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Expert Opinion on Therapeutic Targets Volume 12, 2008 - Issue 12
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Reviews

Toll-like receptors as therapeutic targets in cystic fibrosis

Catherine M Greene Senior Lecturer in Medicine Beaumont Hospital, Education and Research Centre, Royal College of Surgeons in Ireland, Respiratory Research Division, 9 Dublin, Ireland +01 8093712; +01 8093808; [email protected]
, BA PhD,
Peter Branagan Specialist Registrar in Respiratory Medicine
, MB BCh BAO &
Noel G McElvaney Professor of Medicine and Consultant Respiratory Physician
, MB BCh BAO FRCPI, FRCPC
Pages 1481-1495 | Published online: 13 Nov 2008

Bibliography

  • Tsui LC, Buchwald M. Biochemical and molecular genetics of cystic fibrosis. Adv Hum Genet 1991;20:153-266,311-2
  • Welsh MJ, Fick RB. Cystic fibrosis. J Clin Invest 1987;80(6):1523-6
  • Hoiby N. Cystic fibrosis and endobronchial Pseudomonas. infection. Curr Opin Pediatr 1993;5(3):247-54
  • Davis PB. Cystic fibrosis since 1938. Am J Respir Crit Care Med 2006;173(5):475-82
  • Lemaitre B, Nicolas E, Michaut L, et al. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86(6):973-83
  • Gay NJ, Keith FJ. Drosophila. Toll and IL-1 receptor. Nature 1991;351(6325):355-6
  • Akira S, Hemmi H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 2003;85(2):85-95
  • O'Neill LA, Greene C. Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J Leukoc Biol 1998;63(6):650-7
  • O'Neill LA. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr Top Microbiol Immunol 2002;270:47-61
  • Bell JK, Mullen GE, Leifer CA, et al. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol 2003;24(10):528-33
  • Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998;282(5396):2085-8
  • Malley R, Henneke P, Morse SC, et al. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc Natl Acad Sci USA 2003;100(4):1966-71
  • Gomi K, Kawasaki K, Kawai Y, et al. Toll-like receptor 4-MD-2 complex mediates the signal transduction induced by flavolipin, an amino acid-containing lipid unique to Flavobacterium meningosepticum. J Immunol 2002;168(6):2939-43
  • Kurt-Jones EA, Popova L, Kwinn L, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 2000;1(5):398-401
  • Rassa JC, Meyers JL, Zhang Y, et al. Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci USA 2002;99(4):2281-6
  • Sasu S, LaVerda D, Qureshi N, et al. Chlamydia pneumoniae and chlamydial heat shock protein 60 stimulate proliferation of human vascular smooth muscle cells via toll-like receptor 4 and p44/p42 mitogen-activated protein kinase activation. Circ Res 2001;89(3):244-50
  • Jiang D, Liang J, Fan J, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 2005;11(11):1173-9
  • Devaney JM, Greene CM, Taggart CC, et al. Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4. FEBS Lett 2003;544(1-3):129-32
  • Armstrong L, Medford AR, Uppington KM, et al. Expression of functional toll-like receptor-2 and -4 on alveolar epithelial cells. Am J Respir Cell Mol Biol.2004;31(2):241-5
  • Chu HW, Jeyaseelan S, Rino JG, et al. TLR2 signaling is critical for Mycoplasma pneumoniae-induced airway mucin expression. J Immunol 2005;174(9):5713-9
  • Gon Y, Asai Y, Hashimoto S, et al. A20 inhibits toll-like receptor 2- and 4-mediated interleukin-8 synthesis in airway epithelial cells. Am J Respir Cell Mol Biol 2004;31(3):330-6
  • Wetzler LM. The role of Toll-like receptor 2 in microbial disease and immunity. Vaccine 2003;21(Suppl 2):S55-60
  • Schmeck B, Huber S, Moog K, et al. Pneumococci induced TLR- and Rac1-dependent NF-κB-recruitment to the IL-8 promoter in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 2006;290(4):L730-7
  • Takeuchi O, Kawai T, Muhlradt PF, et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 2001;13(7):933-40
  • Adamo R, Sokol S, Soong G, et al. Pseudomonas aeruginosa flagella activate airway epithelial cells through asialoGM1 and toll-like receptor 2 as well as toll-like receptor 5. Am J Respir Cell Mol Biol 2004;30(5):627-34
  • Hewson CA, Jardine A, Edwards MR, et al. Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells. J Virol 2005;79(19):12273-9
  • Ritter M, Mennerich D, Weith A, et al. Characterization of Toll-like receptors in primary lung epithelial cells: strong impact of the TLR3 ligand poly(I:C) on the regulation of Toll-like receptors, adaptor proteins and inflammatory response. J Inflamm (Lond) 2005;2(1):16
  • Mayer AK, Muehmer M, Mages J, et al. Differential recognition of TLR-dependent microbial ligands in human bronchial epithelial cells. J Immunol 2007;178(5):3134-42
  • Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002;3(2):196-200
  • Jurk M, Heil F, Vollmer J, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 2002;3(6):499
  • Diebold SS, Kaisho T, Hemmi H, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004;303(5663):1529-31
  • Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004;303(5663):1526-9
  • Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000;408(6813):740-5
  • Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001;410(6832):1099-103
  • Hawn TR, Verbon A, Lettinga KD, et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J Exp Med 2003;198(10):1563-72.
