1 Centre for Infection and Immunity, Queen's University of Belfast, Belfast, United Kingdom; and.
Am J Respir Crit Care Med. 2014 Jun 15;189(12):1520-9. doi: 10.1164/rccm.201310-1892OC.
Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown.
To test whether KGF can attenuate alveolar injury in a human model of ARDS.
Volunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50 μg LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury.
KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor.
KGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF). Clinical trial registered with ISRCTN 98813895.
增加上皮修复和再生可能会加速急性呼吸窘迫综合征（ARDS）患者的肺损伤恢复。在 ARDS 的动物模型中，角质细胞生长因子（KGF）可减少损伤并增加上皮细胞增殖和修复。KGF 在人类肺泡中的作用尚不清楚。
在 ARDS 的人类模型中测试 KGF 是否可以减轻肺泡损伤。
志愿者随机分为静脉注射 KGF（60μg/kg）或安慰剂组，连续 3 天，然后吸入 50μg LPS。6 小时后，通过支气管肺泡灌洗（BAL）来量化肺泡炎症和细胞特异性损伤的标志物。
KGF 并未改变白细胞浸润或 LPS 反应中的通透性标志物。KGF 增加了 BAL 中表面活性剂蛋白 D、基质金属蛋白酶（MMP）-9、白细胞介素 1 受体拮抗剂（IL-1Ra）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和 C 反应蛋白的浓度。在体外，用 KGF 处理的 BAL 液抑制了肺成纤维细胞的增殖，但增加了肺泡上皮细胞的增殖。活性 MMP-9 增加了肺泡上皮细胞的伤口修复。最后，与安慰剂组相比，KGF 预处理组的 BAL 增强了巨噬细胞对凋亡上皮细胞和细菌的吞噬作用，该作用被 GM-CSF 受体抑制剂阻断。
KGF 治疗可增加 BAL 中的表面活性剂蛋白 D，这是急性肺损伤人类模型中 II 型肺泡上皮细胞增殖的标志物。此外，KGF 增加了抗炎细胞因子 IL-1Ra 以及促进上皮修复（MMP-9）和增强巨噬细胞清除死亡细胞和细菌（GM-CSF）的介质在肺泡中的浓度。该临床试验已在 ISRCTN 注册，注册号为 98813895。
