Abstract
Production of inflammatory cytokines in the pancreas, lung, and liver is believed to play a major role in the development of severe pancreatitis. This tissue-specific production could lend itself to directed anticytokine gene therapy if an appropriate delivery system could be developed. This study was undertaken to examine a novel approach for the delivery of protein-based therapies to the tissues involved during acute pancreatitis. Healthy mice received an intraperitoneal injection of cationic liposomes and a DNA plasmid containing the chloramphenicol acetyltransferase (CAT) reporter gene. Animals were killed at 12 hours and 1, 2, 3, 7, and 14 days with serum, pancreas, lung, and liver harvested. Acute pancreatitis was induced (cerulein, 50 μg/kg/hr intraperitoneally × 4) in additional mice before or after CAT transfection. The presence of pancreatitis was established in all animals by histologic scoring of pancreata and by serum amylase and lipase levels. CAT transfection efficiency was determined by quantitative CAT enzyme activity within tissue homogenates. Animals that received the liposome were successfully transfected with the CAT gene into the pancreas, lungs, and liver. Maximal transfection in each tissue occurred at 12 hours with decreasing CAT activity over the ensuing 14 days. No healthy animals receiving the CAT gene developed elevations in amylase, lipase, or any histologic parameter of pancreatitis. Transfection efficiency in the pancreas was markedly increased by preexisting or delayed induction of pancreatitis, whereas transfection of the lung and liver was increased to a lesser extent. Gene’transfection into the pancreas, liver, and lungs is possible using a cationic liposome delivery system that does not induce pancreatitis or pancreatic inflammation. Pancreatic expression of the gene product is equal to or greater than that of the organs of the reticuloendothelial system and continues at very high efficiency rates during acute pancreafitis.
Similar content being viewed by others
References
Grewal HP, Koth M, Mohey el Din A, Ohman M, Salem A, Gaber L, Gaber OA. Induction of tumor necrosis factor in severe acute panereatitis and its subsequent reduction after hepatic passage. Surgery 1994; 115:213–221.
Norman J, Franz M, Rikker A, Gower R. Rapid elevation of pro-inflammatory eytokines during acute pancreatitis and their origination within the pancreas. Surg Forum 1994;45:148–150.
Norman J, Fink G, Franz M. Acute pancreatitis induces intrapancreatie tumor necrosis factor gene expression. Arch Surg 1995;130:966–970.
Norman J, Fink G, Denham W, Yang J, Carter G, Sexton C, Falkner J, Gower W, Franz M. Tissue specific eytokine production during experimental acute pancreatitis: A probable mechanism for distant organ dysfunction. Dig Dis Sci 1997;42:1783–1788.
Norman J, Franz M, Fink G, Messina J, Gower WR, Carey LC. Decreased mortality of severe acute pancreatitis following proximal cytokine blockade. Ann Surg 1995;221:456–463.
Norman J, Messina J, Franz M, Rosemurgy AS, Gower WR. Interleukin1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery 1995;117:648–655.
Tanaka N, Murata A, Uda K, Toda H, Kato T, Hayashida H, Matsuura N, Mori T. Interleuldn-1 receptor antagonist modifies the changes in vital organs induced by acute pancreatitis in a rat experimental model. Crit Care Med 1995;23:901–908.
Grewal HP, Mohey el Din A, Gaber L, Kotb M, Gaber AO. Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-c~ polyclonal antibody. AmJ Surg 1994;167:214–219.
Hughes CB, Grewal HP, Gaber LW, Kotb M, Mohey el Din A, Mann L, Gaber AO. Anti-TNF therapy improves survival and ameliorates the pathophysiologic sequelae in acute pancreatitis in the rat. AmJ Surg 1996;171:274–280.
Mulligan RC. The basic science of gene therapy. Science 1993;260:926–931.
Brigham KL, Canonico A_E, Meyrick BO, Schreier H, Ste-cenko AA, Conary JT. Gene therapy for inflammatory diseases. Prog Clin Biol Res 1994;388:361–365.
McClane SJ, Hamilton TE, Burke C, Raper SE. Functional effect of pancreatic gene transfer using a recombinant adenovirus. Surg Forum 1996;47:145–148.
Raper SE, DeMatteo. Adenovirus-mediated in vivo gene transfer and expression in normal rat pancreas. Pancreas 1996;12:401–410.
Schmid RM, Weidenbach H, Draenert GF, Lerch MM, Lip-tay S, Schorr J, Beckh KH, Adler G. Liposome-mediated in vivo gene transfer into different tissues of the gastrointestinal tract. Z Gastroenterol 1994;32:665–670.
Edwards PD, Solorzano CC, Hess PJ, Pruitt JH, Tannahill CL, Abouhamze AS, Abouhamze KS, Kaibara A, Auffenberg T, Philip R, Philip M, Copeland EM, MacKay SLD, Moldawer LL. Cationic liposome-mediated gene transfer: Tissue specificity, duration, and effect of acute inflammation. J Biol Chem (in press).
Schmidt EV, Christoph G, Zeller R, Leder P. The cytomegalovirus enhancer: A pan-active control element in transgenic mice. Mol Cell Biol 1990;10:4406–4411.
Philip R, Liggitt D, Philip M, Dazin P, Debs R. In vivo gene delivery. J Biol Chem 1993;268:16087–16090.
Zhu N, Liggitt D, Liu Y, Debs R. Systemic gene expression after intravenous DNA delivery in adult mice. Science 1993; 261:209–211.
Thierry AR, Lunardi-Iskandar Y, Bryant JL, Rabinovich P, Gallo RG, Mahan LC. Systemic gene therapy: Biodistribution and long-term expression of transgene mice. Proc Nad Acad Sci USA 1995;92:9742–9746.
Liu Y, Liggitt D, Zhong W, Tu G, Gaensler K, Debs R. Cationic liposome-mediated intravenous gene delivery. J Biol Chem 1995;270:24864–24870.
Philip R, Brunette E, Kilinski L, Murugesh D, McNally MA, Ucar K, Rosenblatt J, Okarma TB, Lebkowski JS. Efficient and sustained gene expression in primary T lymphocytes and primary and cultured tumor cells mediated by adeno-associated virus plasmid DNA complexed to liposomes. Mol Cell Biol 1994;14:2411–2418.
Xing Z, Braciak T, Jordana M, Croitoru K, Graham FL, Gauldie J. Adenovirus-mediated cytokine gene transfer at tissue sites. J Immunol 1994; 153:4053–4069.
Canonico AE, Pliunan JD, Conary JT, Meyrick BO, Brigham KL. No lung toxicity after repeated aerosol or intravenous delivery of plasmid-cationic liposome complexes. J Appl Physiol 1994;77:415–419.
Author information
Authors and Affiliations
Additional information
Supported by a VA Merit Review Grant (I.N.) and by grants GM-53252(S.M.) and R01-GM-40586 (L.M.) awarded by the National Institute of General Medical Sciences.
Rights and permissions
About this article
Cite this article
Denham, W., Yang, J., MacKay, S. et al. Cationic liposome-mediated gene transfer during acute pancreatitis: Tissue specificity, duration, and effects of acute inflammation. J Gastrointest Surg 2, 95–101 (1998). https://doi.org/10.1016/S1091-255X(98)80109-1
Issue Date:
DOI: https://doi.org/10.1016/S1091-255X(98)80109-1