A群鏈球菌是引起人類疾病中相當重要的病原菌，從輕微的感染到較為嚴重的感染常造成壞死性肌膜炎及鏈球菌毒性休克症候群。臨床研究報告指出，在嚴重侵入性感染的病人中有高量的發炎細胞激素與nitric oxide (NO) 的生成。Dextromethorphan (DM) 是一廣泛使用的止咳藥物，近年來的研究指出此藥物具有抗發炎作用，研究結果顯示此藥物可以降低reactive oxygen species和發炎細胞激素TNF-與IL-6的產生。因此本研究探討具抗發炎特性之止咳藥物DM對A群鏈球菌的感染是否能提供保護的效果。研究結果證實，給予小鼠DM處理後確實能增加A群鏈球菌感染小鼠的存活率。進一步研究發現，DM能維持浸潤到感染部位嗜中性球的存活率並且減低感染部位的細菌量，另一方面也發現DM可避免細菌散佈到血液中，且降低血清中發炎細胞激素與趨化激素的產生。此外，觀察感染後小鼠肝臟的病理變化與血清中AST及ALT濃度也顯示DM可以減輕A群鏈球菌感染所造成的肝損傷。活體外細胞實驗的結果顯示A群鏈球菌可以誘發巨噬細胞轉錄因子NF-B活化，而DM可以降低NF-B的活化。分析轉錄因子NF-B下游所調控的發炎性蛋白質，結果亦證實DM可以抑制A群鏈球菌所誘發的iNOS表現與NO的產生。綜合這些研究結果，DM透過維持浸潤細胞的存活率與降低全身性發炎反應，進而提供A群鏈球菌感染的保護效果。

Group A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of disorders, ranging from mild infections to severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. Patients suffering from severe invasive infection have higher levels of inflammatory cytokines and nitric oxide (NO) compared with non-invasive infection. Dextromethorphan (DM) is a widely-used anti-tussive drug. Recent reports show that DM has anti-inflammatory properties through reducing the levels of reactive oxygen species and inflammatory cytokines including TNF- and IL-6. In the present study, we investigate the potential protective effect of DM in GAS infection. Our results showed that DM treatment increased the survival rate of GAS-infected mice. DM administration reduced bacterial numbers and increased neutrophil viability in local infection site. Moreover, DM treatment prevented bacterial dissemination to the blood and reduced serum levels of proinflammatory cytokines and chemokines. In addition, examination of liver histology and serum AST and ALT levels in GAS-infected mice revealed that DM reduced liver injury. Further in vitro studies showed that GAS induced NF-B activation in macrophages and DM treatment reduced this activation. DM also reduced iNOS expression and NO production in GAS-infected macrophages. Taken together, DM treatment increased the viability of infiltrated neutrophils and reduced systemic inflammatory responses to provide the protective effect in GAS infection.

Betschel S. D., Borgia S. M., Barg N. L., Low D. E. and De Azavedo J. C. (1998) Reduced virulence of group A streptococcal Tn916 mutants that do not produce streptolysin S. Infect Immun 66, 1671-9.
Bhakdi S., Tranum-Jensen J. and Sziegoleit A. (1985) Mechanism of membrane damage by streptolysin-O. Infect Immun 47, 52-60.
Bisno A. L., Brito M. O. and Collins C. M. (2003) Molecular basis of group A streptococcal virulence. Lancet Infect Dis 3, 191-200.
Bonizzi G. and Karin M. (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25, 280-8.
Brinkmann V., Reichard U., Goosmann C., Fauler B., Uhlemann Y., Weiss D. S., Weinrauch Y. and Zychlinsky A. (2004) Neutrophil extracellular traps kill bacteria. Science 303, 1532-5.
Buchanan J. T., Simpson A. J., Aziz R. K., Liu G. Y., Kristian S. A., Kotb M., Feramisco J. and Nizet V. (2006) DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 16, 396-400.
Carapetis J. R., Steer A. C., Mulholland E. K. and Weber M. (2005) The global burden of group A streptococcal diseases. Lancet Infect Dis 5, 685-94.
Carlsson F., Berggard K., Stalhammar-Carlemalm M. and Lindahl G. (2003) Evasion of phagocytosis through cooperation between two ligand-binding regions in Streptococcus pyogenes M protein. J Exp Med 198, 1057-68.
Choi D. W. (1987) Dextrorphan and dextromethorphan attenuate glutamate neurotoxicity. Brain Res 403, 333-6.
Christ E. A., Meals E. and English B. K. (1997) Streptococcal pyrogenic exotoxins A (SpeA) and C (SpeC) stimulate the production of inducible nitric oxide synthase (iNOS) protein in RAW 264.7 macrophages. Shock 8, 450-3.
Cleary P. P., Prahbu U., Dale J. B., Wexler D. E. and Handley J. (1992) Streptococcal C5a peptidase is a highly specific endopeptidase. Infect Immun 60, 5219-23.
Cunningham M. W. (2000) Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 13, 470-511.
