Abstract
There has been growing interest in the last 10 years in the study of innate immunity, in particular because of the possible role that toll-like receptors (TLR) may play in the pathogenesis of some respiratory diseases including, asthma, chronic obstructive pulmonary disease, and infections. TLR are a family of type 1 transmembrane proteins, responsible for recognising molecular patterns associated with pathogens (PAMP, pathogen-associated molecular patterns), and expressed by a broad spectrum of infectious agents. This recognition leads to a quick production of cytokines and chemokines which provides a long-lasting adaptive response to the pathogen. At present, it is considered //It is currently considered that the administration of drugs which modulate the activity of these receptors upwards or downwards may represent major therapeutic progress for handling these diseases.
The aim of this review is to describe the different TLS, define their possible role in the pathogenesis of the main respiratory diseases and finally, speculate over the therapeutic possibilities which their modulation, agonist or antagonist, offers as possible therapeutic targets.
Keywords: Innate immunity, Acquired immunity, Toll-like receptors, Asthma, COPD
Resumen
En los últimos 10 años se ha constatado un creciente interés por el estudio de la inmunidad innata, particularmente por el posible papel que los denominados “receptores toll-like” (TLR) pueden desempeñar en la patogenia de algunas enfermedades respiratorias, como, por ejemplo, el asma, la enfermedad pulmonar obstructiva crónica y las infecciones. Los TLR son una familia de proteínas transmembranarias de tipo I, responsables del reconocimiento de patrones moleculares asociados a patógenos (PAMP, de pathogen-associated molecular patterns), y expresados por un amplio espectro de agentes infecciosos. Este reconocimiento lleva a una rápida producción de citocinas y quimiocinas, lo que proporciona una respuesta adaptativa duradera contra el patógeno. En la actualidad se considera que la administración de fármacos que modulen, al alza o a la baja, la actividad de estos receptores puede suponer un gran avance terapéutico en el manejo de dichas enfermedades.
El propósito de la presente revisión es describir los diferentes TLR, definir su posible papel en la patogenia de las principales enfermedades respiratorias y, finalmente, conjeturar las posibilidades terapéuticas que su modulación, agonista o antagonista, ofrece como posibles dianas terapéuticas.
Palabras clave: Inmunidad innata, Inmunidad adquirida, Receptores toll-like, Asma, EPOC
References
- 1.Arancibia S., Beltrán C., Aguirre I., Silva P., Peralta A., Malinarich F. Toll-like receptor are key participants in innate immune responses [revision] Biol Res. 2007;40:97–112. doi: 10.4067/s0716-97602007000200001. [DOI] [PubMed] [Google Scholar]
- 2.Xu D., Liu H., Komai-Koma M. Direct and indirect role of toll-like receptor in T cell mediated immunity [revisión] Cell Mol Inmunol. 2004;1:239–246. [PubMed] [Google Scholar]
- 3.Redecke V., Häcker H., Datta S., Fermin A., Pitha P., Broide D. Cutting edge: activation of toll-like receptor 2 induces a Th2 immune respose and promote experimental asthma. J Immunol. 2004;172:2739–2743. doi: 10.4049/jimmunol.172.5.2739. [DOI] [PubMed] [Google Scholar]
- 4.Duez C., Gosset P., Tonnel A. Dendritic cells and toll-like receptors in allergy and asthma [revisión] Eur J Dermatol. 2006;16:12–16. [PubMed] [Google Scholar]
- 5.Gon Y. Toll-Like receptors and airway inflammation [revision] Allergol Int. 2008;57:33–37. doi: 10.2332/allergolint.R-07-157. [DOI] [PubMed] [Google Scholar]
