Jagarapu Jawahar, Kelchtermans Jelte, Rong Min, Chen Shaoyi, Hehre Dorothy, Hummler Stefanie, Faridi Mohd Hafeez, Gupta Vineet, Wu Shu
1 Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
2 Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.
Am J Respir Cell Mol Biol. 2015 Dec;53(6):793-801. doi: 10.1165/rcmb.2014-0422OC.
Lung inflammation plays a key role in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants. The challenge in BPD management is the lack of effective and safe antiinflammatory agents. Leukadherin-1 (LA1) is a novel agonist of the leukocyte surface integrin CD11b/CD18 that enhances leukocyte adhesion to ligands and vascular endothelium and thus reduces leukocyte transendothelial migration and influx to the injury sites. Its functional significance in preventing hyperoxia-induced neonatal lung injury is unknown. We tested the hypothesis that administration of LA1 is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) and received twice-daily intraperitoneal injection of LA1 or placebo for 14 days. Hyperoxia exposure in the presence of the placebo resulted in a drastic increase in the influx of neutrophils and macrophages into the alveolar airspaces. This increased leukocyte influx was accompanied by decreased alveolarization and angiogenesis and increased pulmonary vascular remodeling and pulmonary hypertension (PH), the pathological hallmarks of BPD. However, administration of LA1 decreased macrophage infiltration in the lungs during hyperoxia. Furthermore, treatment with LA1 improved alveolarization and angiogenesis and decreased pulmonary vascular remodeling and PH. These data indicate that leukocyte recruitment plays an important role in the experimental model of BPD induced by hyperoxia. Targeting leukocyte trafficking using LA1, an integrin agonist, is beneficial in preventing lung inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting integrin-mediated leukocyte recruitment and inflammation may provide a novel strategy in preventing and treating BPD in preterm infants.
肺部炎症在支气管肺发育不良（BPD）的发病机制中起关键作用，BPD是一种早产儿慢性肺部疾病。BPD治疗面临的挑战是缺乏有效且安全的抗炎药物。白细胞黏附素-1（LA1）是白细胞表面整合素CD11b/CD18的新型激动剂，可增强白细胞与配体及血管内皮的黏附，从而减少白细胞跨内皮迁移及向损伤部位的流入。其在预防高氧诱导的新生儿肺损伤中的功能意义尚不清楚。我们检验了LA1给药有助于预防高氧诱导的新生儿肺损伤这一假说，高氧诱导的新生儿肺损伤是BPD的一种实验模型。将新生大鼠暴露于常氧（21% O2）或高氧（85% O2）环境，并每天两次腹腔注射LA1或安慰剂，持续14天。在给予安慰剂的情况下暴露于高氧会导致中性粒细胞和巨噬细胞大量流入肺泡腔。这种白细胞流入增加伴随着肺泡化和血管生成减少，以及肺血管重塑和肺动脉高压（PH）增加，这些都是BPD的病理特征。然而，给予LA1可减少高氧期间肺内巨噬细胞浸润。此外，LA1治疗改善了肺泡化和血管生成，并减少了肺血管重塑和PH。这些数据表明白细胞募集在高氧诱导的BPD实验模型中起重要作用。使用整合素激动剂LA1靶向白细胞运输，有助于预防肺部炎症，并在高氧期间保护肺泡和血管结构。因此，靶向整合素介导的白细胞募集和炎症可能为预防和治疗早产儿BPD提供一种新策略。
