Carnosine and Lung Disease

Ken-Ichiro      Tanaka; Masahiro        Kawahara
Abstract

Carnosine (β-alanyl-L-histidine) is a small dipeptide with numerous activities, including antioxidant effects, metal ion chelation, proton buffering capacity, and inhibitory effects on protein carbonylation and glycation. Carnosine has been mostly studied in organs where it is abundant, including skeletal muscle, cerebral cortex, kidney, spleen, and plasma. Recently, the effect of supplementation with carnosine has been studied in organs with low levels of carnosine, such as the lung, in animal models of influenza virus or lipopolysaccharide-induced acute lung injury and pulmonary fibrosis. Among the known protective effects of carnosine, its antioxidant effect has attracted increasing attention for potential use in treating lung disease. In this review, we describe the in vitro and in vivo biological and physiological actions of carnosine. We also report our recent study and discuss the roles of carnosine or its related compounds in organs where carnosine is present in only small amounts (especially the lung) and its protective mechanisms.
Keywords: Carnosine, Reactive Oxygen Species (ROS), acute lung injury, peptide, antioxidant, oxidative stress.
[1] 
Crush, K.G. Carnosine and related substances in animal tissues. Comp. Biochem. Physiol.,  1970, 34(1), 3-30.
[http://dx.doi.org/10.1016/0010-406X(70)90049-6] [PMID: 4988625] 
[2] 
Suyama, M.; Maruyama, M. Identification of methylated beta-alanylhistidine in the muscles of snake and dolphin. J. Biochem.,  1969, 66(3), 405-407.
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a129159] [PMID: 5348589] 
[3] 
Dennis, P.O.; Lorkin, P.A. Isolation and synthesis of balenine, a dipeptide occurring in whale-meat extract. J. Chem. Soc. Perkin Trans. I,  1965, 1, 4968-4972.
[http://dx.doi.org/10.1039/JR9650004968] [PMID: 5891952] 
[4] 
Winnick, R.E.; Moikeha, S.; Winnick, T. Intracellular distribution of carnosine and anserine in skeletal muscle. J. Biol. Chem.,  1963, 238, 3645-3647.
[PMID: 14109199] 
[5] 
Clifford, W.M. The distribution of carnosine in the animal kingdom. Biochem. J.,  1921, 15(6), 725-735.
[http://dx.doi.org/10.1042/bj0150725] [PMID: 16743047] 
[6] 
Sjaastad, O.; Berstad, J.; Gjesdahl, P.; Gjessing, L. Homocarnosinosis. 2. A familial metabolic disorder associated with spastic paraplegia, progressive mental deficiency, and retinal pigmentation. Acta Neurol. Scand.,  1976, 53(4), 275-290.
[http://dx.doi.org/10.1111/j.1600-0404.1976.tb04348.x] [PMID: 1266573] 
[7] 
O’Dowd, J.J.; Cairns, M.T.; Trainor, M.; Robins, D.J.; Miller, D.J. Analysis of carnosine, homocarnosine, and other histidyl derivatives in rat brain. J. Neurochem.,  1990, 55(2), 446-452.
[http://dx.doi.org/10.1111/j.1471-4159.1990.tb04156.x] [PMID: 2370547] 
[8] 
Kamal, M.A.; Jiang, H.; Hu, Y.; Keep, R.F.; Smith, D.E. Influence of genetic knockout of Pept2 on the in vivo disposition of endogenous and exogenous carnosine in wild-type and Pept2 null mice. Am. J. Physiol. Regul. Integr. Comp. Physiol.,  2009, 296(4), R986-R991.
[http://dx.doi.org/10.1152/ajpregu.90744.2008] [PMID: 19225147] 
[9] 
Kawahara, M.; Tanaka, K.I.; Kato-Negishi, M. Zinc, carnosine, and neurodegenerative diseases. Nutrients,  2018, 10(2)E147
[http://dx.doi.org/10.3390/nu10020147] [PMID: 29382141] 
[10] 
Jung, S.; Bae, Y.S.; Kim, H.J.; Jayasena, D.D.; Lee, J.H.; Park, H.B.; Heo, K.N.; Jo, C. Carnosine, anserine, creatine, and inosine 5′-monophosphate contents in breast and thigh meats from 5 lines of Korean native chicken. Poult. Sci.,  2013, 92(12), 3275-3282.
[http://dx.doi.org/10.3382/ps.2013-03441] [PMID: 24235239] 
[11] 
Peiretti, P.G.; Medana, C.; Visentin, S.; Giancotti, V.; Zunino, V.; Meineri, G. Determination of carnosine, anserine, homocarnosine, pentosidine and thiobarbituric acid reactive substances contents in meat from different animal species. Food Chem.,  2011, 126(4), 1939-1947.
[http://dx.doi.org/10.1016/j.foodchem.2010.12.036] [PMID: 25213980] 
[12] 
Everaert, I.; Mooyaart, A.; Baguet, A.; Zutinic, A.; Baelde, H.; Achten, E.; Taes, Y.; De Heer, E.; Derave, W. Vegetarianism, female gender and increasing age, but not CNDP1 genotype, are associated with reduced muscle carnosine levels in humans. Amino Acids,  2011, 40(4), 1221-1229.