- 6.Lemaitre B., Nicolas E., Michaut L., Reichhart J.M., Hoffmann J.A. The dorsoventral regulatory gene cassette spatzle/toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–983. doi: 10.1016/s0092-8674(00)80172-5. [DOI] [PubMed] [Google Scholar]
- 7.Medzhitov R., Preston-Hurlburt P., Janeway C.A. A human homologue of the Drosophila toll protein signals activation of adaptative immunity. Nature. 1997;388:394–397. doi: 10.1038/41131. [DOI] [PubMed] [Google Scholar]
- 8.Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801. doi: 10.1016/j.cell.2006.02.015. [DOI] [PubMed] [Google Scholar]
- 9.Creagh E.M., O’Neill L.A. TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol. 2006;27:352–357. doi: 10.1016/j.it.2006.06.003. [DOI] [PubMed] [Google Scholar]
- 10.Akira S. Mammalian. Toll-like receptors. Curr Opin Immunol. 2003;15:5–11. doi: 10.1016/s0952-7915(02)00013-4. [DOI] [PubMed] [Google Scholar]
- 11.Yamamoto M., Takeda K., Akira S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol. 2004;40:861–868. doi: 10.1016/j.molimm.2003.10.006. [DOI] [PubMed] [Google Scholar]
- 12.Kopp E.B., Medzhitov R. The toll-receptor family and control of innate immunity. Curr Opin Immunol. 1999;11:13–18. doi: 10.1016/s0952-7915(99)80003-x. [DOI] [PubMed] [Google Scholar]
- 13.Gay N.J., Keith F.J. Drosophila toll and IL-1 receptor. Nature. 1991;351:355–356. doi: 10.1038/351355b0. [DOI] [PubMed] [Google Scholar]
- 14.Fritz J.H., Girardon D.E. How toll-like receptors and Nod-like receptors contribute to innate immunity in mammals. J Endotoxin Res. 2005;11:390–394. doi: 10.1179/096805105X76850. [DOI] [PubMed] [Google Scholar]
- 15.Takeda K., Kaisho T., Akira S. Toll-like receptors. Annu Rev Immunol. 2006;27:352–357. doi: 10.1146/annurev.immunol.21.120601.141126. [DOI] [PubMed] [Google Scholar]
- 16.Eiland C.W., Knapp S., Florquin S., De Vos A.F., Takeda K., Akira S. Non-mannose-capped lipoarabinomannan induces ling inflammation via toll-like receptor 2. Am J Respir Crit Care Med. 2004;170:1367–1374. doi: 10.1164/rccm.200404-525OC. [DOI] [PubMed] [Google Scholar]
- 17.Sa Silva J., Soldau K., Cristen U., Tobias P.S., Ulevith R.J. Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex, transfer from CD14 to TLR4 and MD-2. J Biol Chem. 2001;276:21129–21135. doi: 10.1074/jbc.M009164200. [DOI] [PubMed] [Google Scholar]
- 18.Smith K.D., Andersen E., Hayashi F., Cookson B.T., Aderem A. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat Immunol. 2003;4:1247–1253. doi: 10.1038/ni1011. [DOI] [PubMed] [Google Scholar]
- 19.Jefferies C.A., Fitzgerald K.A. Interferon gene regulation:not all roads lead to Tolls. Trends Mol Med. 2005;11:403–411. doi: 10.1016/j.molmed.2005.07.006. [DOI] [PubMed] [Google Scholar]
- 20.Bowie A.G., Haga I.R. The role of toll-like receptors in the host response to viruses. Mol Immunol. 2005;42:859–867. doi: 10.1016/j.molimm.2004.11.007. [DOI] [PubMed] [Google Scholar]
- 21.Boehme K.W., Compton T. Innate sensing of viruses by toll-like receptors. J Virol. 2004;78:7867–7873. doi: 10.1128/JVI.78.15.7867-7873.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kawai T., Sato S., Ishii K.J., Coban C., Hemmi H., Yamamoto M. Interferon-alpha induction through toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol. 2004;5:1061–1068. doi: 10.1038/ni1118. [DOI] [PubMed] [Google Scholar]
- 23.Moynagh P.N. TLR signalling and activation of IRFs: revisiting old friends from the NF-kappaB pathway. Trends Immunol. 2005;26:469–476. doi: 10.1016/j.it.2005.06.009. [DOI] [PubMed] [Google Scholar]
- 24.Du X., Poltorak A., Wei Y., Beutler B. Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur Cytokine Netw. 2000;11:362–371. [PubMed] [Google Scholar]
