Patients who suffer from severe burns develop metabolic imbalances and systemic inflammatory response syndrome (SIRS) which can result in multiple organ failure and death. Research aimed at reducing the inflammatory process has yielded new insight into burn injury therapies. In this review, we discuss strategies used to curb inflammation in burn injuries and note that further studies with high quality evidence are necessary. 1. Introduction Trauma resulting from severe burn injury triggers a systemic inflammatory response syndrome (SIRS) and serious metabolic disturbances. One of the best known systemic manifestations observed in the first hours after a major burn injuries is related to increased systemic capillary permeability with protein leakage into the interstitial space, generalized edema, and a tendency toward hypovolemic shock. Adequate fluid replacement is mandatory in the first hours after a traumatic burn. However, in burn patients, other systemic disorders are also accompanied by SIRS such as cardiac dysfunction, acute respiratory distress syndrome, acute renal failure, increased intestinal permeability resulting in bacterial translocation, hypermetabolism, hypercatabolism, and sepsis [1–4]. These intense disruptions in body’s homeostatic balance may result in multiple organ failure and death. Therefore, research seeking new mechanisms by which to attenuate inflammation after severe burn injury is needed. In this review, we address and discuss the available options. 2. Burns and Inflammation Burn injury induces global changes to the entire immune system resulting in suppressed immune function and increased susceptibility to infection. This immunopathological response can contribute to the development of SIRS and subsequent multiple organ failure. Patients with severe burns are more likely to die from sepsis due to the massive release of inflammatory mediators from the burn wounds. Total body surface area (BSA) involved and smoke inhalation are predictors of death. Each one percent increase in total body surface area burned was associated with a six percent increase in mortality risk. Also, the presence of smoke inhalation increased mortality risk by ninefold [5]. In addition, the depth of the burn also affects mortality risk as full thickness burns have a poorer prognosis compared to partial thickness. Nevertheless, the systemic disorders observed in the first hours after a severe burn injury are related to increased systemic capillary permeability with protein leakage and a tendency toward hypovolemic shock. Burns greater than 10% BSA in
References
[1]
R. F. Oppeltz, Q. Zhang, M. Rani, J. R. Sasaki, and M. G. Schwacha, “Increased expression of cardiac IL-17 after burn,” Journal of Inflammation, vol. 7, article 38, 2010.
[2]
K. Ipaktchi and S. Arbabi, “Advances in burn critical care,” Critical Care Medicine, vol. 34, no. 9, pp. S239–S244, 2006.
[3]
A. Soejima, N. Miyake, N. Matsuzawa, et al., “Clinical characterization of acute renal failure in multiple organ dysfunction syndrome,” Clinical and Experimental Nephrology, vol. 2, no. 2, pp. 142–150, 1998.
[4]
D. K. Macintire and T. L. Bellhorn, “Bacterial translocation: clinical implications and prevention,” Veterinary Clinics of North America—Small Animal Practice, vol. 32, no. 5, pp. 1165–1178, 2002.
[5]
S. Meshulam-Derazon, S. Nachumovsky, D. Ad-El, J. Sulkes, and D. J. Hauben, “Prediction of morbidity and mortality on admission to a burn unit,” Plastic and Reconstructive Surgery, vol. 118, no. 1, pp. 116–120, 2006.
[6]
H. L. Ashworth, T. C. Cubison, P. M. Gilbert, and K. M. Sim, “Treatment before transfer: the patient with burns,” Emergency Medicine Journal, vol. 18, no. 5, pp. 349–351, 2001.
[7]
J. R. Saffle, “The phenomenon of “fluid creep” in acute burn resuscitation,” Journal of Burn Care and Research, vol. 28, no. 3, pp. 382–395, 2007.
[8]
B. A. Pruitt Jr., “Protection from excessive resuscitation:‘pushing the pendulum back’,” Journal of Trauma, vol. 49, no. 3, pp. 567–568, 2000.
[9]
I. Faraklas, A. Cochran, and J. Saffle, “Review of a fluid resuscitation protocol: “fluid creep” is not due to nursing error,” Journal of Burn Care and Research, vol. 33, no. 1, pp. 74–83, 2012.
