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Genetic replacement of surfactant protein-C reduces respiratory syncytial virus induced lung injury.

AbstractBACKGROUND:
Individuals with deficiencies of pulmonary surfactant protein C (SP-C) develop interstitial lung disease (ILD) that is exacerbated by viral infections including respiratory syncytial virus (RSV). SP-C gene targeted mice (Sftpc -/-) lack SP-C, develop an ILD-like disease and are susceptible to infection with RSV.
METHODS:
In order to determine requirements for correction of RSV induced injury we have generated compound transgenic mice where SP-C expression can be induced on the Sftpc -/- background (SP-C/Sftpc -/-) by the administration of doxycycline (dox). The pattern of induced SP-C expression was determined by immunohistochemistry and processing by Western blot analysis. Tissue and cellular inflammation was measured following RSV infection and the RSV-induced cytokine response of isolated Sftpc +/+ and -/- type II cells determined.
RESULTS:
After 5 days of dox administration transgene SP-C mRNA expression was detected by RT-PCR in the lungs of two independent lines of bitransgenic SP-C/Sftpc -/- mice (lines 55.3 and 54.2). ProSP-C was expressed in the lung, and mature SP-C was detected by Western blot analysis of the lavage fluid from both lines of SP-C/Sftpc -/- mice. Induced SP-C expression was localized to alveolar type II cells by immunostaining with an antibody to proSP-C. Line 55.3 SP-C/Sftpc -/- mice were maintained on or off dox for 7 days and infected with 2.6x107 RSV pfu. On day 3 post RSV infection total inflammatory cell counts were reduced in the lavage of dox treated 55.3 SP-C/Sftpc -/- mice (p = 0.004). The percentage of neutrophils was reduced (p = 0.05). The viral titers of lung homogenates from dox treated 55.3 SP-C/Sftpc -/- mice were decreased relative to 55.3 SP-C/Sftpc -/- mice without dox (p = 0.01). The cytokine response of Sftpc -/- type II cells to RSV was increased over that of Sftpc +/+ cells.
CONCLUSIONS:
Transgenic restoration of SP-C reduced inflammation and improved viral clearance in the lungs of SP-C deficient mice. The loss of SP-C in alveolar type II cells compromises their response to infection. These findings show that the restoration of SP-C in Sftpc -/- mice in response to RSV infection is a useful model to determine parameters for therapeutic intervention.
AuthorsStephan W Glasser, Albert P Senft, Melissa D Maxfield, Teah L Ruetschilling, John E Baatz, Kristen Page, Thomas R Korfhagen
JournalRespiratory research (Respir Res) Vol. 14 Pg. 19 (Feb 12 2013) ISSN: 1465-993X [Electronic] England
PMID23399055 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Pulmonary Surfactant-Associated Protein C
Topics
  • Animals
  • Cells, Cultured
  • Down-Regulation (genetics)
  • Lung Injury (genetics, metabolism, prevention & control)
  • Mice
  • Mice, 129 Strain
  • Mice, Transgenic
  • Pulmonary Surfactant-Associated Protein C (biosynthesis, genetics)
  • Respiratory Syncytial Virus Infections (genetics, metabolism, prevention & control)
  • Respiratory Syncytial Viruses
  • Viral Load (methods)

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