- 25.Chuang T.H., Ulevitch R.J. Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur Cytokine Netw. 2000;11:372–378. [PubMed] [Google Scholar]
- 26.Rock F.L., Hardiman G., Timans J.C., Kastelein R.A., Bazan J.F. A family of human receptors structurally related to Drosophila toll. Proc Natl Acad Sci U S A. 1998;95:588–593. doi: 10.1073/pnas.95.2.588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Zarember K.A., Godowski P.J. Tissue expression of human toll-like receptors and differential regulation of toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol. 2002;168:554–561. doi: 10.4049/jimmunol.168.2.554. [fe de errores en: J Immunol. 2002;169:1136.] [DOI] [PubMed] [Google Scholar]
- 28.Ochoa M.T., Legaspi A.J., Hatziris Z., Godowski P.J., Modlin R.L., Sieling P.A. Distribution of toll-like receptor 1 and toll-like receptor 2 in human lymphoid tissue. Immunology. 2003;108:10–15. doi: 10.1046/j.1365-2567.2003.01563.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Muzio M., Bosisio D., Polentarutti N., D’Amico G., Stoppacciaro A., Mancinelli R. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol. 2000;164:5998–6004. doi: 10.4049/jimmunol.164.11.5998. [DOI] [PubMed] [Google Scholar]
- 30.Hornung V., Rothenfusser S., Britsch S., Krug A., Jahrsdörfer B., Giese T. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002;168:4531–4537. doi: 10.4049/jimmunol.168.9.4531. [DOI] [PubMed] [Google Scholar]
- 31.Compton T., Kurt-Jones E.A., Boehme K.W., Belko J., Latz E., Golenbock D.T. Human cytomegalovirus activates inflammatory cytokine responses via CD14 and toll-like receptor 2. J Virol. 2003;77:4588–4596. doi: 10.1128/JVI.77.8.4588-4596.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Muroi M., Ohnishi T., Tanamoto K. Regions of the mouse CD14 molecule required for toll-like receptor 2- and 4-mediated activation of NF-kappa B. J Biol Chem. 2002;277:42372–42379. doi: 10.1074/jbc.M205966200. [DOI] [PubMed] [Google Scholar]
- 33.Rehli M. Of mice and men: species variations of toll-like receptor expression. Trends Immunol. 2002;23:375–378. doi: 10.1016/s1471-4906(02)02259-7. [DOI] [PubMed] [Google Scholar]
- 34.Zhang H., Tay P.N., Cao W., Li W., Lu J. Integrin-nucleated toll-like receptor (TLR) dimerization reveals subcellular targeting of TLRs and distinct mechanisms of TLR4 activation and signaling. FEBS Lett. 2002;532:171–176. doi: 10.1016/s0014-5793(02)03669-4. [DOI] [PubMed] [Google Scholar]
- 35.Takeuchi O., Kawai T., Sanjo H., Copeland N.G., Gilbert D.J., Jenkins N.A. TLR6: a novel member of an expanding toll-like receptor family. Gene. 1999;231:59–65. doi: 10.1016/s0378-1119(99)00098-0. [DOI] [PubMed] [Google Scholar]
- 36.Heine H., Lien E. Toll-like receptors and their function in innate and adaptive immunity. Int Arch Allergy Immunol. 2003;130:180–192. doi: 10.1159/000069517. [DOI] [PubMed] [Google Scholar]
- 37.Dunne A., O’Neill L.A. The interleukin-1 receptor/toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci STKE. 2003;171:re3. doi: 10.1126/stke.2003.171.re3. [DOI] [PubMed] [Google Scholar]
- 38.Chuang T.H., Ulevitch R.J. Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur Cytokine Netw. 2000;11:372–378. [PubMed] [Google Scholar]
- 39.Skrepnek G.H., Skrepnek S.V. Epidemiology, clinical and economic burden, and natural history of chronic obstructive pulmonary disease and asthma. Am J Manag Care. 2004;10:S129–S138. [PubMed] [Google Scholar]
- 40.Leung D.Y., Bieber T. Atopic dermatitis. Lancet. 2003;361:151–160. doi: 10.1016/S0140-6736(03)12193-9. [DOI] [PubMed] [Google Scholar]
- 41.Hoffjan S., Ober C. Present status on the genetic studies of asthma. Curr Opin Immunol. 2002;14:709–717. doi: 10.1016/s0952-7915(02)00393-x. [DOI] [PubMed] [Google Scholar]