  • Lopez-Boado YS, Cobb LM, Deora R. Bordatella bronchiseptica flagellin is a proinflammatory determinant for airway epithelial cells. Infect Immun 2005;73(11):7525-34
  • Sadikot RT, Blackwell TS, Christman JW, et al. Pathogen-host interactions in Pseudomonas aeruginosa pneumonia. Am J Respir Crit Care Med 2005;171(11):1209-23
  • Zhang Z, Louboutin JP, Weiner DJ, et al. Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5. Infect Immun 2005;73(11):7151-60
  • Hasan U, Chaffois C, Gaillard C, et al. Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol 2005;174(5):2942-50
  • Yamamoto M, Takeda K, Akira S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol 2004;40(12):861-8
  • Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4(7):499-511
  • Yamamoto M, Sato S, Hemmi H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003;301(5633):640-3
  • Schroder NW, Pfeil D, Opitz B, et al. Activation of mitogen-activated protein kinases p42/44, p38, and stress-activated protein kinases in myelo-monocytic cells by Treponema lipoteichoic acid. J Biol Chem 2001;276(13):9713-9
  • Nagai Y, Akashi S, Nagafuku M, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol 2002;3(7):667-72
  • Chow JC, Young DW, Golenbock DT, et al. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 1999;274(16):10689-92
  • Medzhitov R, Preston-Hurlburt P, Kopp E, et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 1998;2(2):253-8
  • Fitzgerald KA, Palsson-McDermott EM, Bowie AG et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 2001;413(6851):78-83
  • Horng T, Barton GM, Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2001;2(9):835-41
  • Oshiumi H, Matsumoto M, Funami K, et al. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat Immunol 2003;4(2):161-7
  • Fitzgerald KA, Rowe DC, Barnes BJ, et al. LPS-TLR4 signaling to IRF-3/7 and NF-κB involves the toll adapters TRAM and TRIF. J Exp Med 2003;198(7):1043-55
  • Oshiumi H, Sasai M, Shida K, et al. TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-β. J Biol Chem 2003;278(50):49751-62
  • Yamamoto M, Sato S, Hemmi H et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003;4(11):1144-50
  • Suzuki N, Suzuki S, Duncan GS, et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002;416(6882):750-6
  • Deng L, Wang C, Spencer E, et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 2000;103(2):351-61
  • Wang C, Deng L, Hong M, et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 2001;412(6844):346-51
  • Kawai T, Takeuchi O, Fujita T, et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 2001;167(10):5887-94
  • Sharma S, tenOever BR, Grandvaux N, et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 2003;300(5622):1148-51
  • Greene CM, Carroll TP, Smith SG, et al. TLR-Induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. J Immunol 2005;174(3):1638-46
  • Guillot L, Medjane S, Le-Barillec K, et al. Response of human pulmonary epithelial cells to lipopolysaccharide involves Toll-like receptor 4 (TLR4)-dependent signaling pathways: evidence for an intracellular compartmentalization of TLR4. J Biol Chem 2004;279(4):2712-8
  • Carroll TP, Greene CM, Taggart CC, et al. Viral inhibition of IL-1- and neutrophil elastase-induced inflammatory responses in bronchial epithelial cells. J Immunol 2005;175(11):7594-601
  • Homma T, Kato A, Hashimoto N, et al. Corticosteroid and cytokines synergistically enhance toll-like receptor 2 expression in respiratory epithelial cells. Am J Respir Cell Mol Biol 2004;31(4):463-9
  • Monick MM, Yarovinsky TO, Powers LS, et al. Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin. J Biol Chem 2003;278(52):53035-44
  • Sha Q, Truong-Tran AQ, Plitt JR, et al. Activation of airway epithelial cells by toll-like receptor agonists. Am J Respir Cell Mol Biol 2004;31(3):358-64
  • Hertz CJ, Wu Q, Porter EM, et al. Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human beta defensin-2. J Immunol 2003;171(12):6820-6
