Oxygen regulates growth and differentiation in many systems, including the fetal and neonatal lung. The mechanisms whereby oxygen influences differentiation and specific gene expression in the developing lung are unknown. One such mechanism may be through the regulation of the cAMP system. Cyclic AMP is an important second messenger in the developing lung with the ability to accelerate type II pneumonocyte differentiation in human fetal lung (HFL) in vitro. The intracellular actions of cAMP are dependent upon the activity of cAMP-dependent protein kinase (PKA). We have demonstrated that type II cell differentiation and accumulation of mRNA for the surfactant-associated protein, SP-A, is regulated in a dose- dependent fashion by oxygen in HFL in vitro. Additionally, we have found that the inductive effects of cAMP on type II cell differentiation and SP- A mRNA levels are only observed in HFL tissues incubated in oxygen atmospheres greater than 10 percent. The finding that cAMP action depends on the oxygen concentration of the incubation atmosphere suggests that PKA activity and gene expression may be regulated by oxygen in developing human lung. Thus, the major hypothesis to be explored is that oxygen regulates type II cell differentiation and SP-A mRNA levels in HFL through PKA-dependent mechanisms. The hypothesis will be tested by accomplishing three specific aims: S.A.1: To determine if oxygen regulates type II cell differentiation through the modulation of PKA activity or PKA subunit gene expression in developing lung. S.A.2: To characterize the mechanisms by which oxygen regulates SP-A mRNA expression in HFL. S.A.3: To identify and characterize oxygen-induced mRNAs which may be involved in type II cell differentiation in HFL. An understanding of the mechanisms whereby oxygen regulates type II cell differentiation and SP-A mRNA expression may yield important insights into the role of oxygen in developing tissues and other biological systems.
| Acarregui, M J; Brown, J J; Penisten, S T (1998) Cyclic AMP-dependent protein kinase (PKA) gene expression is developmentally regulated in fetal lung. Biochim Biophys Acta 1402:303-12 |
