Parmley L A, Elkins N D, Fini M A, Liu Y-E, Repine J E, Wright R M
Webb-Waring Institute for Cancer, Aging and Antioxidant Research, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Br J Pharmacol. 2007 Nov;152(6):915-29. doi: 10.1038/sj.bjp.0707443. Epub 2007 Sep 10.
Injury to the alveolar epithelium is a critical feature of acute lung injury (ALI). Using a cytokine model of ALI we demonstrated previously that newly recruited mononuclear phagocytes (MNP) contributed to lung inflammation and injury. We hypothesized that cytokines delivered into the alveolar airspace would have multiple effects on the lung that may contribute to lung injury.
Intratracheal cytokine insufflation and leukocyte adoptive transfer in vivo were combined with in vitro analyses of lung epithelial cell-MNP adhesion and injury. Lung inflammatory injury was assessed by histology, leukocyte infiltration, and release of LDH and RAGE.
Cytokine insufflation was associated with apparent MNP-epithelial adhesion, up-regulation of alveolar ICAM-1 and VCAM-1, and the release of LDH and RAGE into the bronchoalveolar lavage. Insufflation of small molecule integrin antagonists suppressed adhesion of MNP and modulated release of LDH and RAGE. Adoptive transfer of MNP purified from cytokine insufflated lungs into leukopenic rats demonstrated the requirement of MNP for release of LDH that was not induced by cytokine alone. Corroboration that disrupting the ICAM/LFA1 interaction or the VCAM/VLA4 interaction blocked MNP-epithelial cell interaction and injury was obtained in vitro using both blocking monoclonal antibodies and the small molecule integrin antagonists, BIO5192 and XVA143.
MNP recruited following cytokine insufflation contributed to lung injury. Further, integrin antagonists reduced alveolar epithelial cell injury induced during lung inflammation. Intratracheal delivery of small molecule antagonsists of leukocyte-epithelial adhesion that prevent lung injury may have significant clinical utility.
肺泡上皮损伤是急性肺损伤（ALI）的关键特征。我们先前利用ALI的细胞因子模型证明，新募集的单核吞噬细胞（MNP）会导致肺部炎症和损伤。我们推测，注入肺泡腔的细胞因子会对肺部产生多种影响，可能导致肺损伤。
将气管内注入细胞因子和体内白细胞过继转移与肺上皮细胞-MNP黏附及损伤的体外分析相结合。通过组织学、白细胞浸润以及乳酸脱氢酶（LDH）和晚期糖基化终末产物受体（RAGE）的释放来评估肺部炎性损伤。
细胞因子注入与明显的MNP-上皮黏附、肺泡细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）上调以及LDH和RAGE释放到支气管肺泡灌洗液中有关。小分子整合素拮抗剂注入可抑制MNP的黏附，并调节LDH和RAGE的释放。将从注入细胞因子的肺中纯化的MNP过继转移到白细胞减少的大鼠体内，证明LDH的释放需要MNP，而单独的细胞因子不会诱导这种释放。使用阻断单克隆抗体以及小分子整合素拮抗剂BIO5192和XVA143在体外证实，破坏ICAM/LFA1相互作用或VCAM/VLA4相互作用可阻断MNP-上皮细胞相互作用和损伤。
细胞因子注入后募集的MNP会导致肺损伤。此外，整合素拮抗剂可减轻肺部炎症期间诱导的肺泡上皮细胞损伤。气管内递送可预防肺损伤的白细胞-上皮黏附小分子拮抗剂可能具有重要的临床应用价值。