  • Wang X, Zhang Z, Louboutin JP, et al. Airway epithelia regulate expression of human β-defensin 2 through Toll-like receptor 2. Faseb J 2003;17(12):1727-9
  • Jia HP, Kline JN, Penisten A, et al. Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2. Am J Physiol Lung Cell Mol Physiol 2004;287(2):L428-37
  • Ohashi K, Burkart V, Flohe S, et al. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 2000;164(2):558-61
  • Okamura Y, Watari M, Jerud ES, et al. The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 2001;276(13):10229-33
  • Taylor KR, Trowbridge JM, Rudisill JA, et al. Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J Biol Chem 2004;279(17):17079-84
  • Vabulas RM, Ahmad-Nejad P, Ghose S, et al. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 2002;277(17):15107-12
  • Vabulas RM, Braedel S, Hilf N, et al. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J Biol Chem 2002;277(23):20847-53
  • Frantz S, Kelly RA, Bourcier T. Role of TLR-2 in the activation of nuclear factor κB by oxidative stress in cardiac myocytes. J Biol Chem 2001;276(7):5197-203
  • Chaudhuri N, Dower SK, Whyte MK, et al. Toll-like receptors and chronic lung disease. Clin Sci (Lond) 2005;109(2):125-33
  • Syhre M, Scotter JM, Chambers ST. Investigation into the production of 2-Pentylfuran by Aspergillus fumigatus and other respiratory pathogens in vitro and human breath samples. Med Mycol 2008;46(3):209-15
  • Schwartz DA, Quinn TJ, Thorne PS, et al. CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract. J Clin Invest 1997;100(1):68-73
  • Wang EE, Prober CG, Manson B, et al. Association of respiratory viral infections with pulmonary deterioration in patients with cystic fibrosis. N Engl J Med 1984;311(26):1653-8
  • Abman SH, Ogle JW, Butler-Simon N, et al. Role of respiratory syncytial virus in early hospitalizations for respiratory distress of young infants with cystic fibrosis. J Pediatr 1988;113(5):826-30
  • Smyth AR, Smyth RL, Tong CY, et al. Effect of respiratory virus infections including rhinovirus on clinical status in cystic fibrosis. Arch Dis Child 1995;73(2):117-20
  • Hiatt PW, Grace SC, Kozinetz CA, et al. Effects of viral lower respiratory tract infection on lung function in infants with cystic fibrosis. Pediatrics 1999;103(3):619-26
  • Abman SH, Ogle JW, Harbeck RJ, et al. Early bacteriologic, immunologic, and clinical courses of young infants with cystic fibrosis identified by neonatal screening. J Pediatr 1991;119(2):211-7
  • Armstrong D, Grimwood K, Carlin JB, et al. Severe viral respiratory infections in infants with cystic fibrosis. Pediatr Pulmonol 1998;26(6):371-9
  • Mastronarde JG, Monick MM, Hunninghake GW. Oxidant tone regulates IL-8 production in epithelium infected with respiratory syncytial virus. Am J Respir Cell Mol Biol 1995;13(2):237-44
  • Ohrui T, Yamaya M, Sekizawa K, et al. Effects of rhinovirus infection on hydrogen peroxide-induced alterations of barrier function in the cultured human tracheal epithelium. Am J Respir Crit Care Med 1998;158(1):241-8
  • Walsh JJ, Dietlein LF, Low FN, et al. Bronchotracheal response in human influenza. Type A, Asian strain, as studied by light and electron microscopic examination of bronchoscopic biopsies. Arch Intern Med 1961;108:376-88
  • Winther B, Gwaltney JM, Hendley JO. Respiratory virus infection of monolayer cultures of human nasal epithelial cells. Am Rev Respir Dis 1990;141(4 Pt 1):839-45
  • Hament JM, Kimpen JL, Fleer A, et al. Respiratory viral infection predisposing for bacterial disease: a concise review. FEMS Immunol Med Microbiol 1999;26(3-4):189-95
  • Van Ewijk BE, Wolfs TF, Aerts PC, et al. RSV mediates Pseudomonas aeruginosa binding to cystic fibrosis and normal epithelial cells. Pediatr Res 2007;61(4):398-403
  • Oliver BG, Lim S, Wark P, et al. Rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages. Thorax 2008;63(6):519-25
  • Dharmaj P,Tan A, Smyth R. Vaccines for preventing influenza in people with cystic fibrosis. Cochrane Database Syst Rev2000(2):CD001753. Published online 24 January 2000, doi:10.1002/14651858.CD001753