[http://dx.doi.org/10.1007/s00726-010-0749-2] [PMID: 20865290] 
[13] 
Peters, V.; Kebbewar, M.; Jansen, E.W.; Jakobs, C.; Riedl, E.; Koeppel, H.; Frey, D.; Adelmann, K.; Klingbeil, K.; Mack, M.; Hoffmann, G.F.; Janssen, B.; Zschocke, J.; Yard, B.A. Relevance of allosteric conformations and homocarnosine concentration on carnosinase activity. Amino Acids,  2010, 38(5), 1607-1615.
[http://dx.doi.org/10.1007/s00726-009-0367-z] [PMID: 19915793] 
[14] 
Bellia, F.; Vecchio, G.; Rizzarelli, E. Carnosinases, their substrates and diseases. Molecules,  2014, 19(2), 2299-2329.
[http://dx.doi.org/10.3390/molecules19022299] [PMID: 24566305] 
[15] 
Unno, H.; Yamashita, T.; Ujita, S.; Okumura, N.; Otani, H.; Okumura, A.; Nagai, K.; Kusunoki, M. Structural basis for substrate recognition and hydrolysis by mouse carnosinase CN2. J. Biol. Chem.,  2008, 283(40), 27289-27299.
[http://dx.doi.org/10.1074/jbc.M801657200] [PMID: 18550540] 
[16] 
Pavlin, M.; Rossetti, G.; De Vivo, M.; Carloni, P. Carnosine and homocarnosine degradation mechanisms by the human carnosinase enzyme CN1: insights from multiscale simulations. Biochemistry,  2016, 55(19), 2772-2784.
[http://dx.doi.org/10.1021/acs.biochem.5b01263] [PMID: 27105448] 
[17] 
Pegova, A.; Abe, H.; Boldyrev, A. Hydrolysis of carnosine and related compounds by mammalian carnosinases. Comp. Biochem. Physiol. B Biochem. Mol. Biol.,  2000, 127(4), 443-446.
[http://dx.doi.org/10.1016/S0305-0491(00)00279-0] [PMID: 11281261] 
[18] 
Lenney, J.F.; George, R.P.; Weiss, A.M.; Kucera, C.M.; Chan, P.W.; Rinzler, G.S. Human serum carnosinase: characterization, distinction from cellular carnosinase, and activation by cadmium. Clin. Chim. Acta,  1982, 123(3), 221-231.
[http://dx.doi.org/10.1016/0009-8981(82)90166-8] [PMID: 7116644] 
[19] 
Everaert, I.; Taes, Y.; De Heer, E.; Baelde, H.; Zutinic, A.; Yard, B.; Sauerhöfer, S.; Vanhee, L.; Delanghe, J.; Aldini, G.; Derave, W. Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans. Am. J. Physiol. Renal Physiol.,  2012, 302(12), F1537-F1544.
[http://dx.doi.org/10.1152/ajprenal.00084.2012] [PMID: 22496410] 
[20] 
Lenney, J.F. Human cytosolic carnosinase: evidence of identity with prolinase, a non-specific dipeptidase. Biol. Chem. Hoppe Seyler,  1990, 371(2), 167-171.
[http://dx.doi.org/10.1515/bchm3.1990.371.1.167] [PMID: 2334521] 
[21] 
Teufel, M.; Saudek, V.; Ledig, J.P.; Bernhardt, A.; Boularand, S.; Carreau, A.; Cairns, N.J.; Carter, C.; Cowley, D.J.; Duverger, D.; Ganzhorn, A.J.; Guenet, C.; Heintzelmann, B.; Laucher, V.; Sauvage, C.; Smirnova, T. Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J. Biol. Chem.,  2003, 278(8), 6521-6531.
[http://dx.doi.org/10.1074/jbc.M209764200] [PMID: 12473676] 
[22] 
Tamba, M.; Torreggiani, A. Hydroxyl radical scavenging by carnosine and Cu(II)-carnosine complexes: a pulse-radiolysis and spectroscopic study. Int. J. Radiat. Biol.,  1999, 75(9), 1177-1188.
[http://dx.doi.org/10.1080/095530099139656] [PMID: 10528926] 
[23] 
Babizhayev, M.A.; Seguin, M.C.; Gueyne, J.; Evstigneeva, R.P.; Ageyeva, E.A.; Zheltukhina, G.A. L-carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities. Biochem. J.,  1994, 304(Pt 2), 509-516.
[http://dx.doi.org/10.1042/bj3040509] [PMID: 7998987] 
[24] 
Nagasawa, T.; Yonekura, T.; Nishizawa, N.; Kitts, D.D. In vitro and in vivo inhibition of muscle lipid and protein oxidation by carnosine. Mol. Cell. Biochem.,  2001, 225(1-), 29-34.
[http://dx.doi.org/10.1023/A:1012256521840] [PMID: 11716361] 
[25] 
Dobbie, H.; Kermack, W.O. Complex-formation between polypeptides and metals. 2. The reaction between cupric ions and some dipeptides. Biochem. J.,  1955, 59(2), 246-257.
[http://dx.doi.org/10.1042/bj0590246] [PMID: 14351188] 
[26] 
Matsukura, T.; Tanaka, H. Applicability of zinc complex of L-carnosine for medical use. Biochemistry (Mosc.),  2000, 65(7), 817-823.
