A Mechanism for Inhaled Anesthetic-Induced Solid Organ Injury: Inflammation


Background: Inhaled anesthetics, including halothane, iso- and sevoflurane induce proinflammatory cytokine release. Halothane is an inhaled anesthetic agent that is metabolized by the liver into a highly reactive product, trifluoroacetyl chloride, which can react endogenously to form a trifluoroacetyl-adduct (TFA-adduct). The MAA-adduct is formed by acetaldehyde and malondialdehyde reacting with endogenousproteins and is found in both patients and animals post-consumption of alcohol. These TFA and MAA-adducts have been shown to cause the release of proinflammatorycytokines by endogenous inflammatory cells. If both adducts share a similar mechanism of cell activation, receiving general anesthesia following alcohol ingestion could exacerbate the inflammatory response caused by the inhaled general anesthetic halothane and lead to solid organ (including liver and brain) injury. Methods: Control diet and alcohol-fed rats were randomized to receive halothane pretreatments by intraperitoneal injection mixed in sesame oil. Following the intraperitoneal injections, the intact heart was removed, HECs were isolated and stimulated with unmodified bovine serum albumin (Alb), MAA-modified Alb (MAA-Alb), Hexyl-MAA, or lipopolysaccharide (LPS), and supernatant concentrations of TNF-α were determined. Results: Halothane pre-treated rat HECs demonstrated significantly greater TNF-α concentration following MAA-adduct and LPS stimulation than the non-halothane pre-treated in both pair and alcohol-fed rats, but was significantly greater in the alcohol-fed groups. Conclusion: These results demonstrate that halothane and MAA-adduct pre-treatment will increase the inflammatory response (TNF-α release) in rat HECs following LPS and MAA stimulation in vitro. Also, these results suggest that halothane exposure may increase the risk of alcohol-induced solid organ injury secondary to TNF-induced inflammation. Other investigators have reported similar proinflammatory cytokine release with other (isoflurane and sevoflurane) inhaled anesthetic exposure, suggesting that inhaled anesthetics should be used with caution in alcohol consuming humans.

Share and Cite:

Hill, G. , Gasanova, I. and Thiele, G. (2014) A Mechanism for Inhaled Anesthetic-Induced Solid Organ Injury: Inflammation. Open Journal of Anesthesiology, 4, 72-80. doi: 10.4236/ojanes.2014.43012.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Oropeza-Hernandez, L.F., Quintanilla-Vega, B., Reyes-Mejia, R.A., Serrano, C.J., Garcia-Latorre, E.A., Dekant, W., Manno, M. and Albores, A. (2003) Trifluoroacetylated Adducts in Spermatozoa, Testes, Liver and Plasma and CYP2EI Induction in Rats after Subchronic Inhalatory Exposure to Halothane. Toxicology Letters, 144, 105-116.
[2] Boutayeb, A. and Boutayeb, S. (2005) The Burden of Non Communicable Diseases in Developing Countries. International Journal of Equity Health, 4, 2.
[3] Trudell, J.R., Ardies, C.M. and Anderson, W.R. (1991) The Effect of Alcohol Andanesthetic Metabolites on Cell Membranes. A Possible Direct Immune Mechanism. Annals of the New York Academy of Sciences, 625, 806-817.
[4] Tuma, D.J., Hoffman, T. and Sorrell, M.F. (1991) The Chemistry of Acetaldehyde-Protein Adducts. Alcohol AlcoholSuppl, 1, 271-276.
[5] Xu, D., Thiele, G.M., Beckenhauer, J.L., Klassen, L.W., Sorrell, M.F. and Tuma, D.J. (1998) Detection of Circulating Antibodies to Malondialdehyde-Acetaldehyde Adducts in Ethanol-Fed Rats. Gastroenterology, 115, 686-692.
[6] Rolla, R., Vay, D., Mottaran, E., Parodi, M., Traverso, N., Arico, S., Sartori, M., Bellomo, G., Klassen, L.W., Thiele, G.M., Tuma, D.J. and Albano, E. (2000) Detection of Circulating Antibodies against Malondialdehyde-Acetaldehyde Adducts in Patients with Alcohol-Induced Liver Disease. Hepatology, 31, 878-884.
[7] Slatter, D.A., Murray, M. and Bailey, A.J. (1998) Formation of a Dihydropyridine Derivative as a Potential Cross-Link Derived from Malondialdehyde in Physiological Systems. FEBS Letters, 421, 180-184.
[8] Christen, U., Burgin, M. and Gut, J. (1991) Halothane Metabolism: Immunochemical Evidence for Molecular Mimicry of Trifluoroacetylated Liver Protein Adducts by Constitutive Polypeptides. Molecular Pharmacology, 40, 390-400.
