Liu Tianju, Yu Hongfeng, Ullenbruch Matthew, Jin Hong, Ito Toshihiro, Wu Zhe, Liu Jianhua, Phan Sem H
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
PLoS One. 2014 Feb 6;9(2):e88362. doi: 10.1371/journal.pone.0088362. eCollection 2014.
FIZZ (found in inflammatory zone) 1, a member of a cysteine-rich secreted protein family, is highly induced in lung allergic inflammation and bleomycin induced lung fibrosis, and primarily expressed by airway and type II alveolar epithelial cells. This novel mediator is known to stimulate α-smooth muscle actin and collagen expression in lung fibroblasts. The objective of this study was to investigate the in vivo effects of FIZZ1 on the development of lung fibrosis by evaluating bleomycin-induced pulmonary fibrosis in FIZZ1 deficient mice. FIZZ1 knockout mice exhibited no detectable abnormality. When these mice were treated with bleomycin they exhibited significantly impaired pulmonary fibrosis relative to wild type mice, along with impaired proinflammatory cytokine/chemokine expression. Deficient lung fibroblast activation was also noted in the FIZZ1 knockout mice. Moreover, recruitment of bone marrow-derived cells to injured lung was deficient in FIZZ1 knockout mice. Interestingly in vitro FIZZ1 was shown to have chemoattractant activity for bone marrow cells, including bone marrow-derived dendritic cells. Finally, overexpression of FIZZ1 exacerbated fibrosis. These findings suggested that FIZZ1 exhibited profibrogenic properties essential for bleomycin induced pulmonary fibrosis, as reflected by its ability to induce myofibroblast differentiation and recruit bone marrow-derived cells.
富含半胱氨酸的分泌蛋白家族成员FIZZ（发现于炎症区域）1在肺部过敏性炎症和博来霉素诱导的肺纤维化中高度表达，主要由气道和II型肺泡上皮细胞表达。已知这种新型介质可刺激肺成纤维细胞中α平滑肌肌动蛋白和胶原蛋白的表达。本研究的目的是通过评估博来霉素诱导的FIZZ1基因敲除小鼠的肺纤维化，来研究FIZZ1在体内对肺纤维化发展的影响。FIZZ1基因敲除小鼠未表现出可检测到的异常。当用博来霉素处理这些小鼠时，相对于野生型小鼠，它们表现出明显受损的肺纤维化，同时促炎细胞因子/趋化因子表达也受损。在FIZZ1基因敲除小鼠中还发现肺成纤维细胞活化不足。此外，FIZZ1基因敲除小鼠中骨髓来源的细胞向受损肺的募集不足。有趣的是，在体外FIZZ1对包括骨髓来源的树突状细胞在内的骨髓细胞具有趋化活性。最后，FIZZ1的过表达加剧了纤维化。这些发现表明，FIZZ1表现出对博来霉素诱导的肺纤维化至关重要的促纤维化特性，这体现在其诱导肌成纤维细胞分化和募集骨髓来源细胞的能力上。