[PMID: 10951100] 
[27] 
Abe, H.; Dobson, G.P.; Hoeger, U.; Parkhouse, W.S. Role of histidine-related compounds to intracellular buffering in fish skeletal muscle. Am. J. Physiol.,  1985, 249(4 Pt 2), R449-R454.
[http://dx.doi.org/10.1152/ajpregu.1985.249.4.R449] [PMID: 4051030] 
[28] 
Brownson, C.; Hipkiss, A.R. Carnosine reacts with a glycated protein. Free Radic. Biol. Med.,  2000, 28(10), 1564-1570.
[http://dx.doi.org/10.1016/S0891-5849(00)00270-7] [PMID: 10927182] 
[29] 
Szwergold, B.S. Carnosine and anserine act as effective transglycating agents in decomposition of aldose-derived Schiff bases. Biochem. Biophys. Res. Commun.,  2005, 336(1), 36-41.
[http://dx.doi.org/10.1016/j.bbrc.2005.08.033] [PMID: 16112643] 
[30] 
Corona, C.; Frazzini, V.; Silvestri, E.; Lattanzio, R.; La Sorda, R.; Piantelli, M.; Canzoniero, L.M.; Ciavardelli, D.; Rizzarelli, E.; Sensi, S.L. Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One,  2011, 6(3)e17971
[http://dx.doi.org/10.1371/journal.pone.0017971] [PMID: 21423579] 
[31] 
Kawahara, M.; Koyama, H.; Nagata, T.; Sadakane, Y. Zinc, copper, and carnosine attenuate neurotoxicity of prion fragment PrP106-126. Metallomics,  2011, 3(7), 726-734.
[http://dx.doi.org/10.1039/c1mt00015b] [PMID: 21442127] 
[32] 
Chez, M.G.; Buchanan, C.P.; Aimonovitch, M.C.; Becker, M.; Schaefer, K.; Black, C.; Komen, J. Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J. Child Neurol.,  2002, 17(11), 833-837.
[http://dx.doi.org/10.1177/08830738020170111501] [PMID: 12585724] 
[33] 
Baraniuk, J.N.; El-Amin, S.; Corey, R.; Rayhan, R.; Timbol, C. Carnosine treatment for gulf war illness: a randomized controlled trial. Glob. J. Health Sci.,  2013, 5(3), 69-81.
[http://dx.doi.org/10.5539/gjhs.v5n3p69] [PMID: 23618477] 
[34] 
Mizuno, D.; Konoha-Mizuno, K.; Mori, M.; Sadakane, Y.; Koyama, H.; Ohkawara, S.; Kawahara, M. Protective activity of carnosine and anserine against zinc-induced neurotoxicity: a possible treatment for vascular dementia. Metallomics,  2015, 7(8), 1233-1239.
[http://dx.doi.org/10.1039/C5MT00049A] [PMID: 25846004] 
[35] 
Jackson, M.C.; Lenney, J.F. The distribution of carnosine and related dipeptides in rat and human tissues. Inflamm. Res.,  1996, 45(3), 132-135.
[http://dx.doi.org/10.1007/BF02265166] [PMID: 8689392] 
[36] 
Cuzzocrea, S.; Genovese, T.; Failla, M.; Vecchio, G.; Fruciano, M.; Mazzon, E.; Di Paola, R.; Muià, C.; La Rosa, C.; Crimi, N.; Rizzarelli, E.; Vancheri, C. Protective effect of orally administered carnosine on bleomycin-induced lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2007, 292(5), L1095-L1104.
[http://dx.doi.org/10.1152/ajplung.00283.2006] [PMID: 17220373] 
[37] 
Tanaka, K.I.; Sugizaki, T.; Kanda, Y.; Tamura, F.; Niino, T.; Kawahara, M. Preventive effects of carnosine on lipopolysaccharide-induced lung injury. Sci. Rep.,  2017, 7, 42813.
[http://dx.doi.org/10.1038/srep42813] [PMID: 28205623] 
[38] 
Xu, T.; Wang, C.; Zhang, R.; Xu, M.; Liu, B.; Wei, D.; Wang, G.; Tian, S. Carnosine markedly ameliorates H9N2 swine influenza virus-induced acute lung injury. J. Gen. Virol.,  2015, 96(10), 2939-2950.
[http://dx.doi.org/10.1099/jgv.0.000238] [PMID: 26233716] 
[39] 
Boldyrev, A.A.; Aldini, G.; Derave, W. Physiology and pathophysiology of carnosine. Physiol. Rev.,  2013, 93(4), 1803-1845.
[http://dx.doi.org/10.1152/physrev.00039.2012] [PMID: 24137022] 
[40] 
Hipkiss, A.R. Carnosine and its possible roles in nutrition and health. Adv. Food Nutr. Res.,  2009, 57, 87-154.
[http://dx.doi.org/10.1016/S1043-4526(09)57003-9] [PMID: 19595386] 
[41] 
Sarma, J.V.; Ward, P.A. Oxidants and redox signaling in acute lung injury. Compr. Physiol.,  2011, 1(3), 1365-1381.