[9] Hill, G.E., Miller, J.A., Baxter, B.T., Klassen, L.W., Duryee, M.J., Tuma, D.J. and Thiele, G.M. (1998) Association of Malondialdehyde-Acetaldehyde (MAA) Adducted Proteins with Atherosclerotic-Induced Vascular Inflammatory Injury. Atherosclerosis, 141, 107-116. http://dx.doi.org/10.1016/S0021-9150(98)00153-1
[10] Pumford, N.R., Martin, B.M., Thomassen, D., Burris, J.A., Kenna, J.G., Martin, J.L., Pohlm L.R. (1993) Serum Antibodies from Halothane Hepatitis Patients React with the Rat Endoplasmic Reticulum Protein ERp72. Chemical Research in Toxicology, 6, 609-615. http://dx.doi.org/10.1021/tx00035a004
[11] Huwyler, J. and Gut, J. (1992) Exposure to the Chlorofluorocarbon Substitute 2,2-Dichloro-1,1,1-trifluoroethane and the Anesthetic Agent Halothane Is Associated with Transient Protein Adduct Formation in the Heart. Biochemical and Biophysical Research Communications, 184, 1344-1349. http://dx.doi.org/10.1016/S0006-291X(05)80030-0
[12] Spracklin, D.K., Hankins, D.C., Fisher, J.M., Thummel, K.E. and Kharasch, E.D. (1997) Cytochrome P450 2EI Is the Principal Catalyst of Human Oxidative Halothane Metabolism in Vitro. Journal of Pharmacology and Experimental Therapeutics, 281, 400-411.
[13] Meskar, A., Plee-Gautier, E., Amet, Y., Berthou, F. and Lucas, D. (2001) Alcohol-Xenobiotic Interactions. Role of Cytochrome P450 2EI. Pathological Biology (Paris), 49, 696-702. http://dx.doi.org/10.1016/S0369-8114(01)00235-8
[14] Kikugawa, K., Kosugi, H. and Asakura, T. (1984) Effect of Malondialdehyde, Aproduct of Lipid Peroxidation, on the Function and Stability of Hemoglobin. Archives of Biochemistry Biophysics, 229, 7-14.
[15] Tuma, D.J., Thiele, G.M., XuD, D., Klassen, L.W. and Sorrell, M.F. (1996) Acetaldehyde and Malondialdehyde React Together to Generate Distinctprotein Adducts in the Liver during Long-Term Ethanol Administration. Hepatology, 23, 872-880. http://dx.doi.org/10.1002/hep.510230431
[16] Bradford, M.M. (1976) A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Analytical Biochemistry, 72, 248-254.
[17] Lieber, C.S. and DeCarli, L.M. (1986) The Feeding of Ethanol in Liquid Diets. Alcoholism: Clinical and Experimental Research, 10, 550-553. http://dx.doi.org/10.1111/j.1530-0277.1986.tb05140.x
[18] Ferry, B., Halttunen, J., Leszczynski, D., Schellekens, H., Meide, P.H. and Hayry, P. (1987) Impact of Class II Major Histocompatibility Complex Antigen Expression on the Immunogenic Potential of Isolated Rat Vascular Endothelial Cells. Transplantation, 44, 499-503. http://dx.doi.org/10.1097/00007890-198710000-00008
[19] Korzeniewski, C. and Callewaert, D.M. (1983) An Enzyme-Release Assay for Natural Cytotoxicity. Journal of Immunological Methods, 64, 313-320.
[20] Niemela, O., Parkkila, S., Yla-Herttuala, S., Villanueva, J., Ruebner, B. and Halsted, C.H. (1995) Sequential Acetaldehyde Production, Lipid Peroxidation, and Fibrogenesis in Micropig Model of Alcohol-Induced Liver Disease. Hepatology, 22, 1208-1214. http://dx.doi.org/10.1016/0270-9139(95)90630-4
[21] Jorens, P.G., Van Overveld, F.J., Bult, H., Vermeire, P.A. and Herman, A.G. (1991) L-Arginine-Dependent Production of Nitrogen Oxides by Rat Pulmonary Macrophages. European Journal of Pharmacology, 200, 205-209.
[22] Pober, J.S. (1988) TNF as an Activator of Vascular Endothelium. Annales de l’Institut Pasteur Immunology, 139, 317-323. http://dx.doi.org/10.1016/0769-2625(88)90149-3
[23] Ferrari, R., Bachetti, T., Agnoletti, L., Comini, L. and CurelloS, S. (1998) Endothelial Function and Dysfunction in Heart Failure. European Heart Journal, 19, G41-47.
[24] Bour, E.S., Ward, L.K., Cornman, G.A. and Lsom, H.C. (1996) Tumor Necrosis Factor-Alpha-Induced Apoptosis in Hepatocytes in Long-Term Culture. American Journal of Pathology, 148, 485-495.
[25] Rossig, L., Hoffmann, J., Hugel, B., Mallat, Z., Haase, A., Freyssinet, J.M., Tedgui, A., Aicher, A., Zeiher, A.M. and Dimmeler, S. (2001) Vitamin C Inhibits Endothelial Cell Apoptosis in Congestive Heart Failure. Circulation, 104, 2182-2187. http://dx.doi.org/10.1161/hc4301.098284
[26] Chandrasekar, B., Vemula, K., Surabhi, R.M., Li-Weber, M., Owen-Schaub, L.B., Jensen, L.E. and Mummidi, S. (2004) Activation of Intrinsic and Extrinsic Proapoptotic Signaling Pathways in Interleukin-18-Mediatedhuman Cardiac Endothelial Cell Death. Journal of Biological Chemistry, 279, 20221-20233.