  • Wat D, Gelder C, Hibbitts S, et al. Is there a role for influenza vaccination in cystic fibrosis? J Cyst Fibros 2008;7(1):85-8
  • Fiore AE, Shay DK, Haber P, et al. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep 2007;56(RR-6):1-54
  • Antiviral therapy and prophylaxis for influenza in children. Pediatrics 2007;119(4):852-60
  • O'Reilly SM, Moynagh PN. Regulation of Toll-like receptor 4 signalling by A20 zinc finger protein. Biochem Biophys Res Commun 2003;303(2):586-93
  • Boone DL, Turer EE, Lee EG, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 2004;5(10):1052-60
  • Yokota S, Okabayashi T, Yokosawa N, et al. Measles virus P protein suppresses Toll-like receptor signal through up-regulation of ubiquitin-modifying enzyme A20. FASEB J 2008;22(1):74-83
  • Burns K, Clatworthy J, Martin L, et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol 2000;2(6):346-51
  • Zhang G, Ghosh S. Negative regulation of toll-like receptor-mediated signaling by Tollip. J Biol Chem 2002;277(9):7059-65
  • Mantovani A, Locati M, Polentarutti N, et al. Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR. J Leukoc Biol 2004;75(5):738-42
  • Burns K, Janssens S, Brissoni B, et al. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med 2003;197(2):263-8
  • Wesche H, Gao X, Li X, et al. IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J Biol Chem 1999;274(27):19403-10
  • Kobayashi K, Hernandez LD, Galan JE, et al. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 2002;110(2):191-202
  • Rothlin CV, Ghosh S, Zuniga EI, et al. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 2007;131(6):1124-36
  • Carty M, Goodbody R, Schroder M, et al. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol 2006;7(10):1074-81
  • An H, Hou J, Zhou J, et al. Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1. Nat Immunol 2008;9(5):542-50
  • Xu H, An H, Hou J, et al. Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages. Mol Immunol 2008;45(13):3545-52
  • Kato K, Lu W, Kai H, et al. Phosphoinositide 3-kinase is activated by MUC1 but not responsible for MUC1-induced suppression of Toll-like receptor 5 signaling. Am J Physiol Lung Cell Mol Physiol 2007;293(3):L686-92
  • Ueno K, Koga T, Kato K, et al. MUC1 mucin is a negative regulator of toll-like receptor signaling. Am J Respir Cell Mol Biol 2008;38(3):263-8
  • Appel S, Mirakaj V, Bringmann A, et al. PPAR-γ agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-κB pathways. Blood 2005;106(12):3888-94
  • Bowie A, Kiss-Toth E, Symons JA, et al. A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. Proc Natl Acad Sci USA 2000;97(18):10162-7
  • Stack J, Haga IR, Schroder M, et al. Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J Exp Med 2005;201(6):1007-18
  • DiPerna G, Stack J, Bowie AG, et al. Poxvirus protein N1L targets the I-κB kinase complex, inhibits signaling to NF-κB by the tumor necrosis factor superfamily of receptors, and inhibits NF-κB and IRF3 signaling by toll-like receptors. J Biol Chem 2004;279(35):36570-8
  • Shingai M, Azuma M, Ebihara T, et al. Soluble G protein of respiratory syncytial virus inhibits Toll-like receptor 3/4-mediated IFN-beta induction. Int Immunol 2008;20(9):1169-80
  • Newman RM, Salunkhe P, Godzik A, et al. Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins. Infect Immun 2006;74(1):594-601
  • Salcedo SP, Marchesini MI, Lelouard H, et al. Brucella control of dendritic cell maturation is dependent on the TIR-containing protein Btp1. PLoS Pathog 2008;4(2):e21
  • Cirl C, Wieser A, Yadav M, et al. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat Med 2008;14(4):399-406
  • Bartfai T, Behrens MM, Gaidarova S, et al. A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses. Proc Natl Acad Sci USA 2003;100(13):7971-6
  • Davis CN, Mann E, Behrens MM, et al. MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics. Proc Natl Acad Sci USA 2006;103(8):2953-8
