An Essential Role for Resident Fibroblasts in Experimental Lung Fibrosis Is Defined by Lineage-Specific Deletion of High-Affinity Type II Transforming Growth Factor β Receptor
An Essential Role for Resident Fibroblasts in Experimental Lung Fibrosis Is Defined by Lineage-Specific Deletion of High-Affinity Type II Transforming Growth Factor β Receptor
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DOI：
10.1164/rccm.201002-0279oc
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发表时间：
2011-01-15
影响因子：
24.7
通讯作者：
Denton, Christopher P.
中科院分区：
文献类型：
--
作者：
Hoyles, Rachel K.;Derrett-Smith, Emma C.;Denton, Christopher P.
理论基础：肺损伤的纤维化反应取决于肌成纤维细胞群的成纤维性发展。常驻间质成纤维细胞的重要性以及转化生长因子β (TGF β)在这一过程中的作用尚不清楚。目的：明确常驻肺成纤维细胞TGF β信号在实验性肺纤维化发展中的重要性。方法：采用复合遗传策略，将高亲和型II型TGF β受体（T β RII）等位基因的小鼠纯合子与含有成纤维细胞特异性转基因编码配体依赖性cre -重组酶的转基因菌株杂交。T β RII通过出生后给予他莫昔芬超过5天的复合突变小鼠与适当的同侪对照而被删除。II .利用微阵列基因图谱和定量逆转录聚合酶链反应证实外植肺成纤维细胞对TGF β的能量。采用博来霉素肺损伤法诱导肺纤维化，采用组织学和生化方法进行分析。免疫荧光法测定肺损伤后的细胞群。测量结果和主要结果：在常驻成纤维细胞中删除T β RII后，小鼠的纤维化明显减弱。损伤后7天，纤维细胞和肌成纤维细胞的数量明显减少。通过基因表达谱，确定了关键的候选纤维化基因，包括野生型而非突变型肺成纤维细胞表达的结缔组织生长因子和内皮素-1，提示了纤维化的潜在调节因子。结论：常驻肺成纤维细胞中完整的TGF β信号对于肺纤维化的发生至关重要。我们的数据支持这些细胞在决定纤维细胞募集和肌成纤维细胞分化中的关键调节作用。
Rationale: Fibrotic response to lung injury depends on development of a fibrogenic population of myofibroblasts. The importance of resident interstitial fibroblasts and role of transforming growth factor beta (TGF beta) in this process is unclear.Objectives: To define the importance of TGF beta signaling in resident lung fibroblasts in the development of experimental pulmonary fibrosis.Methods: A compound genetic strategy in which mice homozygous for a floxed high-affinity type II TGF beta receptor (T beta RII) allele were crossed with a transgenic strain harboring a fibroblast-specific transgene encoding ligand-dependent Cre-recombinase was used. T beta RII was deleted by postnatal administration of tamoxifen over 5 days to compound mutant mice with appropriate littermate controls. II lumina microarray gene profiling and quantitative reverse transcriptase-polymerase chain reaction were used to confirm anergy to TGF beta in explanted lung fibroblasts. Bleomycin lung injury was used to induce lung fibrosis, which was analyzed by histology and biochemical methods. Immunofluorescence was used to define cell populations after lung injury.Measurements and Main Results: There was significant attenuation of fibrosis in mice after deletion of T beta RII in resident fibroblasts. At 7 days after injury the number of fibrocytes and myofibroblasts was substantially reduced. Potential regulators of fibrosis were suggested by gene expression profiles that identified key candidate profibrotic genes, including connective tissue growth factor and endothelin-1 expressed by wild-type but not mutant lung fibroblasts.Conclusions: Intact TGF beta signaling in resident pulmonary fibroblasts is essential for pulmonary fibrosis to develop. Our data support a key regulatory role of these cells in determining fibrocyte recruitment and myofibroblast differentiation.