Cywes C. and Wessels M. R. (2001) Group A Streptococcus tissue invasion by CD44-mediated cell signalling. Nature 414, 648-52.
D'Costa S. S. and Boyle M. D. (1998) Interaction of a group A Streptococcus within human plasma results in assembly of a surface plasminogen activator that contributes to occupancy of surface plasmin-binding structures. Microb Pathog 24, 341-9.
Dale J. B., Washburn R. G., Marques M. B. and Wessels M. R. (1996) Hyaluronate capsule and surface M protein in resistance to opsonization of group A streptococci. Infect Immun 64, 1495-501.
DeAngelis P. L., Yang N. and Weigel P. H. (1994) The Streptococcus pyogenes hyaluronan synthase: sequence comparison and conservation among various group A strains. Biochem Biophys Res Commun 199, 1-10.
Facklam R. F., Martin D. R., Lovgren M., Johnson D. R., Efstratiou A., Thompson T. A., Gowan S., Kriz P., Tyrrell G. J., Kaplan E. and Beall B. (2002) Extension of the Lancefield classification for group A streptococci by addition of 22 new M protein gene sequence types from clinical isolates: emm103 to emm124. Clin Infect Dis 34, 28-38.
Gloire G., Legrand-Poels S. and Piette J. (2006) NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72, 1493-505.
Goldmann O., Chhatwal G. S. and Medina E. (2003) Immune mechanisms underlying host susceptibility to infection with group A streptococci. J Infect Dis 187, 854-61.
Haberecht M. F., Mitchell C. K., Lo G. J. and Redburn D. A. (1997) N-methyl-D-aspartate-mediated glutamate toxicity in the developing rabbit retina. J Neurosci Res 47, 416-26.
Hanski E. and Caparon M. (1992) Protein F, a fibronectin-binding protein, is an adhesin of the group A streptococcus Streptococcus pyogenes. Proc Natl Acad Sci U S A 89, 6172-6.
Hauser A. R., Stevens D. L., Kaplan E. L. and Schlievert P. M. (1991) Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock-like syndrome. J Clin Microbiol 29, 1562-7.
Hsueh P. R., Liu C. Y. and Luh K. T. (2002) Current status of antimicrobial resistance in Taiwan. Emerg Infect Dis 8, 132-7.
Ji Y., McLandsborough L., Kondagunta A. and Cleary P. P. (1996) C5a peptidase alters clearance and trafficking of group A streptococci by infected mice. Infect Immun 64, 503-10.
Kobayashi S. D., Braughton K. R., Whitney A. R., Voyich J. M., Schwan T. G., Musser J. M. and DeLeo F. R. (2003) Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils. Proc Natl Acad Sci U S A 100, 10948-53.
Kuo C. F., Luo Y. H., Lin H. Y., Huang K. J., Wu J. J., Lei H. Y., Lin M. T., Chuang W. J., Liu C. C., Jin Y. T. and Lin Y. S. (2004) Histopathologic changes in kidney and liver correlate with streptococcal pyrogenic exotoxin B production in the mouse model of group A streptococcal infection. Microb Pathog 36, 273-85.
Kuo C. F., Wu J. J., Lin K. Y., Tsai P. J., Lee S. C., Jin Y. T., Lei H. Y. and Lin Y. S. (1998) Role of streptococcal pyrogenic exotoxin B in the mouse model of group A streptococcal infection. Infect Immun 66, 3931-5.
Kuo C. F., Wu J. J., Tsai P. J., Kao F. J., Lei H. Y., Lin M. T. and Lin Y. S. (1999) Streptococcal pyrogenic exotoxin B induces apoptosis and reduces phagocytic activity in U937 cells. Infect Immun 67, 126-30.
Lahteenmaki K., Kuusela P. and Korhonen T. K. (2001) Bacterial plasminogen activators and receptors. FEMS Microbiol Rev 25, 531-52.
Li G., Liu Y., Tzeng N. S., Cui G., Block M. L., Wilson B., Qin L., Wang T., Liu B., Liu J. and Hong J. S. (2005) Protective effect of dextromethorphan against endotoxic shock in mice. Biochem Pharmacol 69, 233-40.
Liu Y., Qin L., Li G., Zhang W., An L., Liu B. and Hong J. S. (2003) Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther 305, 212-8.
Lukomski S., Montgomery C. A., Rurangirwa J., Geske R. S., Barrish J. P., Adams G. J. and Musser J. M. (1999) Extracellular cysteine protease produced by Streptococcus pyogenes participates in the pathogenesis of invasive skin infection and dissemination in mice. Infect Immun 67, 1779-88.
Medina E., Anders D. and Chhatwal G. S. (2002) Induction of NF-kappaB nuclear translocation in human respiratory epithelial cells by group A streptococci. Microb Pathog 33, 307-13.
Medzhitov R. (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1, 135-45.
Musser J. M., Hauser A. R., Kim M. H., Schlievert P. M., Nelson K. and Selander R. K. (1991) Streptococcus pyogenes causing toxic-shock-like syndrome and other invasive diseases: clonal diversity and pyrogenic exotoxin expression. Proc Natl Acad Sci U S A 88, 2668-72.