[27] Ohki, E., Kato, S., Horie, Y., Mizukami, T., Tarnai, H., Yokoyama, H., Ito, E., Fukuda, M., Suzuki, H., Kurose, I. and Ishii, H. (1996) Chronic Ethanol Consumption Enhances Endotoxin Induced Hepatic Sinusoidal Leukocyte Adhesion. Alcoholism: Clinical and Experimental Research, 20, 350A-355A. http://dx.doi.org/10.1111/j.1530-0277.1996.tb01806.x
[28] Takaishi, M., Kurose, I., Higuchi, H., Watanabe, N., Nakamura, T., Zeki, A., Nishida, J., Kato, S., Miura, S., Mizuno, Y., Kvietys, P.R., Granger, D.N. and Ishii, H. (1996) Ethanol-Induced Leukocyte Adherence and Albumin Leakage in Rat Mesenteric Venules: Role of CD18/Intercellular Adhesion Molecule-1. Alcoholism: Clinical and Experimental Research, 20, 347A-349A. http://dx.doi.org/10.1111/j.1530-0277.1996.tb01805.x
[29] Durak, I., Kurtipek, O., Ozturk, H.S., Birey, M., Guven, T., Kavutcu, M., Kacmaz, M., Dikmen, B., Yel, M. and Canbolat, O. (1997) Impaired Antioxidant Defence in Guinea Pig Heart Tissues Treated with Halothane. Canadian Journal of Anaesthetics, 44, 1014-1020. http://dx.doi.org/10.1007/BF03011975
[30] Harcombe, A.A., Ramsay, L., Kenna, J.G., Koskinas, J., Why, H.J., Richardson, P.J., Weissberg, P.L. and Alexander, G.J. (1995) Circulating Antibodies to Cardiac Protein-Acetaldehyde Adducts in Alcoholic Heart Muscle Disease. Clinical Science (London), 88, 263-268.
[31] Hanna, E.Z., Chou, S.P. and Grant, B.F. (1997) The Relationship between Drinking and Heart Disease Morbidity in the United States: Results from the National Health Interview Survey. Alcoholism: Clinical and Experimental Research, 21, 111-118.
[32] Torre-Amione, G., Kapadia, S., Lee, J., Durand, J.B., Bies, R.D., Young, J.B. and Mann, D.L. (1996) Tumor Necrosis Factor-Alpha and Tumor Necrosisfactor Receptors in the Failing Human Heart. Circulation, 93, 704-711.
[33] Christen, U., Burgin, M. and Gut, J. (1991) Halothane Metabolism: Kupffer Cells Carry and Partially Process Trifluoroacetylated Protein Adducts. Biochemical and Biophysical Research Communications, 175, 256-262.
[34] Smart, S.J. and Casale, T.B. (1994) TNF-Alpha-Induced Transendothelial Neutrophil Migration Is IL-8 Dependent. American Journal of Physiology, 266, L238-L245.
[35] Wu, X., Lu, Y., Dong, Y., Zhang, G., Zhang, Y., Zhipeng, X., Culley, D., Crosby, G., Marcontonio, E., Tanzi, R. and Xie, Z. (2012) The Inhalation Anesthetic Isoflurane Increased Levels of Proinflammatory TNF-α, IL-6, and IL-18. Neurobiological Aging, 33, 1364-1378. http://dx.doi.org/10.1016/j.neurobiolaging.2010.11.002
[36] Lin, D. and Zuo, Z. (2011) Isoflurane Induces Hippocampal Cell Injury and Cognitive Impairments in Adult Rats. Neuropharmacology, 61, 1354-1359. http://dx.doi.org/10.1016/j.neuropharm.2011.08.011
[37] Zhang, L., Zhang, J., Yang, L., Dong, Y., Zhang, Y. and Xie, Z. (2013) Isoflurane and Sevoflurane Increase Interleukin-6 Levels through the Nuclear Factor-Kappa B Pathway in Neuroglioma Cells. British Journal of Anaesthetics, 110, i82-i91. http://dx.doi.org/10.1093/bja/aet115
[38] Xie, Z., Dong, Y., Maeda, U., Moir, R., Inouye, S., Culley, D., Crosby, G. and Tanzi, R. (2006) Isoflurane-Induced Apoptosis: A Potential Pathogenic Link between Delirium and Dementia. Journal of Gerontology, 61A, 1300-1306.
[39] Lin, E., Calvano, S. and Lowry, S. (2000) Inflammatory Cytokines and Cell Response in Surgery. Surgery, 127, 117-126. http://dx.doi.org/10.1067/msy.2000.101584

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.