David R Cool (Advisor), Mauricio Di Fulvio (Committee Member), Nadja Grobe (Committee Member)
Master of Science (MS)
The "surfactant" produced by type II pneumonocytes is deficient in term and preterm infants born and diagnosed with Respiratory Distress Syndrome (RDS). Corticosteroids such as dexamethasone or betamethasone are clinically used as the primary line of treatment to stimulate the production of surfactant. The steroidal hormone, progesterone appears to play a role in the fetal lung development and also appears to increase the expression of inflammatory markers in both term and preterm infants. However, the impact of progesterone on surfactant production remains unknown. Like progesterone, the tocolytic drug terbutaline has also been implicated in phosphatidylcholine production in the pneumonocytes of the human lung. Interestingly, recent reports indicate that leptin, a hormone mainly produced by adipocytes may increase surfactant production in-vitro. However, other authors could not reproduce those results. This study was designed to analyze the long-term effect of progesterone, terbutaline and leptin on surfactant production in-vitro, either alone or in combination with betamethasone as a positive control. As a model, we used the human lung cell line NCI-H441. The production and processing of Surfactant Protein-B (SP-B), in this cell line is almost identical to explant cultures of fetal lung and cultured type II cells. Biochemical, immunochemical and molecular approaches, including thin layer chromatography (TLC) and RealTime-PCR were followed to determine the pharmacological role of progesterone, terbutaline and leptin on surfactant production. Our experiments indicate that betamethasone increased lipid secretion and surfactant-B production at 24 hours. Likewise, progesterone and terbutaline, increased lipid secretion and surfactant production when analyzed by immunocytochemistry. Betamethasone also increased surfactant production when added to these tocolytics. RealTime PCR also showed a similar increase in surfactant-B mRNA. The results suggest that progesterone in combination with betamethasone may improve surfactant production in high preterm risk patients. However terbulatine and leptin need further studies on their mechanisms and future use.
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
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