- 42.Castillo J.A., Mullol J. Rhinitis and asthma comorbidity in Spain: the RINAIR study. Arch Bronconeumol. 2008;44:597–603. [PubMed] [Google Scholar]
- 43.Bowcock A.M., Cookson W.O. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Hum Mol Genet. 2004;13:R43–R55. doi: 10.1093/hmg/ddh094. Spec No 1. [DOI] [PubMed] [Google Scholar]
- 44.Molfino N.A. Genetics of COPD. Chest. 2004;125:1929–1940. doi: 10.1378/chest.125.5.1929. [DOI] [PubMed] [Google Scholar]
- 45.Arnedo-Pena A., García-Marcos L., Carvajal I., Busquets R., Morales M., Miner C. Air pollution and recent symptoms of asthma, allergic rhinitis, and atopic eczema in schoolchildren aged between 6 and 7 years. Arch Bronconeumol. 2009;45:224–229. doi: 10.1016/j.arbres.2008.10.004. [DOI] [PubMed] [Google Scholar]
- 46.Martínez F.D. The coming-of-age of the hygiene hypothesis. Respir Res. 2001;2:129–132. doi: 10.1186/rr48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Weiss S.T. Eat dirt – the hygiene hypothesis and allergic diseases. N Engl J Med. 2002;347:930–931. doi: 10.1056/NEJMe020092. [DOI] [PubMed] [Google Scholar]
- 48.Elías M.T., Sánchez R., Cayuela A., Álvarez F.J., Romero J.A., García A. Risk factors for bronchial asthma in patients with rhinitis. Arch Bronconeumol. 2001;37:429–434. doi: 10.1016/s0300-2896(01)75113-7. [DOI] [PubMed] [Google Scholar]
- 49.Prieto L., Morales C. Allergic rhinitis and asthma as probable clinical manifestations of the same process. Arch Bronconeumol. 1998;34:277–280. doi: 10.1016/s0300-2896(15)30412-9. [DOI] [PubMed] [Google Scholar]
- 50.Leckie M.J., Ten Brinke A., Khan J., Diamant Z., O’Connor B.J., Walls C.M. Effect of an interleukin-5 blocking monoclonal antibody on eosinophiles, airway hyperresponsiveness and the response to allergen in patients with asthma. Lancet. 2000;356:2144–2148. doi: 10.1016/s0140-6736(00)03496-6. [DOI] [PubMed] [Google Scholar]
- 51.Bryan S.A., O’Connor B.J., Matti S., Leckie M.J., Kanabar V., Khan J. Effects of recombinant human interleukin-12 on eosinophiles, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000;356:2149–2153. doi: 10.1016/S0140-6736(00)03497-8. [DOI] [PubMed] [Google Scholar]
- 52.The ENFUMOSA Study Group The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Resp J. 2003;22:470–477. doi: 10.1183/09031936.03.00261903. [DOI] [PubMed] [Google Scholar]
- 53.Pizzichini M.M., Pizzichini E., Efthimiadis A., Chauhan A.J., Johnston S.L., Hussack P. Asthma and natural cold. Inflammatory indices in induced sputum: a feasibility study. Am J Resp Crit Care Med. 1998;158:1178–1184. doi: 10.1164/ajrccm.158.4.9712082. [DOI] [PubMed] [Google Scholar]
- 54.Sur S., Crotty T.B., Kephart G.M., Hyma B.A., Colby T.V., Reed C.E. Sudden-onset fatal asthma. A distinct entity with few eosinophiles and relatively more neutrophils in the airway submucosa. Am Rev Respir Dis. 1993;148:713–719. doi: 10.1164/ajrccm/148.3.713. [DOI] [PubMed] [Google Scholar]
- 55.Álvarez F.J., Valenzuela F., Rodríguez J.A., Sánchez R., Tabernero E., Castillo J. Blood levels of eosinophil cationic protein in patients with allergic rhinitis. Evolution after treatment with corticoids. Arch Bronconeumol. 1997;33:6–11. [PubMed] [Google Scholar]
- 56.Álvarez F.J., Rodríguez J.A., Valenzuela F., Capote F., Sánchez R., Castillo J. Inflammation mediators (eosinophilic cationic protein, ECP) in a normal population and in patients with bronchial asthma or allergic rhinitis. Arch Bronconeumol. 1995;31:280–286. [PubMed] [Google Scholar]
- 57.Gibson P.G., Simpson J.L., Saltos N. Heterogeneity of airway inflammation in persistent asthma. Chest. 2001;119:1329–1336. doi: 10.1378/chest.119.5.1329. [DOI] [PubMed] [Google Scholar]