[10]
B. A. Cotton, J. S. Guy, J. A. Morris Jr., and N. N. Abumrad, “The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies,” Shock, vol. 26, no. 2, pp. 115–121, 2006.
[11]
J. B. Friedrich, S. R. Sullivan, L. H. Engrav et al., “Is supra-Baxter resuscitation in burn patients a new phenomenon?” Burns, vol. 30, no. 5, pp. 464–466, 2004.
[12]
M. E. Ivy, N. A. Atweh, J. Palmer, P. P. Possenti, M. Pineau, and M. D'Aiuto, “Intra-abdominal hypertension and abdominal compartment syndrome in burn patients,” Journal of Trauma, vol. 49, no. 3, pp. 387–391, 2000.
[13]
J. P. Zhang, F. Xiang, D. L. Tong, et al., “Comparative study on the effect of restrictive fluid management strategy on the early pulmonary function of patients with severe burn,” Chinese Journal of Burns, vol. 28, no. 3, pp. 165–169, 2012.
[14]
J. P. Garner and P. S. J. Heppell, “Cerium nitrate in the management of burns,” Burns, vol. 31, no. 5, pp. 539–547, 2005.
[15]
G. A. Schoenenberger, U. R. Bauer, L. B. Cueni, U. Eppenberger, and M. Allg？wer, “Isolation and characterization of a cutaneous lipoprotein with lethal effects produced by thermal energy in mouse skin,” Biochemical and Biophysical Research Communications, vol. 42, no. 5, pp. 975–982, 1971.
[16]
R. G. Molloy, M. O'Riordain, R. Holtzeimer, et al., “Mechanisms of increased tumor necrosis factor production after thermal injury. Altered sensitivity to PG2 and immune modulation by indomethacin,” Journal of Immunology, vol. 151, pp. 2142–2149, 1993.
[17]
C. K. Ogle, J. X. Mao, J. Z. Wu, J. D. Ogle, and J. W. Alexander, “The 1994 Lindberg Award: the production of tumor necrosis factor, interleukin-1, interleukin-6, and prostaglandin E2 by isolated enterocytes and gut macrophages: effect of lipopolysaccharide and thermal injury,” Journal of Burn Care and Rehabilitation, vol. 15, no. 6, pp. 470–477, 1994.
[18]
K. P. Rumbaugh, J. A. Colmer, J. A. Griswold, and A. N. Hamood, “The effects of infection of thermal injury by Pseudomonas aeruginosa PAO1 on the murine cytokine response,” Cytokine, vol. 16, no. 4, pp. 160–168, 2001.
[19]
A. Accardo Palumbo, G. I. Forte, D. Pileri, et al., “Analysis of IL-6, IL-10 and IL-17 genetic polymorphisms as risk factors for sepsis development in burned patients,” Burns, vol. 38, no. 2, pp. 208–213, 2012.
[20]
A. E. Sakallioglu, O. Basaran, H. Karakayali et al., “Interactions of systemic immune response and local wound healing in different burn depths: an experimental study on rats,” Journal of Burn Care and Research, vol. 27, no. 3, pp. 357–366, 2006.
[21]
Y. S. Ong, M. Samuel, and C. Song, “Meta-analysis of early excision of burns,” Burns, vol. 32, no. 2, pp. 145–150, 2006.
[22]
Z. Janzekovic, “A new concept in the early excision and immediate grafting of burns,” Journal of Trauma, vol. 10, no. 12, pp. 1103–1108, 1970.
[23]
Z. T. Wang, Y. M. Yao, Z. Y. Sheng et al., “Effects of escharectomy during shock stage on tissue high mobility group box-1 expression and balance of pro-/anti-inflammatory response in rats after severe thermal injury,” Chinese Journal of Surgery, vol. 42, no. 14, pp. 839–844, 2004.
[24]
X. L. Chen, Z. F. Xia, and H. F. Wei, “Escharectomy and allografting during shock stage reduces insulin resistance induced by major burn,” Journal of Burn Care and Research, vol. 32, no. 3, pp. e59–e66, 2011.
[25]
C. Foresta, M. Schipilliti, L. de Toni et al., “Blood levels, apoptosis, and homing of the endothelial progenitor cells after skin burns and escharectomy,” Journal of Trauma, vol. 70, no. 2, pp. 459–465, 2011.
