Giantsos Kristina M, Kopeckova Pavla, Dull Randal O
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Biomaterials. 2009 Oct;30(29):5885-91. doi: 10.1016/j.biomaterials.2009.06.048. Epub 2009 Jul 16.
Acute changes in lung capillary permeability continue to complicate procedures such as cardiopulmonary bypass, solid organ transplant, and major vascular surgery and precipitate the more severe disease state Adult Respiratory Distress Syndrome (ARDS). To date there is no treatment targeted directly to the lung microvasculature. We hypothesized that biomimetic polymers could be used to enhance passive barrier function by reducing the porosity of the endothelial glycocalyx and attenuate mechanotransduction by restricting the motion of the glycoproteins implicated in signal transduction. To this end, cationic copolymers containing methacrylamidopropyl trimethylammonium chloride (P-TMA Cl) have been developed as an infusible therapy to target the lung capillary glycocalyx in order to mechanically enhance the capillary barrier and turn off pressure-induced mechanotransduction. Copolymers were tested for functional efficacy by measuring both albumin permeability (P(DA)) and hydraulic conductivity (L(p)) across cultured endothelial monolayers. P-TMA Cl significantly decreased P(DA) in normal and inflamed cells and attenuated pressure-induced increases in L(p). Decreases in L(p) across endothelial monolayers in the presence of P-TMA Cl is evidence of a dampening of mechanotransduction-induced barrier dysfunction. We show the potential for biomimetic polymers targeted to lung endothelium as a viable therapy to enhance endothelial barrier function thereby attenuating a major component of vascular inflammation.
肺毛细血管通透性的急性变化持续使诸如体外循环、实体器官移植和大血管手术等操作变得复杂，并引发更严重的疾病状态——成人呼吸窘迫综合征（ARDS）。迄今为止，尚无直接针对肺微血管系统的治疗方法。我们推测，仿生聚合物可通过降低内皮糖萼的孔隙率来增强被动屏障功能，并通过限制参与信号转导的糖蛋白的运动来减弱机械转导。为此，已开发出含有甲基丙烯酰胺丙基三甲基氯化铵（P-TMA Cl）的阳离子共聚物作为一种不可输注的疗法，以靶向肺毛细血管糖萼，从而机械性增强毛细血管屏障并关闭压力诱导的机械转导。通过测量跨培养的内皮单层的白蛋白通透性（P(DA)）和水力传导率（L(p)）来测试共聚物的功能功效。P-TMA Cl显著降低了正常细胞和炎症细胞中的P(DA)，并减弱了压力诱导的L(p)增加。在存在P-TMA Cl的情况下，内皮单层的L(p)降低是机械转导诱导的屏障功能障碍减弱的证据。我们展示了靶向肺内皮的仿生聚合物作为一种可行疗法的潜力，以增强内皮屏障功能，从而减轻血管炎症的一个主要组成部分。
