Anesthetic isoflurane (ISO) has immunomodulatory effects. In the present study, we investigated whether a subanesthetic dose of ISO (0.7%) protected against zymosan (ZY) induced inflammatory responses in the murine lung and isolated neutrophils. At 1 and 6？hrs after ZY administration intraperitoneally, ISO was inhaled for 1？hr, and 24？hrs later, lung inflammation and injury were assessed. We found that ISO improved the survival rate of mice and mitigated lung injury as characterized by the histopathology, wet-to-dry weight ratio, protein leakage, and lung function index. ISO significantly attenuated ZY-induced lung neutrophil recruitment and inflammation. This was suggested by the downregulation of (a) endothelial adhesion molecule expression and myeloperoxidase (MPO) activity in lung tissue and polymorphonuclear neutrophils (b) chemokines, and (c) proinflammatory cytokines in BALF. Furthermore, ZY-induced nuclear translocation and DNA-binding activity of NF-κB p65 were also reduced by ISO. ISO treatment inhibited iNOS expression and activity, as well as subsequent nitric oxide generation. Consistent with these in vivo observations, in vitro studies confirmed that ISO blocked NF-κB and iNOS activation in primary mouse neutrophils challenged by ZY. These results provide evidence that 0.7% ISO ameliorates inflammatory responses in ZY-treated mouse lung and primary neutrophils. 1. Introduction Multiple organ dysfunction syndrome (MODS) leads to high morbidity and mortality rates in the intensive care unit and is one of the most urgent and challenging public health problems worldwide [1, 2]. The lung is frequently the first organ that fails during the development of this syndrome. However, the mechanism of lung injury induced by inflammation remains to be determined, and the therapeutic regimen requires further investigation. Zymosan-induced generalized inflammation (ZIGI) mouse model can reproduce many characteristics of human MODS, which is adopted by many research groups [3, 4]. Several reports have shown that the onset of ZY-induced inflammatory response in mouse lung is associated with the gas exchange barrier and that it culminates with maximal neutrophil accumulation, exudate formation, and proinflammatory cytokines production [5–7]. ZY is recognized by toll-like receptor 2 (TLR-2) on immune cells (e.g., neutrophils), which subsequently trigger signal cascade for nuclear factor-κB (NF-κB) activation [8]. NF-κB activation is required for maximal expression of many proinflammatory cytokines and chemokines and iNOS involved in the pathogenesis of acute
References
[1]
G. S. Martin, D. M. Mannino, S. Eaton, and M. Moss, “The epidemiology of sepsis in the United States from 1979 through 2000,” New England Journal of Medicine, vol. 348, no. 16, pp. 1546–1554, 2003.
[2]
C. Alberti, C. Brun-Buisson, H. Burchardi et al., “Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study,” Intensive Care Medicine, vol. 28, no. 2, pp. 108–121, 2002.
[3]
R. J. Goris, W. K. Boekholtz, and I. P. van Bebber, “Multiple-organ failure and sepsis without bacteria: an experimental model,” Archives of Surgery, vol. 121, no. 8, pp. 897–901, 1986.
[4]
S. Cuzzocrea, G. Costantino, E. Mazzon, et al., “Protective effect of N-acetylcysteine on multiple organ failure induced by zymosan in the rat,” Critical Care Medcine, vol. 27, no. 8, pp. 1524–1532, 1999.
[5]
R. Di Paola, E. Mazzon, T. Genovese et al., “Ethyl pyruvate reduces the development of zymosan-induced generalized inflammation in mice,” Critical Care Medicine, vol. 37, no. 1, pp. 270–282, 2009.
[6]
R. E. Young, R. D. Thompson, K. Y. Larbi et al., “Neutrophil Elastase (NE)-deficient mice demonstrate a nonredundant role for NE in neutrophil migration, generation of proinflammatory mediators, and phagocytosis in response to zymosan particles in vivo,” Journal of Immunology, vol. 172, no. 7, pp. 4493–4502, 2004.
[7]
H. V. Chaves, R. A. Ribeiro, A. M. de Souza et al., “Experimental model of zymosan-induced arthritis in the rat temporomandibular joint: role of nitric oxide and neutrophils,” Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 707985, 11 pages, 2011.
[8]
Y. Ikeda, Y. Adachi, T. Ishii, N. Miura, H. Tamura, and N. Ohno, “Dissociation of toll-like receptor 2-mediated innate immune response to zymosan by organic solvent-treatment without loss of dectin-1 reactivity,” Biological and Pharmaceutical Bulletin, vol. 31, no. 1, pp. 13–18, 2008.
[9]
J. Fan, R. D. Ye, and A. B. Malik, “Transcriptional mechanisms of acute lung injury,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 281, no. 5, pp. L1037–L1050, 2001.
[10]
G. J. Crystal, G. Malik, S.-H. Yoon, and S.-J. Kim, “Isoflurane late preconditioning against myocardial stunning is associated with enhanced antioxidant defenses,” Acta Anaesthesiologica Scandinavica, vol. 56, no. 1, pp. 39–47, 2012.
