Basis of Susceptibility to Lung Infection

  • Frank C. Schmalstieg
  • Armond S. Goldman
Part of the Molecular Pathology Library book series (MPLB, volume 1)


The myriad microbial pathogens encountered by the lung presents a daunting challenge to the human immune system. Nowhere else in the body is such a vast surface area (approximately 100 m2)1 directly exposed to airborne pathogens at about 20 times per minute. Not only is the area and exposure extreme, but the underlying blood circulation is only two cell layers, of about 0.5 µm each, removed from the alveolar surface. Furthermore, gravity and manifold branching of bronchioles and bronchi interfere with the expulsion of these organisms and tissue debris that occurs during lung infection. It is not surprising, then, that pneumonias are among the most common infectious diseases in the United States.2


Alveolar Macrophage Respir Crit Lung Infection Surfactant Protein Primary Ciliary Dyskinesia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ochs M, Nyengaard JR, Jung A, et al. The number of alveoli in the human lung. Am J Respir Crit Care Med 2004;169:120–124.CrossRefPubMedGoogle Scholar
  2. 2.
    Marston BJ, Plouffe JF, File TM Jr, et al. Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance Study in Ohio. The Community-Based Pneumonia Incidence Study Group. Arch Intern Med 1997;157:1709–1718.CrossRefPubMedGoogle Scholar
  3. 3.
    Charan NB, Turk GM, Dhand R. Gross and subgross anatomy of bronchial circulation in sheep. J Appl Physiol 1984;57:658–664.PubMedGoogle Scholar
  4. 4.
    Doerschuk CM, Beyers N, Coxson HO, et al. Comparison of neutrophil and capillary diameters and their relation to neutrophil sequestration in the lung. J Appl Physiol 1993;74:3040–3045.PubMedGoogle Scholar
  5. 5.
    Hogg JC, Coxson HO, Brumwell ML, et al. Erythrocyte and polymorphonuclear cell transit time and concentration in human pulmonary capillaries. J Appl Physiol 1994;77:1795–1800.PubMedGoogle Scholar
  6. 6.
    Kubo H, Doyle NA, Graham L, et al. L-and P-selectin and CD11/CD18 in intracapillary neutrophil sequestration in rabbit lungs. Am J Respir Crit Care Med 1999;159:267–274.PubMedGoogle Scholar
  7. 7.
    Doerschuk CM. The role of CD18-mediated adhesion in neutrophil sequestration induced by infusion of activated plasma in rabbits. Am J Respir Cell Mol Biol 1992;7:140–148.PubMedGoogle Scholar
  8. 8.
    Stothert JC Jr, Ashley KD, Kramer GC, et al. Intrapulmonary distribution of bronchial blood flow after moderate smoke inhalation. J Appl Physiol 1990;69:1734–1739.PubMedGoogle Scholar
  9. 9.
    Sakurai H, Johnigan R, Kikuchi Y, et al. Effect of reduced bronchial circulation on lung fluid flux after smoke inhalation in sheep. J Appl Physiol 1998;84:980–986.PubMedGoogle Scholar
  10. 10.
    Widdicombe JH, Bastacky SJ, Wu DX, Lee CY. Regulation of depth and composition of airway surface liquid. Eur Respir J 1997;10:2892–2897.CrossRefPubMedGoogle Scholar
  11. 11.
    Afzelius BA, Eliasson R, Johnsen O, Lindholmer C. Lack of dynein arms in immotile human spermatozoa. J Cell Biol 1975;66:225–232.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhan X, Li D, Johns RA. Expression of endothelial nitric oxide synthase in ciliated epithelia of rats. J Histochem Cytochem 2003;51:81–87.PubMedGoogle Scholar
  13. 13.
    Lindberg S, Cervin A, Runer T. Nitric oxide (NO) production in the upper airways is decreased in chronic sinusitis. Acta Otolaryngol 1997;117:113–117.CrossRefPubMedGoogle Scholar
  14. 14.
    Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J 1995;8:1193–1202.CrossRefPubMedGoogle Scholar
  15. 15.
    Addington WR, Stephens RE, Widdicombe JG, Rekab K. Effect of stroke location on the laryngeal cough reflex and pneumonia risk. Cough 2005;1:4.CrossRefPubMedGoogle Scholar
  16. 16.
    Molina H, Holers VM, Li B, Fung Y, et al. Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc Natl Acad Sci USA 1996;93:3357–3361.CrossRefPubMedGoogle Scholar
  17. 17.
    Kaya Z, Afanasyeva M, Wang Y, et al. Contribution of the innate immune system to autoimmune myocarditis: a role for complement. Nat Immunol 2001;2:739–745.CrossRefPubMedGoogle Scholar
  18. 18.