  • Toshchakov VY, Vogel SN. Cell-penetrating TIR BB loop decoy peptides a novel class of TLR signaling inhibitors and a tool to study topology of TIR–TIR interactions. Expert Opin Biol Ther 2007;7(7):1035-50
  • Thompson RC, Ohlsson K. Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci USA 1986;83(18):6692-6
  • Bingle L, Tetley TD. Secretory leukoprotease inhibitor: partnering α1-proteinase inhibitor to combat pulmonary inflammation. Thorax 1996;51(12):1273-4
  • Doumas S, Kolokotronis A, Stefanopoulos P. Anti-inflammatory and antimicrobial roles of secretory leukocyte protease inhibitor. Infect Immun 2005;73(3):1271-4
  • Hiemstra PS, Fernie-King BA, McMichael J, et al. Antimicrobial peptides: mediators of innate immunity as templates for the development of novel anti-infective and immune therapeutics. Curr Pharm Des 2004;10(23):2891-905
  • Williams SE, Brown TI, Roghanian A, et al. SLPI and elafin: one glove, many fingers. Clin Sci (Lond) 2006;110(1):21-35
  • Wiedow O, Harder J, Bartels J, et al. Antileukoprotease in human skin: an antibiotic peptide constitutively produced by keratinocytes. Biochem Biophys Res Commun 1998;248(3):904-9
  • McNeely TB, Dealy M, Dripps DJ, et al. Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro J Clin Invest 1995;96(1):456-64
  • Greene CM, McElvaney NG, O'Neill SJ, et al. Secretory leucoprotease inhibitor impairs Toll-like receptor 2- and 4-mediated responses in monocytic cells. Infect Immun 2004;72(6):3684-7
  • Jin F, Nathan CF, Radzioch D, et al. Lipopolysaccharide-related stimuli induce expression of the secretory leukocyte protease inhibitor, a macrophage-derived lipopolysaccharide inhibitor. Infect Immun 1998;66(6):2447-52
  • Taggart CC, Greene CM, McElvaney NG, et al. Secretory leucoprotease inhibitor prevents lipopolysaccharide-induced IκBα degradation without affecting phosphorylation or ubiquitination. J Biol Chem 2002;277(37):33648-53
  • Taggart CC, Cryan SA, Weldon S, et al. Secretory leucoprotease inhibitor binds to NF-κB binding sites in monocytes and inhibits p65 binding. J Exp Med 2005;202(12):1659-68
  • Tomee JF, Hiemstra PS, Heinzel-Wieland R, et al. Antileukoprotease: an endogenous protein in the innate mucosal defense against fungi. J Infect Dis 1997;176(3):740-7
  • Tomee JF, Wierenga AT, Hiemstra PS, et al. Proteases from Aspergillus fumigatus induce release of proinflammatory cytokines and cell detachment in airway epithelial cell lines. J Infect Dis 1997;176(1):300-3
  • Griffin S, Carroll TP, Greene CM, et al. Effect of pro-inflammatory stimuli on mucin expression and inhibition by secretory leucoprotease inhibitor. Cell Microbiol 2007;9(3):670-9
  • Sallenave JM, Marsden MD, Ryle AP. Isolation of elafin and elastase-specific inhibitor (ESI) from bronchial secretions. Evidence of sequence homology and immunological cross-reactivity. Biol Chem Hoppe Seyler 1992;373(1):27-33
  • Guyot N, Zani ML, Berger P, et al. Proteolytic susceptibility of the serine protease inhibitor trappin-2 (pre-elafin): evidence for tryptase-mediated generation of elafin. Biol Chem 2005;386(4):391-9
  • Sallenave JM, Shulmann J, Crossley J, et al. Regulation of secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (ESI/elafin) in human airway epithelial cells by cytokines and neutrophilic enzymes. Am J Respir Cell Mol Biol 1994;11(6):733-41
  • Butler MW, Robertson I, Greene CM, et al. Elafin prevents lipopolysaccharide-induced AP-1 and NF-κB activation via an effect on the ubiquitin-proteasome pathway. J Biol Chem 2006;281(46):34730-5
  • Baranger K, Zani ML, Chandenier J, et al. The antibacterial and antifungal properties of trappin-2 (pre-elafin) do not depend on its protease inhibitory function. FEBS J 2008;275(9):2008-20
  • Janciauskiene S, Larsson S, Larsson P, et al. Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by α1-antitrypsin. Biochem Biophys Res Commun 2004;321(3):592-600
  • Subramaniyam D, Glader P, von Wachenfeldt K, et al. C-36 peptide, a degradation product of α1-antitrypsin, modulates human monocyte activation through LPS signaling pathways. Int J Biochem Cell Biol 2006;38(4):563-75