[http://dx.doi.org/10.1002/cphy.c100068] [PMID: 23733646] 
[42] 
Tasaka, S.; Amaya, F.; Hashimoto, S.; Ishizaka, A. Roles of oxidants and redox signaling in the pathogenesis of acute respiratory distress syndrome. Antioxid. Redox Signal.,  2008, 10(4), 739-753.
[http://dx.doi.org/10.1089/ars.2007.1940] [PMID: 18179359] 
[43] 
Mak, J.C. Pathogenesis of COPD. Part II. Oxidative-antioxidative imbalance. Int. J. Tuberc. Lung Dis.,  2008, 12(4), 368-374.
[PMID: 18371260] 
[44] 
Kinnula, V.L.; Fattman, C.L.; Tan, R.J.; Oury, T.D. Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. Am. J. Respir. Crit. Care Med.,  2005, 172(4), 417-422.
[http://dx.doi.org/10.1164/rccm.200501-017PP] [PMID: 15894605] 
[45] 
Klebanov, G.I.; Teselkin YuO, ; Babenkova, I.V.; Popov, I.N.; Levin, G.; Tyulina, O.V.; Boldyrev, A.A.; Vladimirov YuA,  Evidence for a direct interaction of superoxide anion radical with carnosine. Biochem. Mol. Biol. Int.,  1997, 43(1), 99-106.
[http://dx.doi.org/10.1080/15216549700203861] [PMID: 9315287] 
[46] 
Zhang, Z.Y.; Sun, B.L.; Yang, M.F.; Li, D.W.; Fang, J.; Zhang, S. Carnosine attenuates early brain injury through its antioxidative and anti-apoptotic effects in a rat experimental subarachnoid hemorrhage model. Cell. Mol. Neurobiol.,  2015, 35(2), 147-157.
[http://dx.doi.org/10.1007/s10571-014-0106-1] [PMID: 25179154] 
[47] 
Xie, R.X.; Li, D.W.; Liu, X.C.; Yang, M.F.; Fang, J.; Sun, B.L.; Zhang, Z.Y.; Yang, X.Y. Carnosine attenuates brain oxidative stress and apoptosis after intracerebral hemorrhage in rats. Neurochem. Res.,  2017, 42(2), 541-551.
[http://dx.doi.org/10.1007/s11064-016-2104-9] [PMID: 27868153] 
[48] 
Sahin, S.; Burukoglu Donmez, D. Effects of Carnosine (Beta-Alanyl-L-Histidine) in an experimental rat model of acute kidney injury due to septic shock. Med. Sci. Monit.,  2018, 24, 305-316.
[http://dx.doi.org/10.12659/MSM.905181] [PMID: 29334583] 
[49] 
Aydın, A.F.; Bingül, İ.; Küçükgergin, C.; Doğan-Ekici, I.; Doğru Abbasoğlu, S.; Uysal, M. Carnosine decreased oxidation and glycation products in serum and liver of high-fat diet and low-dose streptozotocin-induced diabetic rats. Int. J. Exp. Pathol.,  2017, 98(5), 278-288.
[http://dx.doi.org/10.1111/iep.12252] [PMID: 29205589] 
[50] 
Ozdoğan, K.; Taşkın, E.; Dursun, N. Protective effect of carnosine on adriamycin-induced oxidative heart damage in rats. Anadolu Kardiyol. Derg.,  2011, 11(1), 3-10.
[http://dx.doi.org/10.5152/akd.2011.003] [PMID: 21183419] 
[51] 
Hambidge, M. Human zinc deficiency. J Nutr.,  2000, 130(5S Suppl), 1344S-1349S.
[http://dx.doi.org/10.1093/jn/130.5.1344S] [PMID: 10801941] 
[52] 
Prasad, A.S. Impact of the discovery of human zinc deficiency on health. J. Am. Coll. Nutr.,  2009, 28(3), 257-265.
[http://dx.doi.org/10.1080/07315724.2009.10719780] [PMID: 20150599] 
[53] 
Sandstead, H.H. Subclinical zinc deficiency impairs human brain function. J. Trace Elem. Med. Biol.,  2012, 26(2-3), 70-73.
[http://dx.doi.org/10.1016/j.jtemb.2012.04.018] [PMID: 22673824] 
[54] 
Hsu, H.H.; Tzao, C.; Chang, W.C.; Wu, C.P.; Tung, H.J.; Chen, C.Y.; Perng, W.C. Zinc chloride (smoke bomb) inhalation lung injury: clinical presentations, high-resolution CT findings, and pulmonary function test results. Chest,  2005, 127(6), 2064-2071.
[http://dx.doi.org/10.1378/chest.127.6.2064] [PMID: 15947321] 
[55] 
Phillips, J.I.; Green, F.Y.; Davies, J.C.; Murray, J. Pulmonary and systemic toxicity following exposure to nickel nanoparticles. Am. J. Ind. Med.,  2010, 53(8), 763-767.
[http://dx.doi.org/10.1002/ajim.20855] [PMID: 20623660] 
[56] 
Fukui, H.; Iwahashi, H.; Endoh, S.; Nishio, K.; Yoshida, Y.; Hagihara, Y.; Horie, M. Ascorbic acid attenuates acute pulmonary oxidative stress and inflammation caused by zinc oxide nanoparticles. J. Occup. Health,  2015, 57(2), 118-125.