[26]
T. H. Han, S. Y. Lee, J. E. Kwon, I. S. Kwak, and K. M. Kim, “The limited immunomodulatory effects of escharectomy on the kinetics of endotoxin, cytokines, and adhesion molecules in major burns,” Mediators of Inflammation, vol. 13, no. 4, pp. 241–246, 2004.
[27]
L. T. Sun, E. Friedrich, J. L. Heuslein, et al., “Reduction of burn progression with topical delivery of (antitumor necrosis factor-α)-hyaluronic acid conjugates,” Wound Repair and Regeneration, vol. 20, no. 4, pp. 563–572, 2012.
[28]
E. R. Sherwood, T. K. Varma, R. Y. Fram, C. Y. Lin, A. P. Koutrouvelis, and T. E. Toliver-Kinsky, “Glucan phosphate potentiates endotoxin-induced interferon-γ expression in immunocompetent mice, but attenuates induction of endotoxin tolerance,” Clinical Science, vol. 101, no. 6, pp. 541–550, 2001.
[29]
D. L. Williams, R. B. McNamee, E. L. Jones et al., “A method for the solubilization of a (1→3)-β-D-glucan isolated from Saccharomyces cerevisiae,” Carbohydrate Research, vol. 219, pp. 203–213, 1991.
[30]
O. I. Lyuksutova, E. D. Murphey, T. E. Toliver-Kinsky et al., “Glucan phosphate treatment attenuates burn-induced inflammation and improves resistance to Pseudomonas aeruginosa burn wound infection,” Shock, vol. 23, no. 3, pp. 224–232, 2005.
[31]
Y. Z. Cao, Y. Y. Tu, X. Chen, et al., “Protective effect of ulinastatin against murine models of sepsis: inhibition of TNF-alpha and IL-6 and augmentation of IL-10 and IL-13,” Experimental and Toxicologic Pathology, vol. 64, pp. 543–547, 2012.
[32]
H. M. Luo, S. Hu, G. Y. Zhou, et al., “The effects of ulinastatin on systemic inflammation, visceral vasopermeability and tissue water content in rats with scald injury,” Burns, 2012.
[33]
S. Rehberg, P. Enkhbaatar, R. A. Cox, and D. L. Traber, “Coagulopathy after burn and smoke inhalation injury: the evidence is there, let’s take advantage of it!,” The Journal of Trauma and Acute Care Surgery, vol. 72, no. 4, pp. 1121–1122, 2012.
[34]
A. Lavrentieva, “Replacement of specific coagulation factors in patients with burn: a review,” Burns, vol. 39, no. 4, pp. 543–548, 2013.
[35]
A. Lavrentieva, T. Kontakiotis, M. Bitzani et al., “Early coagulation disorders after severe burn injury: impact on mortality,” Intensive Care Medicine, vol. 34, no. 4, pp. 700–706, 2008.
[36]
G. Lippi, L. Ippolito, and G. Cervellin, “Disseminated intravascular coagulation in burn injury,” Seminars in Thrombosis and Hemostasis, vol. 36, no. 4, pp. 429–436, 2010.
[37]
A. García-Avello, J. A. Lorente, J. Cesar-Perez et al., “Degree of hypercoagulability and hyperfibrinolysis is related to organ failure and prognosis after burn trauma,” Thrombosis Research, vol. 89, no. 2, pp. 59–64, 1998.
[38]
M. Niedermayr, W. Schramm, L. Kamolz et al., “Antithrombin deficiency and its relationship to severe burns,” Burns, vol. 33, no. 2, pp. 173–178, 2007.
[39]
R. H. Bartlett, S. V. Fong, G. Maruggo, T. Hardeman, and V. Anderson, “Coagulation and platelets changes after thermal injury in man,” Burns, vol. 7, pp. 370–377, 1981.
[40]
A. Kowal-Vern, R. L. Gamelli, J. M. Walenga et al., “The effect of burn wound size on hemostasis: a correlation of the hemostatic changes to the clinical state,” Journal of Trauma, vol. 33, no. 1, pp. 50–56, 1992.
[41]
M. Nisanci, M. Eski, I. Sahin, S. Ilgan, and S. Isik, “Saving the zone of stasis in burns with activated protein C: an experimental study in rats,” Burns, vol. 36, no. 3, pp. 397–402, 2010.
