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SP-B deficiency causes respiratory failure in adult mice
Kristin R Melton1, Lori L Nesslein, Machiko Ikegami
1Cincinnati Children's Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA.
Abstract:
Targeted deletion of the surfactant protein (SP)-B locus in mice causes lethal neonatal respiratory distress. To assess the importance of SP-B for postnatal lung function, compound transgenic mice were generated in which the mouse SP-B cDNA was conditionally expressed under control of exogenous doxycycline in SP-B-/- mice. Doxycycline-regulated expression of SP-B fully corrected lung function in compound SP-B-/- mice and protected mice from respiratory failure at birth. Withdrawal of doxycycline from adult compound SP-B-/- mice resulted in decreased alveolar content of SP-B, causing respiratory failure when SP-B concentration was reduced to <25% of normal levels. Decreased SP-B was associated with low alveolar content of phosphatidylglycerol, accumulation of misprocessed SP-C proprotein in the air spaces, increased protein content in bronchoalveolar lavage fluid, and altered surfactant activity in vitro. Consistent with surfactant dysfunction, hysteresis, maximal tidal volumes, and end expiratory volumes were decreased. Reduction of alveolar SP-B content causes surfactant dysfunction and respiratory failure, indicating that SP-B is required for postnatal lung function.
Insights
Surfactant protein (SP)-B is crucial for newborn lung function. Conditional SP-B expression in mice prevented respiratory failure, demonstrating its essential role in postnatal lung health.
Area of Science:
- Pulmonary physiology
- Molecular biology
- Respiratory medicine
Background:
- Targeted deletion of surfactant protein (SP)-B in mice leads to lethal neonatal respiratory distress.
- SP-B is a key component of pulmonary surfactant, essential for lung function.
Purpose of the Study:
- To investigate the critical role of SP-B in postnatal lung function.
- To determine the consequences of reduced SP-B levels on lung physiology and surfactant function.
Main Methods:
- Generation of compound transgenic mice with doxycycline-regulated SP-B expression in SP-B knockout mice.
- Assessment of lung function and surfactant composition following doxycycline withdrawal in adult mice.
- In vitro analysis of surfactant activity and measurement of respiratory mechanics.
Main Results:
- Conditional SP-B expression fully corrected lung function and prevented neonatal respiratory failure.
- Doxycycline withdrawal in adult mice led to decreased SP-B, resulting in respiratory failure at <25% normal levels.
- Reduced SP-B was associated with altered surfactant composition (low phosphatidylglycerol), SP-C accumulation, and impaired surfactant activity.
Conclusions:
- SP-B is indispensable for maintaining normal postnatal lung function.
- Reduced SP-B levels cause surfactant dysfunction, leading to respiratory failure.
- This study highlights the critical importance of SP-B for neonatal and adult lung health.