[http://dx.doi.org/10.1539/joh.14-0161-OA] [PMID: 25735507] 
[57] 
Chang, X.H.; Zhu, A.; Liu, F.F.; Zou, L.Y.; Su, L.; Liu, S.K.; Zhou, H.H.; Sun, Y.Y.; Han, A.J.; Sun, Y.F.; Li, S.; Li, J.; Sun, Y.B. Nickel oxide nanoparticles induced pulmonary fibrosis via TGF-beta1 activation in rats. Hum. Exp. Toxicol., 2016.
[http://dx.doi.org/10.1177/0960327116666650] [PMID: 27596071] 
[58] 
Torreggiani, A.; Taddei, P.; Fini, G. Characterization of dioxygenated cobalt(II)-carnosine complexes by Raman and IR spectroscopy. Biopolymers,  2002, 67(1), 70-81.
[http://dx.doi.org/10.1002/bip.10025] [PMID: 11842416] 
[59] 
Trombley, P.Q.; Horning, M.S.; Blakemore, L.J. Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. Biochemistry (Mosc.),  2000, 65(7), 807-816.
[PMID: 10951099] 
[60] 
Baran, E.J. Metal complexes of carnosine. Biochemistry (Mosc.),  2000, 65(7), 789-797.
[PMID: 10951097] 
[61] 
Fouad, A.A.; Qureshi, H.A.; Yacoubi, M.T.; Al-Melhim, W.N. Protective role of carnosine in mice with cadmium-induced acute hepatotoxicity. Food Chem. Toxicol.,  2009, 47(11), 2863-2870.
[http://dx.doi.org/10.1016/j.fct.2009.09.009] [PMID: 19748544] 
[62] 
Hasanein, P.; Felegari, Z. Chelating effects of carnosine in ameliorating nickel-induced nephrotoxicity in rats. Can. J. Physiol. Pharmacol.,  2017, 95(12), 1426-1432.
[http://dx.doi.org/10.1139/cjpp-2016-0647] [PMID: 28675793] 
[63] 
Rubenfeld, G.D.; Caldwell, E.; Peabody, E.; Weaver, J.; Martin, D.P.; Neff, M.; Stern, E.J.; Hudson, L.D. Incidence and outcomes of acute lung injury. N. Engl. J. Med.,  2005, 353(16), 1685-1693.
[http://dx.doi.org/10.1056/NEJMoa050333] [PMID: 16236739] 
[64] 
Ranieri, V.M.; Rubenfeld, G.D.; Thompson, B.T.; Ferguson, N.D.; Caldwell, E.; Fan, E.; Camporota, L.; Slutsky, A.S.; Slutsky, A.S. Acute respiratory distress syndrome: the Berlin Definition. JAMA,  2012, 307(23), 2526-2533.
[http://dx.doi.org/10.1001/jama.2012.5669] [PMID: 22797452] 
[65] 
Dushianthan, A.; Grocott, M.P.; Postle, A.D.; Cusack, R. Acute respiratory distress syndrome and acute lung injury. Postgrad. Med. J.,  2011, 87(1031), 612-622.
[http://dx.doi.org/10.1136/pgmj.2011.118398] [PMID: 21642654] 
[66] 
Han, S.; Mallampalli, R.K. The acute respiratory distress syndrome: from mechanism to translation. J. Immunol.,  2015, 194(3), 855-860.
[http://dx.doi.org/10.4049/jimmunol.1402513] [PMID: 25596299] 
[67] 
Baron, R.M.; Levy, B.D. Recent advances in understanding and treating ARDS. F1000 Res.,  2016, 5, 5.
[http://dx.doi.org/10.12688/f1000research.7646.1] [PMID: 27158460] 
[68] 
Lucas, R.; Verin, A.D.; Black, S.M.; Catravas, J.D. Regulators of endothelial and epithelial barrier integrity and function in acute lung injury. Biochem. Pharmacol.,  2009, 77(12), 1763-1772.
[http://dx.doi.org/10.1016/j.bcp.2009.01.014] [PMID: 19428331] 
[69] 
Lamb, N.J.; Gutteridge, J.M.; Baker, C.; Evans, T.W.; Quinlan, G.J. Oxidative damage to proteins of bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome: evidence for neutrophil-mediated hydroxylation, nitration, and chlorination. Crit. Care Med.,  1999, 27(9), 1738-1744.
[http://dx.doi.org/10.1097/00003246-199909000-00007] [PMID: 10507592] 
[70] 
Quinlan, G.J.; Lamb, N.J.; Tilley, R.; Evans, T.W.; Gutteridge, J.M. Plasma hypoxanthine levels in ARDS: implications for oxidative stress, morbidity, and mortality. Am. J. Respir. Crit. Care Med.,  1997, 155(2), 479-484.
[http://dx.doi.org/10.1164/ajrccm.155.2.9032182] [PMID: 9032182] 
[71] 
Han, W.; Li, H.; Segal, B.H.; Blackwell, T.S. Bioluminescence imaging of NADPH oxidase activity in different animal models. J. Vis. Exp.,  2012, 3925(68), 3925.