[42]
F. J. Walker, P. W. Sexton, and C. T. Esmon, “The inhibition of blood coagulation by activated protein C through the selective inactivation of activated factor V.,” Biochimica et Biophysica Acta, vol. 571, no. 2, pp. 333–342, 1979.
[43]
M. Hoffman, “A cell-based model of coagulation and the role of factor VIIa,” Blood Reviews, vol. 17, no. 1, pp. S1–S5, 2003.
[44]
J. Fan, Q. Meng, G. Guo et al., “Effects of early enteral nutrition supplemented with arginine on intestinal mucosal immunity in severely burned mice,” Clinical Nutrition, vol. 29, no. 1, pp. 124–130, 2010.
[45]
A. Garcia de Lorenzo y Mateos, A. Caparros Fernandez de Aguilar, and A. Blesa Malpica, “Multiple trauma and burns,” Nutrición Hospitalaria, vol. 15, no. 1, pp. 121–127, 2000.
[46]
R. Kraft, D. N. Herndon, G. A. Kulp, et al., “Retinol binding protein: marker for insulin resistance and inflammation postburn?” Journal of Parenteral and Enteral Nutrition, vol. 35, no. 6, pp. 695–703, 2011.
[47]
M. G. Jeschke, D. Klein, and D. N. Herndon, “Insulin treatment improves the systemic inflammatory reaction to severe trauma,” Annals of Surgery, vol. 239, no. 4, pp. 553–560, 2004.
[48]
M. A. Orman, T. T. Nguyen, M. G. Ierapetritou, F. Berthiaume, and I. P. Androulakis, “Comparison of the cytokine and chemokine dynamics of the early inflammatory response in models of burn injury and infection,” Cytokine, vol. 55, no. 3, pp. 362–371, 2011.
[49]
G. M. Lord, G. Matarese, J. K. Howard, R. J. Baker, S. R. Bloom, and R. I. Lechler, “Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression,” Nature, vol. 394, no. 6696, pp. 897–901, 1998.
[50]
G. Fantuzzi and R. Faggioni, “Leptin in the regulation of immunity, inflammation, and hematopoiesis,” Journal of Leukocyte Biology, vol. 68, no. 4, pp. 437–446, 2000.
[51]
F. Caldefie-Chezet, A. Poulin, A. Tridon, B. Sion, and M. P. Vasson, “Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action?” Journal of Leukocyte Biology, vol. 69, no. 3, pp. 414–418, 2001.
[52]
R. Faggioni, K. R. Feingold, and C. Grunfeld, “Leptin regulation of the immune response and the immunodeficiency of malnutrition,” FASEB Journal, vol. 15, no. 14, pp. 2565–2571, 2001.
[53]
B. ？akir, H. ？evik, G. Contuk, F. Ercan, E. Ek？io？lu-Demiralp, and B. ？. Ye？en, “Leptin ameliorates burn-induced multiple organ damage and modulates postburn immune response in rats,” Regulatory Peptides, vol. 125, no. 1–3, pp. 135–144, 2005.
[54]
N. M. Abdel-Hafez, Y. Saleh Hassan, and T. H. El-Metwally, “A study on biomarkers, cytokines, and growth factors in children with burn injuries,” Annuals of Burns Fire Disasters, vol. 20, no. 2, pp. 89–100, 2007.
[55]
M. G. Jeschke, F. N. William, and C. C. Finnerty, “The effect of ketoconazole on post-burn inflammation, hypermetabolism and clinical outcomes,” PLoS One, vol. 7, no. 5, Article ID e35465, 2012.
[56]
C. LaLonde, U. Nayak, J. Hennigan, and R. H. Demling, “Excessive liver oxidant stress causes mortality in response to burn injury combined with endotoxin and is prevented with antioxidants,” Journal of Burn Care and Rehabilitation, vol. 18, no. 3, pp. 187–192, 1997.
[57]
M. M. Berger and A. Shenkin, “Trace element requirements in critically ill burned patients,” Journal of Trace Elements in Medicine and Biology, vol. 21, no. 1, pp. 44–48, 2007.
[58]
A. Soneja, M. Drews, and T. Malinski, “Role of nitric oxide, nitroxidative and oxidative stress in wound healing,” Pharmacological Reports, vol. 57, pp. 108–119, 2005.
