Simultaneous LFA-1 and CD40 ligand antagonism prevents airway remodeling in orthotopic airway transplantation: Implications for the role of respiratory epithelium as a modulator of fibrosis
Simultaneous LFA-1 and CD40 ligand antagonism prevents airway remodeling in orthotopic airway transplantation: Implications for the role of respiratory epithelium as a modulator of fibrosis
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DOI：
10.4049/jimmunol.174.7.3869
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发表时间：
2005-04-01
影响因子：
4.4
通讯作者：
Nicolls, MR
中科院分区：
文献类型：
--
作者：
Murakawa, T;Kerklo, MM;Nicolls, MR
气道重塑是某些免疫介导的肺部疾病（如哮喘和慢性肺移植排斥）的显著特征。在气道炎症的条件下，呼吸道上皮细胞可能在这一重塑过程中发挥重要作用。鉴于呼吸上皮在非特异性损伤模型中的作用，我们研究了免疫特异性睾丸气道移植模型中的呼吸上皮。小鼠中MHC不匹配的气管移植用于产生同种免疫介导的气道病变。这种免疫损伤的减弱和抗供体反应性的改变通过施用组合抗LFA-1/抗CD 40 L mAb来实现。相比之下，在没有免疫治疗的情况下，移植的气道重塑，呼吸道上皮变平，上皮下纤维化明显。持续10天的非对抗性同种免疫损伤与随后的上皮转化和上皮下纤维化相关，免疫治疗无法逆转。免疫治疗延迟了供体气道与原始上皮细胞的重新衬里，导致部分嵌合气道28天。部分上皮细胞嵌合体足以防止管腔纤维化。然而，上皮嵌合体也与气道重塑有关。因此，呼吸道上皮的形态和嵌合水平与同种免疫损伤后气道重塑的程度之间似乎存在密切关系。
Airway remodeling is a prominent feature of certain immune-mediated lung diseases such as asthma and chronic lung transplant rejection. Under conditions of airway inflammation, the respiratory epithelium may serve an important role in this remodeling process. Given the proposed role of respiratory epithelium in nonspecific injury models, we investigated the respiratory epithelium in an immune-specific orchotopic airway transplant model. MHC-mismatched tracheal transplants in mice were used to generate alloimmune-mediated airway lesions. Attenuation of this immune injury and alteration of antidonor reactivity were achieved by the administration of combined anti-LFA-1/anti-CD40L mAbs. By contrast, without immunotherapy, transplanted airways remodeled with a flattening of respiratory epithelium and significant subepithelial fibrosis. Unopposed alloimmune injury for 10 days was associated with subsequent epithelial transformation and subepithelial fibrosis that could not be reversed with immunotherapy. The relining of donor airways with recipient-derived epithelium was delayed with immunotherapy resulting in partially chimeric airways by 28 days. Partial epithelial cell chimerism was sufficient to prevent luminal fibrosis. However, epithelial chimerism was also associated with airway remodeling. Therefore, there appears to be an intimate relationship between the morphology and level of chimerism of the respiratory epithelium and the degree of airway remodeling following alloimmune injury.