[http://dx.doi.org/10.3791/3925] [PMID: 23117583] 
[72] 
Papaiahgari, S.; Yerrapureddy, A.; Reddy, S.R.; Reddy, N.M.; Dodd-O, J.M.; Crow, M.T.; Grigoryev, D.N.; Barnes, K.; Tuder, R.M.; Yamamoto, M.; Kensler, T.W.; Biswal, S.; Mitzner, W.; Hassoun, P.M.; Reddy, S.P. Genetic and pharmacologic evidence links oxidative stress to ventilator-induced lung injury in mice. Am. J. Respir. Crit. Care Med.,  2007, 176(12), 1222-1235.
[http://dx.doi.org/10.1164/rccm.200701-060OC] [PMID: 17901416] 
[73] 
Sun, C.; Wu, Q.; Zhang, X.; He, Q.; Zhao, H. Mechanistic evaluation of the protective effect of carnosine on acute lung injury in sepsis rats. Pharmacology,  2017, 100(5-6), 292-300.
[http://dx.doi.org/10.1159/000479879] [PMID: 28848223] 
[74] 
Sahin, S.; Oter, S.; Burukoğlu, D.; Sutken, E. The effects of carnosine in an experimental rat model of septic shock. Med. Sci. Monit. Basic Res.,  2013, 19, 54-61.
[http://dx.doi.org/10.12659/MSMBR.883758] [PMID: 23396325] 
[75] 
Ohata, S.; Moriyama, C.; Yamashita, A.; Nishida, T.; Kusumoto, C.; Mochida, S.; Minami, Y.; Nakada, J.; Shomori, K.; Inagaki, Y.; Ohta, Y.; Matsura, T. Polaprezinc protects mice against Endotoxin shock. J. Clin. Biochem. Nutr.,  2010, 46(3), 234-243.
[http://dx.doi.org/10.3164/jcbn.09-125] [PMID: 20490319] 
[76] 
Porto, B.N.; Stein, R.T. Neutrophil extracellular traps in pulmonary diseases: too much of a good thing? Front. Immunol.,  2016, 7, 311.
[http://dx.doi.org/10.3389/fimmu.2016.00311] [PMID: 27574522] 
[77] 
Yang, H.; Biermann, M.H.; Brauner, J.M.; Liu, Y.; Zhao, Y.; Herrmann, M. New insights into neutrophil extracellular traps: mechanisms of formation and role in inflammation. Front. Immunol.,  2016, 7, 302.
[http://dx.doi.org/10.3389/fimmu.2016.00302] [PMID: 27570525] 
[78] 
Stoiber, W.; Obermayer, A.; Steinbacher, P.; Krautgartner, W.D. (ETs) in Humans. Biomolecules,  2015, 5(2), 702-723.
[http://dx.doi.org/10.3390/biom5020702] [PMID: 25946076] 
[79] 
Grommes, J.; Soehnlein, O. Contribution of neutrophils to acute lung injury. Mol. Med.,  2011, 17(3-4), 293-307.
[http://dx.doi.org/10.2119/molmed.2010.00138] [PMID: 21046059] 
[80] 
Grootjans, J.; Kaser, A.; Kaufman, R.J.; Blumberg, R.S. The unfolded protein response in immunity and inflammation. Nat. Rev. Immunol.,  2016, 16(8), 469-484.
[http://dx.doi.org/10.1038/nri.2016.62] [PMID: 27346803] 
[81] 
Wei, J.; Rahman, S.; Ayaub, E.A.; Dickhout, J.G.; Ask, K. Protein misfolding and endoplasmic reticulum stress in chronic lung disease. Chest,  2013, 143(4), 1098-1105.
[http://dx.doi.org/10.1378/chest.12-2133] [PMID: 23546482] 
[82] 
Kim, D.S.; Collard, H.R.; King, T.E., Jr Classification and natural history of the idiopathic interstitial pneumonias. Proc. Am. Thorac. Soc.,  2006, 3(4), 285-292.
[http://dx.doi.org/10.1513/pats.200601-005TK] [PMID: 16738191] 
[83] 
Raghu, G.; Rochwerg, B.; Zhang, Y.; Garcia, C.A.; Azuma, A.; Behr, J.; Brozek, J.L.; Collard, H.R.; Cunningham, W.; Homma, S.; Johkoh, T.; Martinez, F.J.; Myers, J.; Protzko, S.L.; Richeldi, L.; Rind, D.; Selman, M.; Theodore, A.; Wells, A.U.; Hoogsteden, H.; Schünemann, H.J. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am. J. Respir. Crit. Care Med.,  2015, 192(2), e3-e19.
[http://dx.doi.org/10.1164/rccm.201506-1063ST] [PMID: 26177183] 
[84] 
Kinnula, V.L.; Myllärniemi, M. Oxidant-antioxidant imbalance as a potential contributor to the progression of human pulmonary fibrosis. Antioxid. Redox Signal.,  2008, 10(4), 727-738.
[http://dx.doi.org/10.1089/ars.2007.1942] [PMID: 18177235] 
[85] 
Sheppard, D. Transforming growth factor beta: a central modulator of pulmonary and airway inflammation and fibrosis. Proc. Am. Thorac. Soc.,  2006, 3(5), 413-417.