[11]
C. Hofstetter, K. A. Boost, S. Hoeg et al., “Norepinephrine and vasopressin counteract anti-inflammatory effects of isoflurane in endotoxemic rats,” International Journal of Molecular Medicine, vol. 20, no. 4, pp. 597–604, 2007.
[12]
Q. F. Li, Y. S. Zhu, H. Jiang, H. Xu, and Y. Sun, “Isoflurane preconditioning ameliorates endotoxin-induced acute lung injury and mortality in rats,” Anesthesia and Analgesia, vol. 109, no. 5, pp. 1591–1597, 2009.
[13]
J. Reutershan, D. Chang, J. K. Hayes, and K. Ley, “Protective effects of isoflurane pretreatment in endotoxin-induced lung injury,” Anesthesiology, vol. 104, no. 3, pp. 511–517, 2006.
[14]
L. W. de Rossi, M. Brueckmann, S. Rex, M. Barderschneider, W. Buhre, and R. Rossaint, “Xenon and isloflurane differentially modulate lipopolysaccharide-induced activation of the nuclear transcription factor κB and production of tumor necrosis factor-α and interleukin-6 in monocytes,” Anesthesia and Analgesia, vol. 98, no. 4, pp. 1007–1012, 2004.
[15]
S. J. Si, F. T. Fi, and C. A. Ti, “Cardiac anesthesia,” in Cardiac Surgery in the Adult, L. H. Cohn and L. H. Edmunds Jr., Eds., pp. 249–281, McGraw-Hill, New York, NY, USA, 2003.
[16]
P. V. Sackey, C. Martling, C. Carlsw？rd, ？. Sundin, and P. J. Radell, “Short- and long-term follow-up of intensive care unit patients after sedation with isoflurane and midazolam-A pilot study,” Critical Care Medicine, vol. 36, no. 3, pp. 801–806, 2008.
[17]
V. Shankar, K. B. Churchwell, and J. K. Deshpande, “Isoflurane therapy for severe refractory status asthmaticus in children,” Intensive Care Medicine, vol. 32, no. 6, pp. 927–933, 2006.
[18]
J. Mu, K. Xie, L. Hou et al., “Subanesthetic dose of isoflurane protects against zymosan-induced generalized inflammation and its associated acute lung injury in mice,” Shock, vol. 34, no. 2, pp. 183–189, 2010.
[19]
J. Li, H. Wang, W. Li, et al., “Anesthetic isoflurane posttreatment attenuates experimental lung injury by inhibiting inflammation and apoptosis,” Mediators of Inflammation, vol. 2013, Article ID 108928, 16 pages, 2013.
[20]
R. Boxio, C. Bossenmeyer-Pourié, N. Steinckwich, C. Dournon, and O. Nü？e, “Mouse bone marrow contains large numbers of functionally competent neutrophils,” Journal of Leukocyte Biology, vol. 75, no. 4, pp. 604–611, 2004.
[21]
T. N. Lin, Y. Y. He, G. Wu, M. Khan, C. Y. Hsu, and A. Marmarou, “Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats,” Stroke, vol. 24, no. 1, pp. 117–121, 1993.
[22]
J. Chen, Y. Li, L. Wang et al., “Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats,” Stroke, vol. 32, no. 4, pp. 1005–1011, 2001.
[23]
R. J. Komotar, G. H. Kim, M. E. Sughrue et al., “Neurologic assessment of somatosensory dysfunction following an experimental rodent model of cerebral ischemia,” Nature Protocols, vol. 2, no. 10, pp. 2345–2347, 2007.
[24]
J. B. Clark and W. J. Nicklas, “The metabolism of rat brain mitochondria. Preparation and characterization,” Journal of Biological Chemistry, vol. 245, no. 18, pp. 4724–4731, 1970.
[25]
S. Ashwal, B. Tone, H. R. Tian, D. J. Cole, and W. J. Pearce, “Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion,” Stroke, vol. 29, no. 5, pp. 1037–1047, 1998.
[26]
J. Li, W. Liu, S. Ding et al., “Hyperbaric oxygen preconditioning induces tolerance against brain ischemia-reperfusion injury by upregulation of antioxidant enzymes in rats,” Brain Research, vol. 1210, pp. 223–229, 2008.
[27]
R. Ye, X. Kong, Q. Yang, Y. Zhang, J. Han, and G. Zhao, “Ginsenoside Rd attenuates redox imbalance and improves stroke outcome after focal cerebral ischemia in aged mice,” Neuropharmacology, vol. 61, no. 4, pp. 815–824, 2011.
[28]
A. Barrientos, L. Kenyon, and C. T. Moraes, “Human xenomitochondrial cybrids: cellular models of mitochondrial complex I deficiency,” Journal of Biological Chemistry, vol. 273, no. 23, pp. 14210–14217, 1998.
[29]
K. R. Dave, R. A. DeFazio, A. P. Raval et al., “Ischemic preconditioning targets the respiration of synaptic mitochondria via protein kinase Cε,” Journal of Neuroscience, vol. 28, no. 16, pp. 4172–4182, 2008.