    Kerr AR, Paterson GK, Riboldi-Tunnicliffe A, Mitchell TJ. Innate immune defense against pneumococcal pneumonia requires pulmonary complement component C3. Infect Immun 2005;73:4245–4252.CrossRefPubMedGoogle Scholar
  19. 19.
    Knapp S, Leemans JC, Florquin S, et al. Alveolar macrophages have a protective antiinflammatory role during murine pneumococcal pneumonia. Am J Respir Crit Care Med 2003;167:171–179.CrossRefPubMedGoogle Scholar
  20. 20.
    Geertsma MF, Nibbering PH, Haagsman HP, et al. Binding of surfactant protein A to C1q receptors mediates phagocytosis of Staphylococcus aureus by monocytes. Am J Physiol 1994;267:L578–L584.PubMedGoogle Scholar
  21. 21.
    van Iwaarden F, Welmers B, Verhoef J, et al. Pulmonary surfactant protein A enhances the host-defense mechanism of rat alveolar macrophages. Am J Respir Cell Mol Biol 1990;2:91–98.PubMedGoogle Scholar
  22. 22.
    Wu H, Kuzmenko A, Wan S, et al. Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability. J Clin Invest 2003;111:1589–1602.PubMedGoogle Scholar
  23. 23.
    Kuzmenko AI, Wu H, McCormack FX. Pulmonary collectins selectively permeabilize model bacterial membranes containing rough lipopolysaccharide. Biochemistry 2006;45:2679–2685.CrossRefPubMedGoogle Scholar
  24. 24.
    Schagat TL, Wofford JA, Wright JR. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils. J Immunol 2001;166:2727–2733.PubMedGoogle Scholar
  25. 25.
    Noah TL, Murphy PC, Alink JJ, et al. Bronchoalveolar lavage fluid surfactant protein-A and surfactant protein-D are inversely related to inflammation in early cystic fibrosis. Am J Respir Crit Care Med 2003;168:685–691.CrossRefPubMedGoogle Scholar
  26. 26.
    Linke MJ, Harris CE, Korfhagen TR, et al. Immunosuppressed surfactant protein A-deficient mice have increased susceptibility to Pneumocystis carinii infection. J Infect Dis 2001;183:943–952.CrossRefPubMedGoogle Scholar
  27. 27.
    Message SD, Johnston SL. Host defense function of the airway epithelium in health and disease: clinical background. J Leukoc Biol 2004;75:5–17.CrossRefPubMedGoogle Scholar
  28. 28.
    McAllister F, Henry A, Kreindler JL, et al. Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J Immunol 2005;175:404–412.PubMedGoogle Scholar
  29. 29.
    Pier GB, Grout M, Zaidi TS, Goldberg JB. How mutant CFTR may contribute to Pseudomonas aeruginosa infection in cystic fibrosis. Am J Respir Crit Care Med 1996;154:S175–S182.PubMedGoogle Scholar
  30. 30.
    Pier GB, Grout M, Zaidi TS, et al. Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science 1996;271:64–67.CrossRefPubMedGoogle Scholar
  31. 31.
    Darling KE, Dewar A, Evans TJ. Role of the cystic fibrosis transmembrane conductance regulator in internalization of Pseudomonas aeruginosa by polarized respiratory epithelial cells. Cell Microbiol 2004;6:521–533.CrossRefPubMedGoogle Scholar
  32. 32.
    Flaherty DM, Monick MM, Hinde SL. Human alveolar macrophages are deficient in PTEN. The role of endogenous oxidants. J Biol Chem 2006;281:5058–5064.CrossRefPubMedGoogle Scholar
  33. 33.
    Tang TT, Dowbenko D, Jackson A, et al. The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. J Biol Chem 2002;277:14255–14265.CrossRefPubMedGoogle Scholar
  34. 34.
    Platt N, Haworth R, Darley L, Gordon S. The many roles of the class A macrophage scavenger receptor. Int Rev Cytol 2002;212:1–40.CrossRefPubMedGoogle Scholar
  35. 35.
    Pearson AM. Scavenger receptors in innate immunity. Curr Opin Immunol 1996;8:20–28.CrossRefPubMedGoogle Scholar
  36. 36.
    Teder P, Vandivier RW, Jiang D, et al. Resolution of lung inflammation by CD44. Science 2002;296:155–158.CrossRefPubMedGoogle Scholar
  37. 37.
    Reidy MF, Wright JR. Surfactant protein A enhances apoptotic cell uptake and TGF-beta1 release by inflammatory alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 2003;285:L854–L861.PubMedGoogle Scholar
  38. 38.
    Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 2002;109:41–50.PubMedGoogle Scholar
  39. 39.
    Fadok VA, Bratton DL, Konowal A, et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998;101:890–898.CrossRefPubMedGoogle Scholar
  40. 40.
    Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311:1770–1773.CrossRefPubMedGoogle Scholar
  41. 41.
    Hajjar AM, Harowicz H, Liggitt HD, et al. An essential role for non-bone marrow-derived cells in control of Pseudomonas aeruginosa pneumonia. Am J Respir Cell Mol Biol 2005;33:470–475.CrossRefPubMedGoogle Scholar
  42. 42.
    Dockrell DH, Marriott HM, Prince LR, et al. Alveolar macrophage apoptosis contributes to pneumococcal clearance in a resolving model of pulmonary infection. J Immunol 2003;171:5380–5388.PubMedGoogle Scholar
  43. 43.
    Segal AW. How neutrophils kill microbes. Annu Rev Immunol 2005;23:197–223.CrossRefPubMedGoogle Scholar
  44. 44.
    Chandra A, Katahira J, Schmalstieg FC, et al. P-selectin blockade fails to improve acute lung injury in sheep. Clin Sci (Lond) 2003;104:313–321.CrossRefGoogle Scholar
  45. 45.
    Anderson DC, Miller LJ, Schmalstieg FC, et al. Contributions of the Mac-1 glycoprotein family to adherence-dependent granulocyte functions: structure-function assessments employing subunit-specific monoclonal antibodies. J Immunol 1986;137:15–27.PubMedGoogle Scholar
  46. 46.
    Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301–314.CrossRefPubMedGoogle Scholar
  47. 47.
    Mizgerd JP, Horwitz BH, Quillen HC, et al. Effects of CD18 deficiency on the emigration of murine neutrophils during pneumonia. J Immunol 1999;163:995–999.PubMedGoogle Scholar
  48. 48.
    Sabroe I, Prince LR, Jones EC, et al. Selective roles for Toll-like receptor (TLR)2 and TLR4 in the regulation of neutrophil activation and life span. J Immunol 2003;170:5268–5275.PubMedGoogle Scholar
  49. 49.
    Madden JF, Burchette JL Jr, Hale LP. Pathology of parainfluenza virus infection in patients with congenital immunodeficiency syndromes. Hum Pathol 2004;35:594–603.CrossRefPubMedGoogle Scholar
  50. 50.
    Schmalstieg FC, Goldman AS. Immune consequences of mutations in the human common gamma-chain gene. Mol Genet Metab 2002;76:163–171.CrossRefPubMedGoogle Scholar
  51. 51.
    Schmalstieg FC, Palkowetz KH, Rudloff HE, Goldman AS. Blood gammadelta T cells and gammadelta TCR V gene specificities in a single missense mutation (L→Q271) in the common gamma chain gene. Scand J Immunol 2001;54:592–598.CrossRefPubMedGoogle Scholar
  52. 52.
    Goldman AS, Palkowetz KH, Rudloff HE, et al. Genesis of progressive T-cell deficiency owing to a single missense mutation in the common gamma chain gene. Scand J Immunol 2001;54:582–591.CrossRefPubMedGoogle Scholar
  53. 53.
    Schmalstieg FC, Leonard WJ, Noguchi M, et al. Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency. J Clin Invest 1995;95:1169–1173.CrossRefPubMedGoogle Scholar
  54. 54.
    Fieschi C, Casanova JL. The role of interleukin-12 in human infectious diseases: only a faint signature. Eur J Immunol 2003;33:1461–1464.CrossRefPubMedGoogle Scholar
  55. 55.
    Fallarino F, Gajewski TF. Cutting edge: differentiation of antitumor CTL in vivo requires host expression of Stat1. J Immunol 1999;163:4109–4113.PubMedGoogle Scholar
  56. 56.
    Sun J, Walsh M, Villarino AV, et al. TLR ligands can activate dendritic cells to provide a MyD88-dependent negative signal for Th2 cell development. J Immunol 2005;174:742–751.PubMedGoogle Scholar
  57. 57.
    van Gisbergen KP, Sanchez-Hernandez M, Geijtenbeek TB, van Kooyk Y. Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN. J Exp Med 2005;201:1281–1292.CrossRefPubMedGoogle Scholar
  58. 58.
    van Gisbergen KP, Ludwig IS, Geijtenbeek TB, van Kooyk Y. Interactions of DC-SIGN with Mac-1 and CEACAM1 regulate contact between dendritic cells and neutrophils. FEBS Lett 2005;579:6159–6168.CrossRefPubMedGoogle Scholar
  59. 59.
