Sphingosine inhalation as a novel treatment for bacterial pneumonia

我们先前已经证明，低微摩尔浓度的鞘氨醇可以杀死许多病原体，包括铜绿假单胞菌、金黄色葡萄球菌(甚至MRSA)、鲍曼不动杆菌、流感嗜血杆菌、卡他莫拉菌和伯克霍尔德氏菌，这些都是许多形式肺炎的重要病原体。给囊性纤维化(CF)小鼠吸入鞘氨醇可防止这些小鼠感染铜绿假单胞菌或金黄色葡萄球菌。CF小鼠吸入鞘氨醇还可以消除已经存在的浮游或生物膜铜绿假单胞菌或金黄色葡萄球菌的急性或慢性感染。此外，我们注意到连续两周每天吸入两次鞘氨醇的小鼠和小型猪没有毒性影响。由于越来越多的多重耐药细菌会导致肺炎和慢性肺部感染，因此需要新的治疗细菌感染的策略。我们假设吸入性鞘氨醇可以发展成为细菌性肺炎或慢性肺部感染患者，特别是慢性肺病患者的一种新的治疗选择。本建议的目的是(I)鉴定鞘氨醇在猪、培养的人呼吸道上皮细胞和分离的人肺中消除铜绿假单胞菌和金黄色葡萄球菌感染的能力；以及(Ii)确定鞘氨醇对培养的人上皮细胞、感染猪的肺和分离的未感染和感染的人肺的潜在不利影响。我们的最终目标是为一项临床研究奠定基础，以测试鞘氨醇在CF患者中的抗菌效果。该项目结合了三个小组的专业知识，例如，将在活体猪身上进行实验，并将提供关于鞘磷脂的专业知识，M.K.将对灌流和通风的猪和人肺进行研究，C.T.将对培养的人类细胞进行所有研究。该项目是一个真正的合资企业，需要所有三个团队的专业知识和努力。

We have previously shown that low micromolar concentrations of sphingosine kill manypathogens, including Pseudomonas aeruginosa, Staphylococcus aureus (even MRSA),Acinetobacter baumannii, Haemophilus influenzae, Moraxella catarrhalis, and Burkholderia species, that are important pathogens in many forms of pneumonia. Administering sphingosine to cystic fibrosis (CF) mice by inhalation prevents infection of these mice with P. aeruginosa or S. aureus. Inhalation of sphingosine by CF mice also eliminates already existing acute or chronic infections with planktonic or biofilm P. aeruginosa or S. aureus.Furthermore, we noticed no toxic effects among mice and minipigs that had inhaledsphingosine twice daily for two weeks. Because an increasing number of multiresistantbacteria cause pneumonia and chronic lung infections, novel strategies for treating bacterial infections are needed. We hypothesize that inhaled sphingosine can be developed into a novel treatment option for patients with bacterial pneumonia or chronic lung infection, in particular CF patients. The present proposal aims (i) to characterize the ability of sphingosine to eliminate P. aeruginosa and S. aureus infection in pigs, in cultured human airway epithelial cells, and in isolated human lungs; and (ii) to determine the potential adverse effects of sphingosine on cultured human epithelial cells, lungs of infected pigs, and isolated uninfected and infected human lungs. Our ultimate aim is to establish the basis for a clinical study testing the antibacterial effects of sphingosine in CF patients.The project combines the expertise of three groups, i.e. E.G. will perform the experiments on pigs in vivo and will provide expertise on sphingolipids, M.K. will perform the studies on perfused and ventilated pigs and human lungs and C.T. will perform all studies on cultured human cells. The project is truly a joint venture and requires the expertise and efforts of all three groups.