[59]
J. P. Kehrer, “Free radicals as mediators of tissue injury and disease,” Critical Reviews in Toxicology, vol. 23, no. 1, pp. 21–48, 1993.
[60]
M. M. Berger, C. Binnert, R. L. Chiolero et al., “Trace element supplementation after major burns increases burned skin trace element concentrations and modulates local protein metabolism but not whole-body substrate metabolism,” The American Journal of Clinical Nutrition, vol. 85, no. 5, pp. 1301–1306, 2007.
[61]
E. Barbosa, J. Faintuch, E. A. MacHado Moreira et al., “Supplementation of vitamin E, vitamin C, and zinc attenuates oxidative stress in burned children: a randomized, double-blind, placebo-controlled pilot study,” Journal of Burn Care and Research, vol. 30, no. 5, pp. 859–866, 2009.
[62]
H. Tanaka, T. Matsuda, Y. Miyagantani, T. Yukioka, H. Matsuda, and S. Shimazaki, “Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study,” Archives of Surgery, vol. 135, no. 3, pp. 326–331, 2000.
[63]
C. Csontos, B. Rezman, V. Foldi, et al., “Effect of N-acetylcysteine treatment on oxidative stress and inflammation after severe burn,” Burns, vol. 38, no. 3, pp. 428–437, 2012.
[64]
P. P. Vinha, E. Z. Martinez, H. Vannucchi, et al., “Effect of acute thermal injury in status of serum vitamins, inflammatory and oxidative stress markers: preliminary data,” Journal of Burn Care and Research, vol. 34, no. 2, pp. e87–e91, 2013.
[65]
J. Wang, C. J. Huang, and C. K. Chow, “Red cell vitamin E and oxidative damage: a dual role of reducing agents,” Free Radical Research, vol. 24, no. 4, pp. 291–298, 1996.
[66]
J. A. Buege and S. D. Aust, “Microsomal lipid peroxidation,” Methods in Enzymology, vol. 52, pp. 302–310, 1978.
[67]
J. A. Farina Jr., A. C. Celotto, M. F. da Silva, and P. R. Evora, “Guanylatecyclase inhibition by methylene blue as an option in the treatment of vasoplegia after a severe burn. A medical hypothesis,” Medical Science Monitor, vol. 18, no. 5, pp. HY13–HY17, 2012.
[68]
A. D. Jaskille, J. C. Jeng, and M. H. Jordan, “Methylene blue in the treatment of vasoplegia following severe burns,” Journal of Burn Care and Research, vol. 29, no. 2, pp. 408–410, 2008.
[69]
H. Inoue, K. Ando, N. Wakisaka, K. I. Matsuzaki, M. Aihara, and N. Kumagai, “Effects of nitric oxide synthase inhibitors on vascular hyperpermeability with thermal injury in mice,” Nitric Oxide—Biology and Chemistry, vol. 5, no. 4, pp. 334–342, 2001.
[70]
P. R. B. Evora, A. J. Rodrigues, W. V. D. A. Vicente et al., “Is the cyclic GMP system underestimated by intensive care and emergency teams?” Medical Hypotheses, vol. 69, no. 3, pp. 564–567, 2007.
[71]
J. B. Sterner, T. B. Zanders, M. J. Morris, and L. C. Cancio, “Inflammatory mediators in smoke inhalation injury,” Inflammation and Allergy—Drug Targets, vol. 8, no. 1, pp. 63–69, 2009.
[72]
B. L. Joyner, S. W. Jones, B. A. Cairns, et al., “DNA and inflammatory mediators in bronchoalveolar lavage fluid from children with acute inhalational injuries,” Journal of Burn Care and Research, vol. 34, no. 3, pp. 326–333, 2013.
[73]
K. K. Kirchner, J. S. Wagener, T. Z. Khan, S. C. Copenhaver, and F. J. Accurso, “Increased DNA levels in bronchoalveolar lavage fluid obtained from infants with cystic fibrosis,” American Journal of Respiratory and Critical Care Medicine, vol. 154, no. 5, pp. 1426–1429, 1996.
[74]
K. Paul, E. Rietschel, M. Ballmann et al., “Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis,” American Journal of Respiratory and Critical Care Medicine, vol. 169, no. 6, pp. 719–725, 2004.
