Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis
Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis
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DOI：
10.1007/s00439-005-0035-7
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发表时间：
2005-11-01
期刊：
影响因子：
5.3
通讯作者：
Selman, M
中科院分区：
文献类型：
--
作者：
Falfán-Valencia, R;Camarena, A;Selman, M
特发性肺纤维化（IPF）是一种以成纤维细胞扩张和组织重塑为特征的慢性疾病。它被认为是一种多因素疾病，但可能涉及的基因在很大程度上是未知的。有趣的是，关于主要组织相容性复合体（MHC）的可能作用的研究很少，并显示出相互矛盾的结果。在这项研究中，我们评估了75例IPF患者和95例对照组的MHC，位点HLA-B，-DRB 1和-DQB 1的多态性，通过使用PCR和序列特异性寡核苷酸探针杂交。此外，我们还通过WST-1细胞活力测定和流式细胞术以及细胞匀浆中切割的caspase-3检测了不同MHC单倍型IPF患者的支气管肺泡灌洗（BAL）对肺泡上皮生长速率的影响。3种单倍型在IPF患者中显著增加：（1）HLA-B*15-DRB 1 *0101-DQB 1 *0501（2）HLA-B*52-DRB 1 *1402-DQB 1 *0301（3）HLA-B*35-DRB 1 *0407-DQB 1 *0302（OR =4.73，CI=1.53-19.5; pC=0.005）。来自具有较晚单倍型的患者的BAL显著降低上皮生长速率（类似于30%）并通过切割的半胱天冬酶-3测定引起上皮细胞凋亡（351.7 +/-16.5 pg/10（6）细胞，对照组为264 +/-24，其他单倍型为274 +/-36.8和256.5 +/-10.7; P < 0.05），流式细胞术标记的DNA断裂（23.7 +/- 6.9%对对照组的3.1 +/- 0.7%，另外两种单倍型的6.5 +/- 0.6%和7.6 +/- 1.2%; P < 0.01）。这些发现表明，某些MHC多态性赋予IPF的易感性，这可能与诱导上皮细胞凋亡有关，这是疾病发展的关键过程。
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblast expansion, and tissue remodeling. It is considered a multifactorial disease but the possible involved genes are largely unknown. Interestingly, studies regarding the possible role of major histocompatibility complex (MHC) are scanty and show contradictory results. In this study, we evaluated the polymorphisms of the MHC, locus HLA-B, -DRB1, and -DQB1 in a cohort of 75 IPF patients and 95 controls by using PCR and hybridization with sequence-specific oligonucleotide probes. In addition, we examined the effect of bronchoalveolar lavage (BAL) from IPF patients with different MHC haplotypes on alveolar epithelial growth rate by WST-1 cell viability assay and on epithelial apoptosis by flow cytometry and by cleaved caspase-3 in cell homogenates. Three haplotypes were significantly increased in IPF: (1) HLA-B*15-DRB1*0101-DQB1*0501 (OR=10.72, CI=1.43-459.6; pC=0.011); (2) HLA-B*52-DRB1*1402-DQB1*0301 (OR=4.42, CI=1.21-24.1; pC=0.024); and (3) HLA-B*35-DRB1*0407-DQB1*0302 (OR=4.73, CI=1.53-19.5; pC=0.005). BAL from patients with the later haplotype significantly reduced epithelial growth rate (similar to 30%) and caused epithelial cell apoptosis assayed by cleaved caspase-3 (351.7 +/- 16.5 pg/10(6) cells versus 264 +/- 24 from controls, and 274 +/- 36.8 and 256.5 +/- 10.7 from the other haplotypes; P < 0.05), and DNA breaks labeling by flow cytometry (23.7 +/- 6.9% versus 3.1 +/- 0.7% from controls, and 6.5 +/- 0.6% and 7.6 +/- 1.2% from the other two haplotypes; P < 0.01). These findings suggest that some MHC polymorphisms confer susceptibility to IPF, which might be related with the induction of epithelial cell apoptosis, a critical process in the development of the disease.