Maishan Mazharul, Taenaka Hiroki, Evrard Bruno, Matsumoto Shotaro, Ringor Angelika, Leroux Carolyn, Lucas Rudolf, Matthay Michael A
Cardiovascular Research Institute and.
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, UCSF, San Francisco, California, USA.
JCI Insight. 2025 Jun 9;10(11). doi: 10.1172/jci.insight.188325.
Bacterial pneumonia is the most common cause of acute respiratory distress syndrome (ARDS), characterized by disrupted pulmonary endothelial barrier function, hyperinflammation, and impaired alveolar epithelial fluid clearance. ARDS has a high mortality rate and no proven pharmacological treatments, stressing the need for new targeted therapies. The TIP peptide, mimicking the lectin-like domain of TNF, directly binds to the α subunit of the epithelial Na+ channel, expressed in both alveolar epithelial and capillary endothelial cells, and may increase lung endothelial barrier function and alveolar fluid clearance during bacterial infection. This study tested these potential therapeutic mechanisms of the TIP peptide in a clinically relevant preparation of the ex vivo-perfused human lung injured by Streptococcus pneumoniae. Therapeutic administration of the TIP peptide reduced pulmonary barrier permeability to protein and lung edema formation, increased alveolar edema fluid clearance, and produced an antiinflammatory effect in the airspaces with reductions in IL-6 and IL-8 levels. Additionally, the TIP peptide reduced the translocation of bacteria into the circulation. These findings establish 3 mechanisms of benefit with the TIP peptide to reduce injury in the human lung and support the clinical relevance as a potential therapeutic for pneumococcal bacterial pneumonia.
细菌性肺炎是急性呼吸窘迫综合征（ARDS）最常见的病因，其特征为肺内皮屏障功能破坏、炎症反应过度及肺泡上皮液体清除功能受损。ARDS死亡率高且尚无经证实有效的药物治疗方法，这凸显了新型靶向治疗的必要性。TIP肽模拟肿瘤坏死因子（TNF）的凝集素样结构域，直接结合在肺泡上皮细胞和毛细血管内皮细胞中均有表达的上皮钠通道α亚基，在细菌感染期间可能增强肺内皮屏障功能并促进肺泡液体清除。本研究在肺炎链球菌损伤的体外灌注人肺这一具有临床相关性的模型中，对TIP肽的这些潜在治疗机制进行了测试。TIP肽的治疗性给药降低了肺对蛋白质的屏障通透性及肺水肿形成，增加了肺泡水肿液清除，并在肺泡腔产生抗炎作用，使白细胞介素-6（IL-6）和白细胞介素-8（IL-8）水平降低。此外，TIP肽减少了细菌向循环系统的移位。这些发现确立了TIP肽减轻人肺损伤的三种有益机制，并支持其作为肺炎球菌性细菌性肺炎潜在治疗方法的临床相关性。