  • Matthews LW, Doershuk CF. Inhalation therapy and postural drainage for the treatment of cystic fibrosis. Bibl Paediatr 1967;86:297-314
  • Spencer LT, Humphries JE, Brantly ML. Antibody response to aerosolized transgenic human alpha1-antitrypsin. N Engl J Med 2005;352(19):2030-1
  • Kudoh S, Azuma A, Yamamoto M, et al. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med 1998;157(6 Pt 1):1829-32
  • Wolter J, Seeney S, Bell S, et al. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002;57(3):212-6
  • Equi A, Balfour-Lynn IM, Bush A, et al. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 2002;360(9338):978-84
  • Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. Jama 2003;290(13):1749-56
  • Saiman L. The use of macrolide antibiotics in patients with cystic fibrosis. Curr Opin Pulm Med 2004;10(6):515-23
  • Cigana C, Assael BM, Melotti P. Azithromycin selectively reduces tumor necrosis factor alpha levels in cystic fibrosis airway epithelial cells. Antimicrob Agents Chemother 2007;51(3):975-81
  • Aghai ZH, Kode A, Saslow JG, et al. Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants. Pediatr Res 2007;62(4):483-8
  • Ivetic Tkalcevic V, Bosnjak B, Hrvacic B, et al. Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice. Eur J Pharmacol 2006;539(1-2):131-8
  • Kawamura-Sato K, Iinuma Y, Hasegawa T, et al. Effect of subinhibitory concentrations of macrolides on expression of flagellin in Pseudomonas aeruginosa and Proteus mirabilis. Antimicrob Agents Chemother 2000;44(10):2869-72
  • Kawamura-Sato K, Iinuma Y, Hasegawa T, et al. Postantibiotic suppression effect of macrolides on the expression of flagellin in Pseudomonas aeruginosa and Proteus mirabilis. J Infect Chemother 2001;7(1):51-4
  • Matsui H, Eguchi M, Ohsumi K, et al. Azithromycin inhibits the formation of flagellar filaments without suppressing flagellin synthesis in Salmonella enterica serovar typhimurium. Antimicrob Agents Chemother 2005;49(8):3396-403
  • Rozkova D, Horvath R, Bartunkova J, et al. Glucocorticoids severely impair differentiation and antigen presenting function of dendritic cells despite upregulation of Toll-like receptors. Clin Immunol 2006;120(3):260-71
  • Eng PA, Morton J, Douglass JA, et al. Short-term efficacy of ultrasonically nebulized hypertonic saline in cystic fibrosis. Pediatr Pulmonol 1996;21(2):77-83
  • Ballmann M, von der Hardt H. Hypertonic saline and recombinant human DNase: a randomised cross-over pilot study in patients with cystic fibrosis. J Cyst Fibros 2002;1(1):35-7
  • Chen LW, Huang HL, Lee IT, et al. Hypertonic saline enhances host defense to bacterial challenge by augmenting Toll-like receptors. Crit Care Med 2006;34(6):1758-68
  • Ranasinha C, Assoufi B, Shak S, et al. Efficacy and safety of short-term administration of aerosolised recombinant human DNase I in adults with stable stage cystic fibrosis. Lancet 1993;342(8865):199-202
  • Ramsey BW, Astley SJ, Aitken ML, et al. Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. Am Rev Respir Dis 1993;148(1):145-51
  • Dawson M, Wirtz D, Hanes J. Enhanced viscoelasticity of human cystic fibrotic sputum correlates with increasing microheterogeneity in particle transport. J Biol Chem 2003;278(50):50393-401
  • Suh J, Dawson M, Hanes J. Real-time multiple-particle tracking: applications to drug and gene delivery. Adv Drug Deliv Rev 2005;57(1):63-78
  • Fink TL, Klepcyk PJ, Oette SM, et al. Plasmid size up to 20 kbp does not limit effective in vivo lung gene transfer using compacted DNA nanoparticles. Gene Ther 2006;13(13):1048-51
  • Ku CL, von Bernuth H, Picard C, et al. Selective predisposition to bacterial infections in IRAK-4-deficient children:IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med 2007;204(10):2407-22
  • Le Goffic R, Balloy V, Lagranderie M, et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog 2006;2(6):e53

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