- 58.Pavord I.D., Brightling C.E., Woltmann G., Wardlaw A.J. Non-eosinophilic corticosteroid unresponsive asthma. Lancet. 1999;353:2213–2214. doi: 10.1016/S0140-6736(99)01813-9. [DOI] [PubMed] [Google Scholar]
- 59.Turner M.O., Hussack P., Sears M.R., Dolovich J., Hargreave F.E. Exacerbations of asthma without sputum eosinophilia. Thorax. 1995;50:1057–1061. doi: 10.1136/thx.50.10.1057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Anees W., Huggins V., Pavord I.D., Robertson A.S., Burge P.S. Occupational asthma due to low molecular weight agents:eosinophilic and non-eosinophilic variants. Thorax. 2002;57:231–236. doi: 10.1136/thorax.57.3.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Wenzel S.E., Schwartz L.B., Langmack E.L., Halliday J.L., Trudeau J.B., Gibbs R.L. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999;160:1001–1008. doi: 10.1164/ajrccm.160.3.9812110. [DOI] [PubMed] [Google Scholar]
- 62.Helenius I., Lumme A., Haahtela T. Asthma, airway inflammation and treatment in elite athletes. Sport Med. 2005;35:565–574. doi: 10.2165/00007256-200535070-00002. [DOI] [PubMed] [Google Scholar]
- 63.Lumme A., Haahtela T., Ounap J., Rytilä P., Obase Y., Helenius M. Airway inflammation, bronchial hyperresponsiveness and asthma in elite ice hockey players. Eur Respir J. 2003;22:113–117. doi: 10.1183/09031936.03.00112403. [DOI] [PubMed] [Google Scholar]
- 64.Wenzel S.E., Balzar S., Cundall M., Chu H.W. Subepithelial basement membrane immunoreactivity for matrix, metalloproteinase 9:association with asthma severity, neutrophilic inflammation and wound repair. J Allergy Clin Immunol. 2003;111:1345–1352. doi: 10.1067/mai.2003.1464. [DOI] [PubMed] [Google Scholar]
- 65.Cundall M., Sun Y., Miranda C., Trudeau J.B., Barnes S., Wenzel S.E. Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids. J Allergy Clin Immunol. 2003;112:1064–1071. doi: 10.1016/j.jaci.2003.08.013. [DOI] [PubMed] [Google Scholar]
- 66.Simpson J.L., Scott R., Boyle M.J., Gibson P.G. Inflammatory subtypes in asthma: assessment and identification using sputum. Respirology. 2006;11:54–61. doi: 10.1111/j.1440-1843.2006.00784.x. [DOI] [PubMed] [Google Scholar]
- 67.Douwes J., Gibson P., Pekkanen J., Pearce N. Non-eosinophilic asthma: importance and posible mechanisms. Thorax. 2002;47:643–648. doi: 10.1136/thorax.57.7.643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Janeway C.A., Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216. doi: 10.1146/annurev.immunol.20.083001.084359. [DOI] [PubMed] [Google Scholar]
- 69.Simpson J., Grissell T., Douwes J., Scott R., Boyle M., Gibson P. Innate immune activation in neutrophilic asthma and bronquiectasis. Thorax. 2007;62:211–218. doi: 10.1136/thx.2006.061358. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Tan W.C. Viruses in asthma exacerbations. Curr Opin Pulm Med. 2005;11:21–26. doi: 10.1097/01.mcp.0000146781.11092.0d. [DOI] [PubMed] [Google Scholar]
- 71.Kline J.N., Krieg A.M. Toll-like receptor 9 activation with CpG oligodeoxynucleotides for asthma therapy. Drug News Perspect. 2008;21:434–439. doi: 10.1358/dnp.2008.21.8.1272133. [DOI] [PubMed] [Google Scholar]
- 72.Fonseca D.E., Kline J.N. Use of CpG oligonucleotides in treatment of asthma and allergic disease. Adv Frug Deliv Rev. 2009;61:256–262. doi: 10.1016/j.addr.2008.12.007. [DOI] [PubMed] [Google Scholar]
- 73.Kline J.N. Inmunotherapy of asthma using CpG oligodeoxynucleotides. Immunol Res. 2007;39:279–286. doi: 10.1007/s12026-007-0083-2. [DOI] [PubMed] [Google Scholar]
- 74.Peter Fritsch . Springer; Klinik. Atlas. Berlin: 2004. Dermatologie Venerologie: Grundlagen. [Google Scholar]