[http://dx.doi.org/10.1513/pats.200601-008AW] [PMID: 16799084] 
[86] 
Alsheblak, M.M.; Elsherbiny, N.M.; El-Karef, A.; El-Shishtawy, M.M. Protective effects of L-carnosine on CCl4 -induced hepatic injury in rats. Eur. Cytokine Netw.,  2016, 27(1), 6-15.
[http://dx.doi.org/10.1684/ecn.2016.0372] [PMID: 27094155] 
[87] 
Kono, T.; Asama, T.; Chisato, N.; Ebisawa, Y.; Okayama, T.; Imai, K.; Karasaki, H.; Furukawa, H.; Yoneda, M. Polaprezinc prevents ongoing thioacetamide-induced liver fibrosis in rats. Life Sci.,  2012, 90(3-4), 122-130.
[http://dx.doi.org/10.1016/j.lfs.2011.10.022] [PMID: 22100444] 
[88] 
Shao, L.; Li, Q.H.; Tan, Z. L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts. Biochem. Biophys. Res. Commun.,  2004, 324(2), 931-936.
[http://dx.doi.org/10.1016/j.bbrc.2004.09.136] [PMID: 15474517] 
[89] 
Drakopanagiotakis, F.; Xifteri, A.; Polychronopoulos, V.; Bouros, D. Apoptosis in lung injury and fibrosis. Eur. Respir. J.,  2008, 32(6), 1631-1638.
[http://dx.doi.org/10.1183/09031936.00176807] [PMID: 19043009] 
[90] 
Maher, T.M.; Evans, I.C.; Bottoms, S.E.; Mercer, P.F.; Thorley, A.J.; Nicholson, A.G.; Laurent, G.J.; Tetley, T.D.; Chambers, R.C.; McAnulty, R.J. Diminished prostaglandin E2 contributes to the apoptosis paradox in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med.,  2010, 182(1), 73-82.
[http://dx.doi.org/10.1164/rccm.200905-0674OC] [PMID: 20203246] 
[91] 
Hirsch, F.R.; Scagliotti, G.V.; Mulshine, J.L.; Kwon, R.; Curran, W.J., Jr; Wu, Y.L.; Paz-Ares, L. Lung cancer: current therapies and new targeted treatments. Lancet,  2017, 389(10066), 299-311.
[http://dx.doi.org/10.1016/S0140-6736(16)30958-8] [PMID: 27574741] 
[92] 
Garofalo, M.; Iovine, B.; Kuryk, L.; Capasso, C.; Hirvinen, M.; Vitale, A.; Yliperttula, M.; Bevilacqua, M.A.; Cerullo, V. Oncolytic adenovirus loaded with L-carnosine as novel strategy to enhance the antitumor activity. Mol. Cancer Ther.,  2016, 15(4), 651-660.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0559] [PMID: 26861248] 
[93] 
Zhang, Z.; Xu, J.; Zhou, T.; Yi, Y.; Li, H.; Sun, H.; Huang, W.; Wang, D.; Li, B.; Ying, G. Risk factors of radiation-induced acute esophagitis in non-small cell lung cancer patients treated with concomitant chemoradiotherapy. Radiat. Oncol.,  2014, 9, 54.
[http://dx.doi.org/10.1186/1748-717X-9-54] [PMID: 24528546] 
[94] 
Yanase, K.; Funaguchi, N.; Iihara, H.; Yamada, M.; Kaito, D.; Endo, J.; Ito, F.; Ohno, Y.; Tanaka, H.; Itoh, Y.; Minatoguchi, S. Prevention of radiation esophagitis by polaprezinc (zinc L-carnosine) in patients with non-small cell lung cancer who received chemoradiotherapy. Int. J. Clin. Exp. Med.,  2015, 8(9), 16215-16222.
[PMID: 26629136] 
[95] 
Severina, I.S.; Bussygina, O.G.; Pyatakova, N.V. Carnosine as a regulator of soluble guanylate cyclase. Biochemistry (Mosc.),  2000, 65(7), 783-788.
[PMID: 10951096] 
[96] 
Rabe, K.F.; Hurd, S.; Anzueto, A.; Barnes, P.J.; Buist, S.A.; Calverley, P.; Fukuchi, Y.; Jenkins, C.; Rodriguez-Roisin, R.; van Weel, C.; Zielinski, J. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med.,  2007, 176(6), 532-555.
[http://dx.doi.org/10.1164/rccm.200703-456SO] [PMID: 17507545] 
[97] 
Vogelmeier, C.F.; Criner, G.J.; Martinez, F.J.; Anzueto, A.; Barnes, P.J.; Bourbeau, J.; Celli, B.R.; Chen, R.; Decramer, M.; Fabbri, L.M.; Frith, P.; Halpin, D.M.; López Varela, M.V.; Nishimura, M.; Roche, N.; Rodriguez-Roisin, R.; Sin, D.D.; Singh, D.; Stockley, R.; Vestbo, J.; Wedzicha, J.A.; Agustí, A. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. Am. J. Respir. Crit. Care Med.,  2017, 195(5), 557-582.
