Leukocyte-derived IL-10 reduces subepithelial fibrosis associated with chronically inhaled endotoxin
Leukocyte-derived IL-10 reduces subepithelial fibrosis associated with chronically inhaled endotoxin
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DOI：
10.1165/rcmb.2006-0055oc
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发表时间：
2006-12-01
影响因子：
6.4
通讯作者：
Schwartz, David A.
中科院分区：
文献类型：
--
作者：
Garantziotis, Stavros;Brass, David M.;Schwartz, David A.
内毒素 (LPS) 是一种革兰氏阴性细胞壁成分，具有有效的促炎特性。急性 LPS 暴露会导致气道炎症；长期接触会导致气道过度反应和重塑。 IL-10 是一种重要的抗炎细胞因子，在患有气道疾病（例如哮喘和囊性纤维化）的患者中其水平会降低。研究 IL-10 在急性和慢性 LPS 相关气道疾病中的生理和治疗作用。小鼠接触雾化 LPS 一次或每天一次，持续 4 周。终点是气道炎症、气道对乙酰甲胆碱的反应性、细胞外基质蛋白表达和组织学分析。与 C5713L/6 小鼠相比，长期吸入 LPS 后，IL-10 缺陷小鼠的气道细胞结构和重塑显着增强。然而，他们表现出与较高的诱导型一氧化氮合酶（iNOS）、内皮型一氧化氮合酶（eNOS）和肺灌洗液亚硝酸盐水平相关的气道高反应性较低。在骨髓移植模型中，IL-10的抗炎作用依赖于造血而不是实质IL-10的表达。诱导上皮人 IL-10 表达可免受 LPS 的影响，并导致胶原蛋白产生减少。 IL-10 可减轻慢性 LPS 引起的气道炎症和重塑。生理学上，IL-10的抗炎作用是由造血细胞介导的。在治疗上，腺病毒驱动的人IL-10在气道上皮细胞中的表达足以发挥其对炎症和重塑的保护作用。 IL-10 对气道高反应性的作用很复杂：IL-10 缺乏可以防止 LPS 诱导的高反应性，并且与较高的 eNOS、iNOS 和气道硝酸盐水平相关。
Endotoxin (LPS), a Gram-negative cell wall component, has potent proinflammatory properties. Acute LPS exposure causes airway inflammation; chronic exposure causes airway hyperreactivity and remodeling. IL-10 is an important antiinflammatory cytokine, which is decreased in patients with airway disease, such as asthma and cystic fibrosis. To examine the physiologic and therapeutic role of IL-10 in acute and chronic LPS-incluced airway disease. Mice were exposed to aerosolized LPS once or daily for 4 wk. Endpoints were airway inflammation, airway reactivity to methacholine, extracellular matrix protein expression, and histologic analysis. IL-10-deficient mice developed significantly enhanced airway cellularity and remodeling when compared with C5713L/6 mice after chronic LPS inhalation. However they demonstrated less airway hyperreactivity associated with higher inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and lung lavage fluid nitrite levels. In a bone marrow transplantation model, the IL-10 antiinflammatory effect was dependent on the hematopoletic but not on the parenchymal IL-10 expression. Induced epithelial human IL-10expression protected from the LPS effects and led to decreased Collagen production. IL-10 attenuates chronic LPS-incluced airway inflammation and remodeling. Physiologically, the antiinflammatory effect of IL-10 is mediated by hematopoietic cells. Therapeutically, adenovirus-driven expression of human IL-10 in airway epithelia is sufficient for its protective effect on inflammation and remodeling. The role of IL-10 on airway hyperreactivity is complex: IL-10 deficiency protects against LPS-induced hyperreactivity, and is associated with higher eNOS, iNOS, and airway nitrate levels.