- 75.Du Q., Zhou L.F., Chen Z., Gu X.Y., Huang M., Yin K.S. Imiquimod, a toll like receptor 7 ligand, inhibits airway remodeling in a murine model of chronic asthma. Clin Exp Pharmacol Physiol. 2009;36:43–48. doi: 10.1111/j.1440-1681.2008.05027.x. [DOI] [PubMed] [Google Scholar]
- 76.Davila S., Hibberd M., Hari R., Wong H., Sahiratmadja E., Bonnard C. Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis. PLoS Genet. 2008;4:e1000218. doi: 10.1371/journal.pgen.1000218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Imai Y., Kuba K., Neely G., Yaghubian-Malhami R., PerKmann T., Loo G. Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133:235–249. doi: 10.1016/j.cell.2008.02.043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Murray L., Knight D., McAlonan L., Argentieri R., Joshi A., Shaheen F. Deleterious role of TLR3 during hyperoxia-induced acute lung injury. Am J Respir Crit Care Med. 2008;178:1227–1237. doi: 10.1164/rccm.200807-1020OC. [DOI] [PubMed] [Google Scholar]
- 79.Wong J.P., Christopher M.F., Viswanathan S., Karpoff N., Dai X., Das D. Activation of toll-like receptor signaling pathway for protection against influenza virus infection. Vaccine. 2009;27:3481–3483. doi: 10.1016/j.vaccine.2009.01.048. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Sarir H., Henricks P.A., Van Houwelingen A.H., Nijkamp F.P., Folkerts G. Cells, mediators and toll-like receptors in COPD. Eur J Pharmacol. 2008;585:346–353. doi: 10.1016/j.ejphar.2008.03.009. [DOI] [PubMed] [Google Scholar]
- 81.Rennard S.I., Vestbo J. COPD: the dangerous underestimate of 15% Lancet. 2006;367:1216–1219. doi: 10.1016/S0140-6736(06)68516-4. [DOI] [PubMed] [Google Scholar]
- 82.Devereux G. ABC of chronic obstructive pulmonary disease. Definition, epidemiology, and risk factors. BMJ. 2006;332:1142–1144. doi: 10.1136/bmj.332.7550.1142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Martorana P.A., Brand T., Gardi C., Van Even P., De Santi M.M., Calzoni P. The pallid mouse. A model of genetic alpha 1-antitrypsin deficiency. Lab Invest. 1993;68:233–241. [PubMed] [Google Scholar]
- 84.Hautamaki R.D., Kobayashi D.K., Senior R.M., Shapiro S.D. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science. 1997;277:2002–2004. doi: 10.1126/science.277.5334.2002. [DOI] [PubMed] [Google Scholar]
- 85.Kuro-o M., Matsumura Y., Aizawa H., Kawaguchi H., Suga T., Utsugi T. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51. doi: 10.1038/36285. [DOI] [PubMed] [Google Scholar]
- 86.Wert S.E., Yoshida M., LeVine A.M., Ikegami M., Jones T., Ross G.F. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc Natl Acad Sci U S A. 2000;97:5972–5977. doi: 10.1073/pnas.100448997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Smith C.A., Harrison D.J. Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema. Lancet. 1997;350:630–633. doi: 10.1016/S0140-6736(96)08061-0. [DOI] [PubMed] [Google Scholar]
- 88.Rangasamy T., Cho C.Y., Thimmulappa R.K., Zhen L., Srisuma S.S., Kensler T.W. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest. 2004;114:1248–1259. doi: 10.1172/JCI21146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2:50–60. doi: 10.1513/pats.200411-056SF. [DOI] [PubMed] [Google Scholar]