[http://dx.doi.org/10.1164/rccm.201701-0218PP] [PMID: 28128970] 
[98] 
Vestbo, J.; Hurd, S.S.; Agustí, A.G.; Jones, P.W.; Vogelmeier, C.; Anzueto, A.; Barnes, P.J.; Fabbri, L.M.; Martinez, F.J.; Nishimura, M.; Stockley, R.A.; Sin, D.D.; Rodriguez-Roisin, R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med.,  2013, 187(4), 347-365.
[http://dx.doi.org/10.1164/rccm.201204-0596PP] [PMID: 22878278] 
[99] 
Sadowska, A.M.; Manuel-Y-Keenoy, B.; De Backer, W.A. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm. Pharmacol. Ther.,  2007, 20(1), 9-22.
[http://dx.doi.org/10.1016/j.pupt.2005.12.007] [PMID: 16458553] 
[100] 
Tanaka, K.; Tanaka, Y.; Miyazaki, Y.; Namba, T.; Sato, K.; Aoshiba, K.; Azuma, A.; Mizushima, T. Therapeutic effect of lecithinized superoxide dismutase on pulmonary emphysema. J. Pharmacol. Exp. Ther.,  2011, 338(3), 810-818.
[http://dx.doi.org/10.1124/jpet.111.179051] [PMID: 21665943] 
[101] 
Xing, Y.F.; Xu, Y.H.; Shi, M.H.; Lian, Y.X. The impact of PM2.5 on the human respiratory system. J. Thorac. Dis.,  2016, 8(1), E69-E74.
[PMID: 26904255] 
[102] 
Brunekreef, B.; Holgate, S.T. Air pollution and health. Lancet,  2002, 360(9341), 1233-1242.
[http://dx.doi.org/10.1016/S0140-6736(02)11274-8] [PMID: 12401268] 
[103] 
Li, R.; Kou, X.; Xie, L.; Cheng, F.; Geng, H. Effects of ambient PM2.5 on pathological injury, inflammation, oxidative stress, metabolic enzyme activity, and expression of c-fos and c-jun in lungs of rats. Environ. Sci. Pollut. Res. Int.,  2015, 22(24), 20167-20176.
[http://dx.doi.org/10.1007/s11356-015-5222-z] [PMID: 26304807] 
[104] 
Bekki, K.; Ito, T.; Yoshida, Y.; He, C.; Arashidani, K.; He, M.; Sun, G.; Zeng, Y.; Sone, H.; Kunugita, N.; Ichinose, T. PM2.5 collected in China causes inflammatory and oxidative stress responses in macrophages through the multiple pathways. Environ. Toxicol. Pharmacol.,  2016, 45, 362-369.
[http://dx.doi.org/10.1016/j.etap.2016.06.022] [PMID: 27393915] 
[105] 
Mizushima, T. Drug discovery and development focusing on existing medicines: drug re-profiling strategy. J. Biochem.,  2011, 149(5), 499-505.
[http://dx.doi.org/10.1093/jb/mvr032] [PMID: 21436140] 
[106] 
Tanaka, K.; Kurotsu, S.; Asano, T.; Yamakawa, N.; Kobayashi, D.; Yamashita, Y.; Yamazaki, H.; Ishihara, T.; Watanabe, H.; Maruyama, T.; Suzuki, H.; Mizushima, T. Superiority of pulmonary administration of mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease. Sci. Rep.,  2014, 4, 4510.
[http://dx.doi.org/10.1038/srep04510] [PMID: 24676126] 
[107] 
Asano, T.; Aida, S.; Suemasu, S.; Tahara, K.; Tanaka, K.; Mizushima, T. Aldioxa improves delayed gastric emptying and impaired gastric compliance, pathophysiologic mechanisms of functional dyspepsia. Sci. Rep.,  2015, 5, 17519.
[http://dx.doi.org/10.1038/srep17519] [PMID: 26620883] 
[108] 
Tanaka, K.; Ishihara, T.; Sugizaki, T.; Kobayashi, D.; Yamashita, Y.; Tahara, K.; Yamakawa, N.; Iijima, K.; Mogushi, K.; Tanaka, H.; Sato, K.; Suzuki, H.; Mizushima, T. Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease. Nat. Commun.,  2013, 4, 2686.
[http://dx.doi.org/10.1038/ncomms3686] [PMID: 24189798] 
[109] 
Fuji, Y.; Matsura, T.; Kai, M.; Kawasaki, H.; Yamada, K. Protection by polaprezinc, an anti-ulcer drug, against indomethacin-induced apoptosis in rat gastric mucosal cells. Jpn. J. Pharmacol.,  2000, 84(1), 63-70.
[http://dx.doi.org/10.1254/jjp.84.63] [PMID: 11043455] 
[110] 
Sakae, K.; Yanagisawa, H. Oral treatment of pressure ulcers with polaprezinc (zinc L-carnosine complex): 8-week open-label trial. Biol. Trace Elem. Res.,  2014, 158(3), 280-288.
[http://dx.doi.org/10.1007/s12011-014-9943-5] [PMID: 24691900] 
[111] 
Matsuda, K.; Yamaguchi, I.; Wada, H. Toxicity of the novel anti-peptic ulcer agent polaprezinc in beagle dogs. Arzneimittelforschung,  1995, 45(1), 52-60.
[PMID: 7893270] 
Cite As
Current Medicinal Chemistry

Carnosine and Lung Disease

Abstract
