Baer Brandon, Veldhuizen Edwin J A, Possmayer Fred, Yamashita Cory, Veldhuizen Ruud
Department of Physiology and Pharmacology, Western University, London, Ontario N6A 4V2, Canada.
Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Discov Med. 2018 Nov;26(144):207-218.
Due to its branching structure, drug delivery to the peripheral areas of the lung is a major challenge. Consequently, most pulmonary therapies utilize large systemic dosing, with the potential for adverse side effects. One proposed strategy to overcome this challenge is to use exogenous surfactant, a material capable of distributing throughout the lung, as a pulmonary drug delivery vehicle. The objective was to develop and test an in vitro system to rapidly assess surfactant based therapies prior to animal studies. The Wet Bridge Transfer System consisted of two connected wells in which drugs were instilled into a delivery well and function was tested in a remote well which mimicked the remote areas of the lung where drug activity would be required. The system was used to assess surfactant as a carrier for antibiotics (Gentamicin, Ciprofloxacin, and Colistin) by measuring their ability to kill Pseudomonas aeruginosa bacteria in the remote well. Anti-inflammatory agents (Budesonide and a host defense peptide, CATH-2) with and without exogenous surfactant were examined using stimulated macrophages in the remote well and IL-6 concentration as an outcome. The results showed that being paired with surfactant, Gentamicin and Ciprofloxacin, but not Colistin, had significantly greater bacterial killing in the remote wells. Similarly, when combined with a surfactant, both Budesonide and CATH-2 significantly lowered IL-6 concentrations. We conclude that the wet-bridge system can be used to rapidly screen surfactant-based therapies prior to their assessment in vivo. Furthermore, exogenous surfactant was an effective delivery vehicle for several antimicrobial and anti-inflammatory therapeutics.
由于其分支结构，将药物输送到肺的外周区域是一项重大挑战。因此，大多数肺部治疗采用大剂量全身给药，存在产生不良副作用的可能性。一种提出的克服这一挑战的策略是使用外源性表面活性剂，一种能够在整个肺部分布的物质，作为肺部药物递送载体。目的是开发并测试一种体外系统，以便在动物研究之前快速评估基于表面活性剂的治疗方法。湿桥转移系统由两个相连的孔组成，在其中一个给药孔中滴注药物，并在一个模拟肺部需要药物活性的偏远区域的远端孔中测试其功能。该系统用于通过测量抗生素（庆大霉素、环丙沙星和黏菌素）在远端孔中杀死铜绿假单胞菌的能力，来评估表面活性剂作为抗生素载体的情况。使用远端孔中的刺激巨噬细胞并以白细胞介素-6浓度作为结果，研究了有无外源性表面活性剂的抗炎剂（布地奈德和一种宿主防御肽CATH-2）。结果表明，与表面活性剂配对时，庆大霉素和环丙沙星在远端孔中的杀菌能力显著增强，但黏菌素没有。同样，当与表面活性剂联合使用时，布地奈德和CATH-2均显著降低了白细胞介素-6的浓度。我们得出结论，湿桥系统可用于在基于表面活性剂的治疗方法进行体内评估之前快速筛选它们。此外，外源性表面活性剂是几种抗菌和抗炎治疗药物的有效递送载体。
