Repurposing tromethamine as inhaled therapy to treat CF airway disease
Repurposing tromethamine as inhaled therapy to treat CF airway disease
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DOI：
10.1172/jci.insight.87535
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发表时间：
2016-06-02
期刊：
影响因子：
8
通讯作者：
Zabner, Joseph
中科院分区：
文献类型：
--
作者：
Abou Alaiwa, Mahmoud H.;Launspach, Janice L.;Zabner, Joseph
在囊性纤维化（CF）中，CF跨膜电导调节剂（CFTR）阴离子通道活性的丧失导致气道表面液体（ASL） pH变为酸性，从而损害气道宿主的防御能力。一种潜在的治疗方法是通过雾化HCO3-和/或非碳酸氢盐pH缓冲液来纠正CF气道中的酸性pH。在这里，我们发现吸入HCO3-提高ASL pH值会增加pH值。然而，效果是短暂的，pH值在30分钟内恢复到基线值。tromeamine （Tham）是一种具有较长血清半衰期的缓冲剂，用于静脉注射治疗代谢性酸中毒。我们发现Tham气溶胶在体内增加ASL pH至少2小时，并增强细菌杀灭。CF患者吸入高渗盐水（7% NaCl）以促进粘液清除。由于增加的离子强度抑制ASL抗菌因子，我们将Tham添加到高渗盐水中并应用于CF痰液。我们发现Tham单独使用和与高渗盐水联合使用可以增加pH值并增强细菌杀灭。这些发现表明，雾化不依赖HCO3的缓冲液Tham，单独或与高渗盐水联合，可能对CF气道疾病有治疗效果。
In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR) anion channel activity causes airway surface liquid (ASL) pH to become acidic, which impairs airway host defenses. One potential therapeutic approach is to correct the acidic pH in CF airways by aerosolizing HCO3- and/or nonbicarbonate pH buffers. Here, we show that raising ASL pH with inhaled HCO3- increased pH. However, the effect was transient, and pH returned to baseline values within 30 minutes. Tromethamine (Tham) is a buffer with a long serum half-life used as an i.v. formulation to treat metabolic acidosis. We found that Tham aerosols increased ASL pH in vivo for at least 2 hours and enhanced bacterial killing. Inhaled hypertonic saline (7% NaCl) is delivered to people with CF in an attempt to promote mucus clearance. Because an increased ionic strength inhibits ASL antimicrobial factors, we added Tham to hypertonic saline and applied it to CF sputum. We found that Tham alone and in combination with hypertonic saline increased pH and enhanced bacterial killing. These findings suggest that aerosolizing the HCO3--independent buffer Tham, either alone or in combination with hypertonic saline, might be of therapeutic benefit in CF airway disease.