Respiratory tract antimicrobial defense system: Difference between revisions
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The respiratory tract antimicrobial defense system is a layered defense mechanism which relies on components of both the innate and adaptive immune systems to protect the lungs and the rest of the respiratory tract against inhaled microorganisms.
In the first line of defense, inhaled bacteria are trapped by mucous and are swept toward the pharynx and are swallowed.[1] Bacteria which penetrate the mucous layer are dealt with a second line of defense which includes antimicrobial peptides that are secreted by the surface epithelium of the respiratory tract which kill many strains of bacteria.[2] Those bacteria that are resistant to antimicrobial peptides are killed by a variety of reactive oxygen species produced by phagocytes. As a last resort, persistent bacterial infections which escape the innate immune system are dealt with by the adaptive immune system.
Lactoferrin
Lactoferrin (LF) is a multifunctional protein which is an essential part of the respiratory tract antimicrobial defense system.[3] LF proteolysis produces the small peptides lactoferricin and kaliocin-1 both with antimicrobial activity.[4]
Reactive oxygen species
Phagocytes possess a superoxide-producing NADPH oxidase enzyme complex.[5] Other cells in the respiratory tract also produce superoxide through the activity of dual oxidase 2 proteins, also known as Duox2.[6][7]
The superoxide generated by these enzymes complexes dismutates into hydrogen peroxide which in turn is used by myeloperoxidase to produce bactericidal hypochlorous acid.[8] In addition, the submucosal glands of the respiratory tract secrete a myeloperoxidase homolog called lactoperoxidase (LPO)[9] that catalyzes the oxidation of thiocyanate to the the antimicrobial hypothiocyanite.[10][11]
The reactive oxygen species produced by the lactoperoxidase system does not attack DNA and is not mutagenic and is known to be safe.[12] Hypothiocyanite generated through this pathway displays broad spectrum bactericidal activity including potent antibacterial action on H. pylori.[13]
Cystic fibrosis
Thiocyanate secretion[14] in cystic fibrosis patients is decreased resulting in a reduced production of the antimicrobial hypothiocyanite and consequently contributes to the increased risk of airway infection.[15][16]
Therapeutic applications
Lactoferrin with hypothiocyanite for the treatment of cystic fibrosis has been been granted orphan drug status by the EMEA[17] and the FDA.[18]
References
- ^ Boucher RC (2003). "Regulation of airway surface liquid volume by human airway epithelia". Pflugers Arch. 445 (4): 495–8. doi:10.1007/s00424-002-0955-1. PMID 12548395.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Ganz T (2002). "Antimicrobial polypeptides in host defense of the respiratory tract". J. Clin. Invest. 109 (6): 693–7. doi:10.1172/JCI15218. PMC 150915. PMID 11901174.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Sánchez L, Calvo M, Brock JH (1992). "Biological role of lactoferrin". Arch. Dis. Child. 67 (5): 657–61. PMC 1793702. PMID 1599309.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Tomita M, Takase M, Bellamy W, Shimamura S (1994). "A review: the active peptide of lactoferrin". Acta Paediatr Jpn. 36 (5): 585–91. PMID 7825467.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Nauseef WM (2004). "Assembly of the phagocyte NADPH oxidase". Histochem. Cell Biol. 122 (4): 277–91. doi:10.1007/s00418-004-0679-8. PMID 15293055.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Thomas EL, Bates KP, Jefferson MM (1980). "Hypothiocyanite ion: detection of the antimicrobial agent in human saliva". J. Dent. Res. 59 (9): 1466–72. PMID 6931123.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Thomas EL, Aune TM (1978). "Lactoperoxidase, peroxide, thiocyanate antimicrobial system: correlation of sulfhydryl oxidation with antimicrobial action". Infect. Immun. 20 (2): 456–63. PMC 421877. PMID 352945.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Klebanoff SJ (2005). "Myeloperoxidase: friend and foe". J. Leukoc. Biol. 77 (5): 598–625. doi:10.1189/jlb.1204697. PMID 15689384.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Wijkstrom-Frei C, El-Chemaly S, Ali-Rachedi R, Gerson C, Cobas MA, Forteza R, Salathe M, Conner GE (2003). "Lactoperoxidase and human airway host defense". Am. J. Respir. Cell Mol. Biol. 29 (2): 206–12. doi:10.1165/rcmb.2002-0152OC. PMID 12626341.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Conner GE, Salathe M, Forteza R (2002). "Lactoperoxidase and hydrogen peroxide metabolism in the airway". Am. J. Respir. Crit. Care Med. 166 (12 Pt 2): S57–61. doi:10.1164/rccm.2206018. PMID 12471090.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Conner GE, Wijkstrom-Frei C, Randell SH, Fernandez VE, Salathe M (2007). "The lactoperoxidase system links anion transport to host defense in cystic fibrosis". FEBS Lett. 581 (2): 271–8. doi:10.1016/j.febslet.2006.12.025. PMC 1851694. PMID 17204267.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ White WE, Pruitt KM, Mansson-Rahemtulla B (1983). "Peroxidase-thiocyanate-peroxide antibacterial system does not damage DNA". Antimicrob. Agents Chemother. 23 (2): 267–72. PMC 186035. PMID 6340603.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Haukioja A, Ihalin R, Loimaranta V, Lenander M, Tenovuo J (2004). "Sensitivity of Helicobacter pylori to an innate defence mechanism, the lactoperoxidase system, in buffer and in human whole saliva". J. Med. Microbiol. 53 (Pt 9): 855–60. PMID 15314191.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Xu Y, Szép S, Lu Z (2009). "The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases". Proc. Natl. Acad. Sci. U.S.A. 106 (48): 20515–9. doi:10.1073/pnas.0911412106. PMC 2777967. PMID 19918082.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B (2007). "A novel host defense system of airways is defective in cystic fibrosis". Am. J. Respir. Crit. Care Med. 175 (2): 174–83. doi:10.1164/rccm.200607-1029OC. PMC 2720149. PMID 17082494.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Minarowski Ł, Sands D, Minarowska A, Karwowska A, Sulewska A, Gacko M, Chyczewska E (2008). "Thiocyanate concentration in saliva of cystic fibrosis patients". Folia Histochem. Cytobiol. 46 (2): 245–6. doi:10.2478/v10042-008-0037-0. PMID 18519245.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ "Public summary of positive opinion for orphan designation of hypothiocyanite / lactoferrin for the treatment of cystic fibrosis" (PDF). Pre-authorisation Evaluation of Medicines for Human Use. European Medicines Agency. 2009-09-07. Retrieved 2010-01-23.
{{cite web}}: Cite has empty unknown parameter:|coauthors=(help) - ^ "Meveol: orphan drug status granted by the FDA for the treatment of cystic fibrosis". United States Food and Drug Administration. c2009-11-05. Retrieved 2010-01-23.
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