz-McGillem L, Birukov KG, Garcia JG. Differential regulation of human lung epithelial and endothelial barrier function by thrombin. Am J Respir Cell Mol Biol31:517–527, 2004.
27.
Ware LB, Kaner RJ, Crystal RG, Schane R, Trivedi NN, McAuley D, Matthay MA. VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema. Eur Respir J26:101–105, 2005.
28.
Wu S, Fang CX, Kim J, Ren J. Enhanced pulmonary inflammation following experimental intracerebral hemorrhage. Exp Neurol200: 245–249, 2006.
29.
Hesse DG, Tracey KJ, Fong Y, Manogue KR, Palladino MA Jr, Cerami A, Shires GT, Lowry SF. Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet166:147–153, 1988.
30.
Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol4:34–42, 2008.
31.
Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg215:356–362, 1992.
32.
Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res66:11580–11584, 2006.
33.
Osburn WO, Karim B, Dolan PM, Liu G, Yamamoto M, Huso DL, Kensler TW. Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment. Int J Cancer121:1883–1891, 2007.
34.
Wang J, Fields J, Zhao C, Langer J, Thimmulappa RK, Kensler TW, Yamamoto M, Biswal S, Doré S. Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med43:408–414, 2007.
35.
Ross D, Siegel D, Beall H, Parkash AS, Mulcahy RT, Gibson NW. DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C. Cancer Metastasis Rev12:83–101, 1993.
36.
Hecht SS. Chemoprevention by isothiocyanates. J Cell Biochem Suppl22:195–209, 1995.
37.
Das A, Kole J, Wang L, Barrios R, Moorthy B, Jaiswal AK. BALT development and augmentation of hyperoxic lung injury in mice deficient in NQO1 and NQO2. Free Radic Biol Med40:1843–1856, 2006.
38.
Saldivar SJ, Wang Y, Zhao H, Shao L, Lin J, Spitz MR, Wu X. An association between a NQO1 genetic polymorphism and risk of lung cancer. Mutat Res582:71–78, 2005.
39.
Saydam N, Kirb A, Demir O, Hazan E, Oto O, Saydam O, Güner G. Determination of glutathione, glutathione reductase, glutathione peroxides and glutathione S-transferase levels in human lung cancer tissues. Cancer Lett119:13–19, 1997.
40.
Kamada F, Mashimo Y, Inoue H, Shao C, Hirota T, Doi S, Kamada M, Fujiwara H, Fujita K, Enomoto T, Sasaki S, Endo H, Takayanagi R, Nakazawa C, Morikawa T, Morikawa M, Miyabayashi S, Chiba Y, Tamura G, Shirakawa T, Matsubara Y, Hata A, Tamari M, Suzuki Y. The GSTP1 gene is a susceptibility gene for childhood asthma and the GSTM1 gene is a modifier of the GSTP1 gene. Int Arch Allergy Immunol144:275–286, 2007.
41.
Sreeja L, Syamala V, Haribaran S, Syamala VS, Raveendran PB, Sivanadan CD, Madhavan J, Ankathil R. Glutathione S-transferase M1, T1 and P1 polymorphisms: susceptinility and outcome in lung cancer patients. J Exp Ther Oncol7:73–85, 2008.