[30]
S. Krahenbuhl, M. Chang, E. P. Brass, and C. L. Hoppel, “Decreased activities of ubiquinol: ferricytochrome c oxidoreductase (complex III) and ferrocytochrome c:oxygen oxidoreductase (complex IV) in liver mitochondria from rats with hydroxycobalamin[c-lactam]-induced methylmalonic aciduria,” Journal of Biological Chemistry, vol. 266, no. 31, pp. 20998–21003, 1991.
[31]
J. W. Soper and P. L. Pedersen, “Isolation of an oligomycin-sensitive ATPase complex from rat liver mitochondria,” Methods in Enzymology C, vol. 55, pp. 328–333, 1979.
[32]
M. M. Kelly, K. McNagny, D. L. Williams et al., “The lung responds to zymosan in a unique manner independent of Toll-like receptors, complement, and dectin-1,” American Journal of Respiratory Cell and Molecular Biology, vol. 38, no. 2, pp. 227–238, 2008.
[33]
H. K. Byung, S. H. Seong, W. K. Soon et al., “Diarctigenin, a lignan constituent from Arctium lappa, down-regulated zymosan-induced transcription of inflammatory genes through suppression of DNA binding ability of nuclear factor-κB in macrophages,” Journal of Pharmacology and Experimental Therapeutics, vol. 327, no. 2, pp. 393–401, 2008.
[34]
J. Grommes, J. Alard, M. Drechsler et al., “Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury,” American Journal of Respiratory and Critical Care Medicine, vol. 185, no. 6, pp. 628–636, 2012.
[35]
S. Choudhury, M. R. Wilson, M. E. Goddard, K. P. O'Dea, and M. Takata, “Mechanisms of early pulmonary neutrophil sequestration in ventilator-induced lung injury in mice,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 287, no. 5, pp. L902–L910, 2004.
[36]
E. Abraham, “Neutrophils and acute lung injury,” Critical Care Medicine, vol. 31, supplement 4, pp. S195–S199, 2003.
[37]
K. P. Steinberg, J. A. Milberg, T. R. Martin, R. J. Maunder, B. A. Cockrill, and L. D. Hudson, “Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome,” American Journal of Respiratory and Critical Care Medicine, vol. 150, no. 1, pp. 113–122, 1994.
[38]
E. Abraham, A. Carmody, R. Shenkar, and J. Arcaroli, “Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 279, no. 6, pp. L1137–L1145, 2000.
[39]
L. W. de Rossi, N. A. Horn, W. Buhre, F. Gass, G. Hutschenreuter, and R. Rossaint, “The effect of isoflurane on neutrophil selectin and β2-integrin activation in vitro,” Anesthesia and Analgesia, vol. 95, no. 3, pp. 583–587, 2002.
[40]
Z. Biao, X. Zhanggang, J. Hao, M. Changhong, and C. Jing, “The in vitro effect of desflurane preconditioning on endothelial adhesion molecules and mRNA expression,” Anesthesia and Analgesia, vol. 100, no. 4, pp. 1007–1013, 2005.
[41]
B. H. Segal, W. Han, J. J. Bushey et al., “NADPH oxidase limits innate immune responses in the lungs in mice,” PloS ONE, vol. 5, no. 3, Article ID e9631, 2010.
[42]
R. Shenkar and E. Abraham, “Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-κB, and cyclic AMP response element binding protein,” Journal of Immunology, vol. 163, no. 2, pp. 954–962, 1999.
[43]
T. S. Blackwell, T. R. Blackwell, E. P. Holden, B. W. Christman, and J. W. Christman, “In vivo antioxidant treatment suppresses nuclear factor-κB activation and neutrophilic lung inflammation,” Journal of Immunology, vol. 157, no. 4, pp. 1630–1637, 1996.
[44]
S. Cuzzocrea, A. Filippelli, B. Zingarelli, M. Falciani, A. P. Caputi, and F. Rossi, “Role of nitric oxide in a nonseptic shock model induced by zymosan in the rat,” Shock, vol. 7, no. 5, pp. 351–357, 1997.
[45]
Q. Xie, Y. Kashiwabara, and C. Nathan, “Role of transcription factor NF-κB/Rel in induction of nitric oxide synthase,” Journal of Biological Chemistry, vol. 269, no. 7, pp. 4705–4708, 1994.
[46]
Y. Nunokawa, S. Oikawa, and S. Tanaka, “Human inducible nitric oxide synthase gene is transcriptionally regulated by nuclear factor-κB dependent mechanism,” Biochemical and Biophysical Research Communications, vol. 223, no. 2, pp. 347–352, 1996.
[47]
K. Kinugawa, T. Shimizu, A. Yao, O. Kohmoto, T. Serizawa, and T. Takahashi, “Transcriptional regulation of inducible nitric oxide synthase in cultured neonatal rat cardiac myocytes,” Circulation Research, vol. 81, no. 6, pp. 911–921, 1997.
[48]
E. L'Her, L. Dy, R. Pili et al., “Feasibility and potential cost/benefit of routine isoflurane sedation using an anesthetic-conserving device: a prospective observational study,” Respiratory Care, vol. 53, no. 10, pp. 1295–1303, 2008.
