Yang Ivana V, Burch Lauranell H, Steele Mark P, Savov Jordan D, Hollingsworth John W, McElvania-Tekippe Erin, Berman Katherine G, Speer Marcy C, Sporn Thomas A, Brown Kevin K, Schwarz Marvin I, Schwartz David A
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, P.O. Box 12233, MD B3-08, Research Triangle Park, NC 27909, USA.
Am J Respir Crit Care Med. 2007 Jan 1;175(1):45-54. doi: 10.1164/rccm.200601-062OC. Epub 2006 Sep 22.
Idiopathic interstitial pneumonia (IIP) and its familial variants are progressive and largely untreatable disorders with poorly understood molecular mechanisms. Both the genetics and the histologic type of IIP play a role in the etiology and pathogenesis of interstitial lung disease, but transcriptional signatures of these subtypes are unknown.
To evaluate gene expression in the lung tissue of patients with usual interstitial pneumonia or nonspecific interstitial pneumonia that was either familial or nonfamilial in origin, and to compare it with gene expression in normal lung parenchyma.
We profiled RNA from the lungs of 16 patients with sporadic IIP, 10 with familial IIP, and 9 normal control subjects on a whole human genome oligonucleotide microarray.
Significant transcriptional differences exist in familial and sporadic IIPs. The genes distinguishing the genetic subtypes belong to the same functional categories as transcripts that distinguish IIP from normal samples. Relevant categories include chemokines and growth factors and their receptors, complement components, genes associated with cell proliferation and death, and genes in the Wnt pathway. The role of the chemokine CXCL12 in disease pathogenesis was confirmed in the murine bleomycin model of lung injury, with C57BL/6(CXCR4+/-) mice demonstrating significantly less collagen deposition than C57BL/6(CXCR4+/+) mice. Whereas substantial differences exist between familial and sporadic IIPs, we identified only minor gene expression changes between usual interstitial pneumonia and nonspecific interstitial pneumonia.
Taken together, our findings indicate that differences in gene expression profiles between familial and sporadic IIPs may provide clues to the etiology and pathogenesis of IIP.
特发性间质性肺炎（IIP）及其家族性变体是进行性疾病，且大多无法治疗，其分子机制尚不清楚。IIP的遗传学和组织学类型在间质性肺病的病因和发病机制中均起作用，但这些亚型的转录特征尚不清楚。
评估家族性或非家族性寻常间质性肺炎或非特异性间质性肺炎患者肺组织中的基因表达，并将其与正常肺实质中的基因表达进行比较。
我们在全人类基因组寡核苷酸微阵列上对16例散发性IIP患者、10例家族性IIP患者和9名正常对照者的肺组织进行RNA分析。
家族性和散发性IIP存在显著的转录差异。区分遗传亚型的基因与区分IIP和正常样本的转录本属于相同的功能类别。相关类别包括趋化因子和生长因子及其受体、补体成分、与细胞增殖和死亡相关的基因以及Wnt信号通路中的基因。趋化因子CXCL12在疾病发病机制中的作用在博来霉素诱导的小鼠肺损伤模型中得到证实，C57BL/6（CXCR4+/-）小鼠的胶原沉积明显少于C57BL/6（CXCR4+/+）小鼠。虽然家族性和散发性IIP之间存在实质性差异，但我们发现寻常间质性肺炎和非特异性间质性肺炎之间只有微小的基因表达变化。
综上所述，我们的研究结果表明，家族性和散发性IIP之间基因表达谱的差异可能为IIP的病因和发病机制提供线索。
