Intrauterine infection, a common antecedent of premature birth, leads to increased levels of interleukin-1 (IL-1) in the amniotic fluid. IL-1 in amniotic fluid and cord blood is a risk factor for the postnatal development of chronic lung disease. On the other hand, intrauterine inflammation may protect the preterm newborn from respiratory distress syndrome. A single intra-amniotic injection of IL-1 given to fetal animals increases surfactant protein synthesis and surfactant pool sizes, and improves lung compliance after premature birth (Bry et al., J Clin Invest 99, 2992-9, 1997).
In order to further characterize the role of IL-1 in maturation and injury, we have developed a transgenic mouse in which IL-1 is expressed in the lung in an externally regulatable manner. These mice bear the reverse tetracycline transactivator under the control of the rat Clara cell secretory protein (CCSP) as well as the tet operator and cDNA for the mature human IL-1 cDNA. When given doxycycline, the mice express human IL-1 in a lung-specific fashion. Surfactant protein expression is increased in these mice antenatally but not postnatally. The expression of CCSP is decreased both antenatally and postnatally. Inflammatory cell infiltrates are seen on histology. Elastin strands appear abnormal in IL-1-overexpressing lungs. Airspace enlargement is evident in IL-1-overexpressing mice by three weeks of postnatal age and becomes progressively worse.
In conclusion, IL-1 exposure accelerates the maturation of the pulmonary surfactant system but leads to abnormal lung development.
Funded by NIH HD28827-09 and HD39278-01.
08 - 11 Apr 2002
British Endocrine Societies