    Filippi C, Hugues S, Cazareth J, et al. CD4+ T cell polarization in mice is modulated by strain-specific major histocompatibility complex-independent differences within dendritic cells. J Exp Med 2003;198:201–209.CrossRefPubMedGoogle Scholar
  60. 60.
    Moser B, Willimann K. Chemokines: role in inflammation and immune surveillance. Ann Rheum Dis 2004;63Suppl 2:ii84–ii89.CrossRefPubMedGoogle Scholar
  61. 61.
    Langenkamp A, Nagata K, Murphy K, et al. Kinetics and expression patterns of chemokine receptors in human CD4+ T lymphocytes primed by myeloid or plasmacytoid dendritic cells. Eur J Immunol 2003;33:474–482.CrossRefPubMedGoogle Scholar
  62. 62.
    Gavin M, Rudensky A. Control of immune homeostasis by naturally arising regulatory CD4+ T cells. Curr Opin Immunol 2003;15:690–696.CrossRefPubMedGoogle Scholar
  63. 63.
    Wildin RS, Freitas A. IPEX and FOXP3: clinical and research perspectives. J Autoimmun 2005;(Suppl 25):56–62.Google Scholar
  64. 64.
    Chensue SW, Warmington KS, Allenspach EJ, et al. Differential expression and cross-regulatory function of RANTES during mycobacterial (type 1) and schistosomal (type 2) antigen-elicited granulomatous inflammation. J Immunol 1999;163:165–173.PubMedGoogle Scholar
  65. 65.
    Sato N, Kuziel WA, Melby PC, et al. Defects in the generation of IFN-gamma are overcome to control infection with Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage inflammatory protein-1 alpha-, or CCR2-deficient mice. J Immunol 1999;163:5519–5525.PubMedGoogle Scholar
  66. 66.
    Palaniappan R, Singh S, Singh UP, et al. CCL5 modulates pneumococcal immunity and carriage. J Immunol 2006;176:2346–2356.PubMedGoogle Scholar
  67. 67.
    Jakubzick C, Tacke F, Llodra J, et al. Modulation of dendritic cell trafficking to and from the airways. J Immunol 2006;176:3578–3584.PubMedGoogle Scholar
  68. 68.
    van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 2005;97:93–101.CrossRefPubMedGoogle Scholar
  69. 69.
    Bozza S, Gaziano R, Spreca A, et al. Dendritic cells transport conidia and hyphae of Aspergillus fumigatus from the airways to the draining lymph nodes and initiate disparate Th responses to the fungus. J Immunol 2002;168:1362–1371.PubMedGoogle Scholar
  70. 70.
    Puck JM. Molecular and genetic basis of X-linked immunodeficiency disorders. J Clin Immunol 1994;14:81–89.CrossRefPubMedGoogle Scholar
  71. 71.
    Nomura K, Kanegane H, Karasuyama H, et al. Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway. Blood 2000;96:610–617.PubMedGoogle Scholar
  72. 72.
    Weiner LS, Howell JT, Langford MP, et al. Effect of specific antibodies on chronic echovirus type 5 encephalitis in a patient with hypogammaglobulinemia. J Infect Dis 1979;140:858–863.PubMedGoogle Scholar
  73. 73.
    Guilbault C, Novak JP, Martin P, et al. Distinct pattern of lung gene expression in the Cfr-KO mice developing spontaneous lung disease compared to their littermate controls. Physiol Genomics 2006;25:179–193.CrossRefPubMedGoogle Scholar
  74. 74.
    Kiechl S, Lorenz E, Reindl M, et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 2002;347:185–192.CrossRefPubMedGoogle Scholar
  75. 75.
    Schaaf B, Rupp J, Muller-Steinhardt M, et al. The interleukin-6-174 promoter polymorphism is associated with extrapulmonary bacterial dissemination in Streptococcus pneumoniae infection. Cytokine 2005;31:324–328.CrossRefPubMedGoogle Scholar
  76. 76.
    Lowe PR, Galley HF, Abdel-Fattah A, Webster NR. Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in critically ill patients. Crit Care Med 2003;31:34–38.CrossRefPubMedGoogle Scholar
  77. 77.
    Fang XM, Schroder S, Hoeft A, Stuber F. Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. 1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Crit Care Med 1999;27:1330–1334.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Frank C. Schmalstieg
    • 1
  • Armond S. Goldman
    • 1
  1. 1.Department of PediatricsUniversity of Texas Medical BranchGalvestonUSA

Personalised recommendations