Norrby-Teglund A., Chatellier S., Low D. E., McGeer A., Green K. and Kotb M. (2000) Host variation in cytokine responses to superantigens determine the severity of invasive group A streptococcal infection. Eur J Immunol 30, 3247-55.
Norrby-Teglund A., Pauksens K., Norgren M. and Holm S. E. (1995) Correlation between serum TNF alpha and IL6 levels and severity of group A streptococcal infections. Scand J Infect Dis 27, 125-30.
Nowak R. (1994) Flesh-eating bacteria: not new, but still worrisome. Science 264, 1665.
O'Loughlin R. E., Roberson A., Cieslak P. R., Lynfield R., Gershman K., Craig A., Albanese B. A., Farley M. M., Barrett N. L., Spina N. L., Beall B., Harrison L. H., Reingold A. and Van Beneden C. (2007) The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000-2004. Clin Infect Dis 45, 853-62.
Ohara-Nemoto Y., Sasaki M., Kaneko M., Nemoto T. and Ota M. (1994) Cysteine protease activity of streptococcal pyrogenic exotoxin B. Can J Microbiol 40, 930-6.
Pahlman L. I., Morgelin M., Eckert J., Johansson L., Russell W., Riesbeck K., Soehnlein O., Lindbom L., Norrby-Teglund A., Schumann R. R., Bjorck L. and Herwald H. (2006) Streptococcal M protein: a multipotent and powerful inducer of inflammation. J Immunol 177, 1221-8.
Papageorgiou A. C. and Acharya K. R. (2000) Microbial superantigens: from structure to function. Trends Microbiol 8, 369-75.
Robinson J. H. and Kehoe M. A. (1992) Group A streptococcal M proteins: virulence factors and protective antigens. Immunol Today 13, 362-7.
Saetre T., Hoiby E. A., Kahler H. and Lyberg T. (2000) Changed expression of leukocyte adhesion molecules and increased production of reactive oxygen species caused by Streptococcus pyogenes in human whole blood. APMIS 108, 573-80.
Schwandner R., Dziarski R., Wesche H., Rothe M. and Kirschning C. J. (1999) Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 274, 17406-9.
Siu A. and Drachtman R. (2007) Dextromethorphan: a review of N-methyl-d-aspartate receptor antagonist in the management of pain. CNS Drug Rev 13, 96-106.
Staali L., Bauer S., Morgelin M., Bjorck L. and Tapper H. (2006) Streptococcus pyogenes bacteria modulate membrane traffic in human neutrophils and selectively inhibit azurophilic granule fusion with phagosomes. Cell Microbiol 8, 690-703.
Stevens D. L. (1992) Invasive group A streptococcus infections. Clin Infect Dis 14, 2-11.
Thiemermann C. (1997) Nitric oxide and septic shock. Gen Pharmacol 29, 159-66.
Tsai P. J., Chen Y. H., Hsueh C. H., Hsieh H. C., Liu Y. H., Wu J. J. and Tsou C. C. (2006) Streptococcus pyogenes induces epithelial inflammatory responses through NF-kappaB/MAPK signaling pathways. Microbes Infect 8, 1440-9.
Tsai W. H., Chang C. W., Chuang W. J., Lin Y. S., Wu J. J., Liu C. C., Chang W. T. and Lin M. T. (2004) Streptococcal pyrogenic exotoxin B-induced apoptosis in a549 cells is mediated by a receptor- and mitochondrion-dependent pathway. Infect Immun 72, 7055-62.
Tsai W. H., Chang C. W., Lin Y. S., Chuang W. J., Wu J. J., Liu C. C., Tsai P. J. and Lin M. T. (2008) Streptococcal pyrogenic exotoxin B-induced apoptosis in A549 cells is mediated through alpha(v)beta(3) integrin and Fas. Infect Immun 76, 1349-57.
Voyich J. M., Musser J. M. and DeLeo F. R. (2004) Streptococcus pyogenes and human neutrophils: a paradigm for evasion of innate host defense by bacterial pathogens. Microbes Infect 6, 1117-23.
Wang J. E., Dahle M. K., McDonald M., Foster S. J., Aasen A. O. and Thiemermann C. (2003) Peptidoglycan and lipoteichoic acid in gram-positive bacterial sepsis: receptors, signal transduction, biological effects, and synergism. Shock 20, 402-14.
Zhang W., Wang T., Qin L., Gao H. M., Wilson B., Ali S. F., Zhang W., Hong J. S. and Liu B. (2004) Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. FASEB J 18, 589-91.
行政院衛生署疫情報導 “法定傳染病統計結果” 2003
行政院衛生署疫情報導 “法定傳染病統計結果” 2006
羅月霞 “Correlation of SPE B with histopathologic change, NO, and cytokine production in a mouse model of Group A streptococcal infection”國立成功大學微生物暨免疫學研究所碩士論文. 2001