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Background  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 2.6x10 7  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.

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