[75]
F. Ratjen, K. Paul, S. van Koningsbruggen, S. Breitenstein, E. Rietschel, and W. Nikolaizik, “DNA concentrations in BAL fluid of cystic fibrosis patients with early lung disease: influence of treatment with dornase alpha,” Pediatric Pulmonology, vol. 39, no. 1, pp. 1–4, 2005.
[76]
F. Zhu, G. H. Guo, W. Chen, Y. Peng, J. J. Xing, and N. Y. Wang, “Effect of bone marrow-derived mesenchymal stem cells transplantation on the inflammatory response and lung injury in rabbit with inhalation injury,” Chinese Journal of Burns, vol. 26, no. 5, pp. 360–365, 2010.
[77]
K. L. Butler, J. Goverman, H. Ma et al., “Stem cells and burns: review and therapeutic implications,” Journal of Burn Care and Research, vol. 31, no. 6, pp. 874–881, 2010.
[78]
L. Huang and A. Burd, “An update review of stem cell applications in burns and wound care,” Indian Journal of Plastic Surgery, vol. 45, no. 2, pp. 229–236, 2012.
[79]
H. Yagi, A. Soto-Gutierrez, Y. Kitagawa, A. W. Tilles, R. G. Tompkins, and M. L. Yarmush, “Bone marrow mesenchymal stromal cells attenuate organ injury induced by LPS and burn,” Cell Transplantation, vol. 19, no. 6-7, pp. 823–830, 2010.
[80]
S. C. Tayyar, B. Ozalp, M. Durgun, et al., “The effect of hyperbaric oxygen treatment on the healing of burn wounds in nicotinized and nonnicotinized rats,” Journal of Burn Care and Research, 2012.
[81]
T. Türkaslan, N. Yogun, M. ？im？it, S. Solakoglu, C. Ozdemir, and Z. Ozsoy, “Is HBOT treatment effective in recovering zone of stasis? An experimental immunohistochemical study,” Burns, vol. 36, no. 4, pp. 539–544, 2010.
[82]
O. Shoshani, A. Shupak, A. Barak et al., “Hyperbaric oxygen therapy for deep second degree burns: an experimental study in the guinea pig,” British Journal of Plastic Surgery, vol. 51, no. 1, pp. 67–73, 1998.
[83]
I. Bilic, N. M. Petri, J. Bezic et al., “Effects of hyperbaric oxygen therapy on experimental burn wound healing in rats: a randomized controlled study,” Undersea and Hyperbaric Medicine, vol. 32, no. 1, pp. 1–9, 2005.
[84]
C. E. White and E. M. Renz, “Advances in surgical care: management of severe burn injury,” Critical Care Medicine, vol. 36, no. 7, pp. S318–324, 2008.
[85]
S. E. Moffatt, “Hypothermia in trauma,” Emergency Medicine Journal, 2012.
[86]
J. A. Rizzo, P. Burgess, R. J. Cartie, and B. M. Prasad, “Moderate systemic hypothermia decreases burn depth progression,” Burns, vol. 39, no. 3, pp. 436–444, 2013.
[87]
C. Stein and S. Küchler, “Non-analgesic effects of opioids: peripheral opioid effects on inflammation and wound healing,” Current Pharmaceutical Design, vol. 18, no. 37, pp. 6053–6069, 2012.
[88]
C. Stein, A. H. S. Hassan, R. Przewlocki, C. Gramsch, K. Peter, and A. Herz, “Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 15, pp. 5935–5939, 1990.
[89]
I. Tegeder and G. Geisslinger, “Opioids as modulators of cell death and survival—unraveling mechanisms and revealing new indications,” Pharmacological Reviews, vol. 56, no. 3, pp. 351–369, 2004.
[90]
H. L. Rittner, H. Machelska, and C. Stein, “Leukocytes in the regulation of pain and analgesia,” Journal of Leukocyte Biology, vol. 78, no. 6, pp. 1215–1222, 2005.
[91]
Y. L. Chen, P. Y. Law, and H. H. Loh, “The other side of the opioid story: modulation of cell growth and survival signaling,” Current Medicinal Chemistry, vol. 15, no. 8, pp. 772–778, 2008.
