AUGMENTATION OF FUNCTIONAL PROSTAGLANDIN-E LEVELS ON THE RESPIRATORY EPITHELIAL SURFACE BY AEROSOL ADMINISTRATION OF PROSTAGLANDIN-E
AUGMENTATION OF FUNCTIONAL PROSTAGLANDIN-E LEVELS ON THE RESPIRATORY EPITHELIAL SURFACE BY AEROSOL ADMINISTRATION OF PROSTAGLANDIN-E
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DOI：
10.1164/ajrccm/144.5.1080
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发表时间：
1991-11-01
期刊：
影响因子：
--
通讯作者：
CRYSTAL, RG
中科院分区：
文献类型：
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作者：
BOROK, Z;GILLISSEN, A;CRYSTAL, RG
前列腺素E（PGE）是一种环加氧酶代谢物，通常以高浓度存在于呼吸道上皮衬里液（ELF）中，能够抑制由多肽衍生的生长因子介导的间充质细胞增殖。尽管PGE在呼吸道ELF中通常是丰富的，但发现患有特发性肺纤维化（IPF）（一种以肺泡内间充质细胞积聚和纤维化为特征的纤维化肺部疾病）的个体的ELF中的PGE水平比正常低50%（p < 0.01）：也就是说，ELF中的相对PGE“缺乏”可能增强IPF中的肺泡内间充质细胞增殖。在此背景下，考虑将增加ELF中的PGE水平作为IPF的未来治疗是合理的。由于全身施用PGE与显著的不良反应相关，因此进行体外和实验动物研究以评估气雾剂施用PGE是否可以增加ELF PGE水平。大于50%的PGE 1溶液可置于小于3 gm质量中值空气动力学直径的液滴中而不丧失功能。将PGE 1雾化吸入绵羊体内（n = 14），导致ELF PGE 1水平显著增加（雾化前20 +/- 7 nM，雾化后30分钟1，150 +/- 210 nM; p < 0.0至0.1）。ELF PGE 1水平在2小时内保持升高（与基线相比p < 0.05），3小时后恢复至基线水平（p > 0.2）。肺间质液（淋巴液）PGE水平略有增加，但水平远低于ELF水平（气雾剂前7 +/- 1 nM，气雾剂后30分钟13 +/- 2 nM; p < 0.01），血浆PGE 1水平没有变化（p > 0.1）。未观察到全身不良反应。沉积在肺泡上皮表面的PGE 1是功能性的，如通过与治疗前ELF相比，治疗后30分钟恢复的ELF抑制肺成纤维细胞增殖的能力所证明的（p < 0.001）。因此，有可能通过雾化显著增加肺ELF中功能性PGE 1的水平，这表明在呼吸ELF PGE缺乏症（例如IPF）中抑制肺泡内间充质细胞积聚的潜在治疗形式。
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.