- 90.Zhang X., Shan P., Jiang G., Cohn L., Lee P. Research article. Toll-like receptor 4 deficiency causes pulmonary emphysema. J Clin Invest. 2006;116:3050–3059. doi: 10.1172/JCI28139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Fuchs B., Braun A. Modulation of asthma and allergy by addressing toll-like receptor 2. J Occup Med Toxicol. 2008;3(Suppl I):S5. doi: 10.1186/1745-6673-3-S1-S5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Pons J., Sauleda J., Regueiro V., Santos C., López M., Ferrer J. Expression of toll-like receptor 2 is up-regulated in monocytes from patients with chronic obstructive pulmonary disease. Respir Res. 2006;7:64. doi: 10.1186/1465-9921-7-64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Paul-Clark M.J., McMaster S.K., Sorrentino R., Sriskandan S., Bailey L.K., Moreno L. Toll-like receptor 2 is essential for the sensing of oxidants during inflammation. Am J Respir Crit Care Med. 2009;179:299–306. doi: 10.1164/rccm.200707-1019OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Droemann D., Goldmann T., Tiedje T., Zabel P., Dalhoff K., Schaaf B. Toll-like receptor 2 expression is decreased on alveolar macrophages in cigarette smokers and COPD patients. Respir Res. 2005;6:68. doi: 10.1186/1465-9921-6-68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Zhou M., Wan H.Y., Huang S.G., Li B., Li M. Expression of toll-like receptor 4 in human alveolar epithelial cells and its role in cellular inflammation. Zhoghua Y Xue Za Zhi. 2008;88:2112–2116. [PubMed] [Google Scholar]
- 96.Pons J., Sauleda J., Regueiro V., Santos C., López M., Ferrer J. Expression of toll-like receptor 2 is up-regulated in monocytes from patients with chronic obstructive pulmonary disease. Respir Res. 2006;7:64. doi: 10.1186/1465-9921-7-64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Doz E., Noulin N., Boichot E., Guénon I., Fick L., Le Bert M. Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent. J Immunol. 2008;180:1169–1178. doi: 10.4049/jimmunol.180.2.1169. [DOI] [PubMed] [Google Scholar]
- 98.Noakers P.S., Hale J., Thomas R., Lane C., Devadason S.G., Prescott S.L. Maternal smoking is associated with impaired neonatal toll-like receptor mediated immune responses. Eur Respir J. 2006;28:675–677. doi: 10.1183/09031936.06.00050206. [DOI] [PubMed] [Google Scholar]
- 99.Hoffjan S., Stemmler S., Parwez Q., Petrasch-Parwez E., Umut A., Rohde G. Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease. BMC Med Genet. 2005;6:34. doi: 10.1186/1471-2350-6-34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Meyers D.A., Larj M.J., Lange L. Genetics of asthma and COPD. Similar results for different phenotypes. Chest. 2004;126:105S–1010S. doi: 10.1378/chest.126.2_suppl_1.105S. [DOI] [PubMed] [Google Scholar]
- 101.Homma T., Kato A., Hashimoto N., Batchelor J., Yoshikawa M., Imai S. Corticosteroid and cytokines synergistically enhance toll-like receptor 2 expression in respiratory epithelial cells. Am J Respir Cell Mol Biol. 2004;31:463–469. doi: 10.1165/rcmb.2004-0161OC. [DOI] [PubMed] [Google Scholar]
- 102.Blohmake C.J., Victor R.E., Hirschfeld A.F., Elias I.M., Hancock D.G., Lane C.R. Innate immunity mediated by TLR5 as a novel antiinflamatory target for cystic fibrosis lung disease. J Immunol. 2008;180:7764–7773. doi: 10.4049/jimmunol.180.11.7764. [DOI] [PubMed] [Google Scholar]
- 103.Koller B., Kappler M., Latzin P., Gaggar A., Schreiner M., Takyar S. TLR expression on neutrophils at the pulmonary site of infection: TLR1/TLR2-mediated up-regulation of TLR5 expression in cystic fibrosis lung disease. J Immunol. 2008;181:2753–2763. doi: 10.4049/jimmunol.181.4.2753. [DOI] [PubMed] [Google Scholar]
- 104.Greene C., Branagan P., McElvaney N. Toll-like receptors as therapeutic targets in cystic fibrosis. Expert Opin Ther Targets. 2008;12:1481–1495. doi: 10.1517/14728220802515293. [DOI] [PubMed] [Google Scholar]
- 105.Vaneker M., Joosten L., Heuks L., Snijdelaar D., Halbertsma F., Egmond J. Low-tidal-volume mechanical ventilation induces a toll like receptor 4-dependent inflammatory response in healthy mice. Anesthesiology. 2008;109:465–472. doi: 10.1097/ALN.0b013e318182aef1. [DOI] [PubMed] [Google Scholar]
