Fan Chunling, Meuchel Lucas W, Su Qingning, Angelini Daniel J, Zhang Ailan, Cheadle Chris, Kolosova Irina, Makarevich Oleg D, Yamaji-Kegan Kazuyo, Rothenberg Marc E, Johns Roger A
1 Department of Anesthesiology and Critical Care Medicine and.
2 School of Medicine, Shenzhen University, Shenzhen, China.
Am J Respir Cell Mol Biol. 2015 Sep;53(3):303-13. doi: 10.1165/rcmb.2014-0322OC.
Resistin-like molecule α (RELMα) has mitogenic, angiogenic, vasoconstrictive, and chemokine-like properties and is highly relevant in lung pathology. Here, we used RELMα knockout (Retnla(-/-)) mice to investigate the role of RELMα in pulmonary vascular remodeling after intermittent ovalbumin (OVA) challenge. We compared saline- and OVA-exposed wild-type (WT) mice and found that OVA induced significant increases in right ventricular systolic pressure, cardiac hypertrophy, pulmonary vascular remodeling of intra-alveolar arteries, goblet cell hyperplasia in airway epithelium, and intensive lung inflammation, especially perivascular inflammation. Genetic ablation of Retnla prevented the OVA-induced increase in pulmonary pressure and cardiac hypertrophy seen in WT mice. Histological analysis showed that Retnla(-/-) mice exhibited less vessel muscularization, less perivascular inflammation, reduced medial thickness of intra-alveolar vessels, and fewer goblet cells in upper airway epithelium (250-600 μm) than did WT animals after OVA challenge. Gene expression profiles showed that genes associated with vascular remodeling, including those related to muscle protein, contractile fibers, and actin cytoskeleton, were expressed at a lower level in OVA-challenged Retnla(-/-) mice than in similarly treated WT mice. In addition, bronchoalveolar lavage from OVA-challenged Retnla(-/-) mice had lower levels of cytokines, such as IL-1β, -1 receptor antagonist, and -16, chemokine (C-X-C motif) ligand 1, -2, -9, -10, and -13, monocyte chemoattractant protein-1, macrophage colony-stimulating factor, TIMP metallopeptidase inhibitor-1, and triggering receptor expressed on myeloid cells-1, than did that from WT mice when analyzed by cytokine array dot blots. Retnla knockout inhibited the OVA-induced T helper 17 response but not the T helper 2 response. Altogether, our results suggest that RELMα is involved in immune response-induced pulmonary vascular remodeling and the associated increase in inflammation typically observed after OVA challenge.
抵抗素样分子α（RELMα）具有促有丝分裂、血管生成、血管收缩和趋化因子样特性，在肺部病理学中具有高度相关性。在此，我们使用RELMα基因敲除（Retnla(-/-)）小鼠来研究RELMα在间歇性卵清蛋白（OVA）激发后肺血管重塑中的作用。我们比较了生理盐水处理组和OVA处理组的野生型（WT）小鼠，发现OVA可导致右心室收缩压显著升高、心脏肥大、肺泡内动脉的肺血管重塑、气道上皮杯状细胞增生以及严重的肺部炎症，尤其是血管周围炎症。Retnla基因敲除可防止WT小鼠出现OVA诱导的肺压力升高和心脏肥大。组织学分析表明，OVA激发后，Retnla(-/-)小鼠与WT动物相比，血管肌化程度更低、血管周围炎症更少、肺泡内血管中膜厚度减小，并且上呼吸道上皮（250 - 600μm）中的杯状细胞更少。基因表达谱显示，与血管重塑相关的基因，包括与肌肉蛋白、收缩纤维和肌动蛋白细胞骨架相关的基因，在OVA激发的Retnla(-/-)小鼠中的表达水平低于同样处理的WT小鼠。此外，通过细胞因子阵列斑点印迹分析，OVA激发的Retnla(-/-)小鼠支气管肺泡灌洗液中细胞因子水平较低，如白细胞介素 - 1β、白细胞介素 - 1受体拮抗剂、白细胞介素 - 16、趋化因子（C - X - C基序）配体1、配体2、配体9、配体10、配体13、单核细胞趋化蛋白 - 1、巨噬细胞集落刺激因子、TIMP金属蛋白酶抑制剂 - 1以及髓样细胞上表达的触发受体 - 1。Retnla基因敲除抑制了OVA诱导的辅助性T细胞17反应，但不影响辅助性T细胞2反应。总之，我们的结果表明，RELMα参与免疫反应诱导的肺血管重塑以及OVA激发后通常观察到的炎症相关增加。
