Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China.
Int Immunopharmacol. 2010 Feb;10(2):259-63. doi: 10.1016/j.intimp.2009.11.005. Epub 2009 Nov 10.
As one of the most important endogenous chemotactic factors for neutrophils, the chemokine CXCL8 (IL-8) is involved in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by massive neutrophil infiltration in the lung. Since neutralization of CXCL8 with polyclonal antibody has been shown to reduce the severity of ALI/ARDS in animal models, we explored the potential of humanized anti-CXCL8 antibody as a preventive or therapeutic agent for ALI. We used a 'two-hit' protocol to induce ALI in rabbits that showed extensive edema in the alveolar lumina, marked infiltration of neutrophils in the lung tissue, fibrin deposition in alveolar space, and destruction of pulmonary architecture, culminating in severe hypoxemia. Concomitant challenge with endotoxin after priming with oleic acid (OA) induced a marked elevation of CXCL8 level in bronchoalveolar lavage fluid. Treatment of the rabbits with a humanized anti-CXCL8 antibody prevented neutrophil infiltration in the lung in association with alleviated ALI syndrome. Our results indicate a promising future for utilization of humanized anti-CXCL8 antibody in the prevention and treatment of ALI and ARDS in human.
作为中性粒细胞最重要的内源性趋化因子之一，趋化因子 CXCL8（IL-8）参与急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的发病机制，其特征是肺内大量中性粒细胞浸润。由于用多克隆抗体中和 CXCL8 已被证明可减轻动物模型中 ALI/ARDS 的严重程度，因此我们探讨了人源化抗 CXCL8 抗体作为 ALI 预防或治疗剂的潜力。我们使用“双打击”方案在兔子中诱导 ALI，其表现为肺泡腔广泛水肿、肺组织中大量中性粒细胞浸润、肺泡腔中纤维蛋白沉积和肺结构破坏，最终导致严重低氧血症。在用油酸（OA）引发后，同时用内毒素引发，可导致支气管肺泡灌洗液中 CXCL8 水平显著升高。用抗人源化 CXCL8 抗体治疗兔子可防止肺内中性粒细胞浸润，并减轻 ALI 综合征。我们的结果表明，人源化抗 CXCL8 抗体在预防和治疗人类 ALI 和 ARDS 方面具有广阔的前景。
