AUGMENTATION OF FUNCTIONAL PROSTAGLANDIN-E LEVELS ON THE RESPIRATORY EPITHELIAL SURFACE BY AEROSOL ADMINISTRATION OF PROSTAGLANDIN-E

Prostaglandin E (PGE), a cyclooxygenase metabolite normally present in high concentrations in respiratory epithelial lining fluid (ELF), is capable of suppressing mesenchymal cell proliferation mediated by polypeptide-derived growth factors. Although PGE is normally abundant in respiratory ELF, PGE levels in ELF of individuals with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disorder characterized by intraalveolar mesenchymal cell accumulation and fibrosis, were found to be 50% lower than normal (p < 0.01): that is, a relative PGE "deficiency" in ELF may enhance intraalveolar mesenchymal cell proliferation in IPF. With this background, It is rational to consider augmenting PGE levels in ELF as a future therapy for IPF. Since systemic administration of PGE is associated with significant adverse effects, in vitro and experimental animal studies were carried out to evaluate whether aerosol PGE administration could augment ELF PGE levels. Greater than 50% of a solution of PGE1 could be placed in droplets < 3 gm mass median aerodynamic diameter without loss of function. Aerosolization of PGE1 to sheep (n = 14) resulted in a marked augmentation of ELF PGE1 levels (preaerosol 20 +/- 7 nM, 30 min postaerosol 1,150 +/- 210 nM; p < 0.0 to 0.1). ELF PGE1 levels remained elevated for up to 2 h (p < 0.05 compared with baseline) and returned to baseline by 3 h (p > 0.2). Lung interstitial fluid (lymph) PGE, levels increased slightly, but to levels far less than ELF levels (preaerosol 7 +/- 1 nM, 30 min postaerosol 13 +/- 2 nM; p < 0.01), and plasma PGE1 levels did not change (p > 0.1). No systemic adverse effects were observed. The PGE1 deposited on the alveolar epithelial surface was functional as evidenced by the ability of ELF recovered 30 min postaerosol to suppress lung fibroblast proliferation compared with pretherapy ELF (p < 0.001). Thus, it is possible to significantly augment the levels of functional PGE1 in lung ELF by aerosolization, suggesting a potential form of therapy to suppress intraalveolar mesenchymal cell accumulation in respiratory ELF PGE deficiency disorders, such as IPF.