Blease K, Mehrad B, Lukacs N W, Kunkel S L, Standiford T J, Hogaboam C M
Department of Pathology, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
J Immunol. 2001 Feb 1;166(3):1832-42. doi: 10.4049/jimmunol.166.3.1832.
Asperigillus fumigatus spores or conidia are quickly eliminated from the airways of nonsensitized individuals but persist in individuals with allergic pulmonary responsiveness to fungus. A. fumigatus-induced allergic airway disease is characterized by persistent airway hyperreactivity, inflammation, and fibrosis. The present study explored the role of CCR2 ligands in the murine airway response to A. fumigatus conidia. Nonsensitized and A. fumigatus-sensitized CBA/J mice received an intratracheal challenge of A. fumigatus conidia, and pulmonary changes were analyzed at various times after conidia. Whole lung levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), but neither MCP-3/CCL7 nor MCP-5/CCL12, were significantly elevated at days 3 and 7 after conidia in nonsensitized mice. MCP-1/CCL2 was significantly increased in lung samples from A. fumigatus-sensitized mice at days 14 and 30 after a conidia challenge. Administration of anti-MCP-1/CCL2 antiserum to nonsensitized mice for14 days after the conidia challenge attenuated the clearance of conidia and significantly increased airway hyperreactivity, eosinophilia, and peribronchial fibrosis compared with nonsensitized mice that received conidia and normal serum. Adenovirus-directed overexpression of MCP-1/CCL2 in A. fumigatus-sensitized mice markedly reduced the number of conidia, airway inflammation, and airway hyperresponsiveness at day 7 after the conidia challenge in these mice. Immunoneutralization of MCP-1/CCL2 levels in A. fumigatus-sensitized mice during days14-30 after the conidia challenge did not affect the conidia burden but significantly reduced airway hyperreactivity, lung IL-4 levels, and lymphocyte recruitment into the airways compared with the control group. These data suggest that MCP-1/CCL2 participates in the pulmonary antifungal and allergic responses to A. fumigatus conidia.
烟曲霉孢子或分生孢子可迅速从非致敏个体的气道中清除，但在对真菌具有过敏性肺反应性的个体中会持续存在。烟曲霉诱导的过敏性气道疾病的特征是持续性气道高反应性、炎症和纤维化。本研究探讨了CCR2配体在小鼠气道对烟曲霉分生孢子反应中的作用。非致敏和烟曲霉致敏的CBA/J小鼠接受烟曲霉分生孢子气管内攻击，并在分生孢子攻击后的不同时间分析肺部变化。在非致敏小鼠中，分生孢子攻击后第3天和第7天，全肺单核细胞趋化蛋白-1（MCP-1/CCL2）水平显著升高，但MCP-3/CCL7和MCP-5/CCL12水平均未升高。分生孢子攻击后第14天和第30天，烟曲霉致敏小鼠的肺样本中MCP-1/CCL2显著增加。在分生孢子攻击后给非致敏小鼠注射抗MCP-1/CCL2抗血清14天，与接受分生孢子和正常血清的非致敏小鼠相比，分生孢子的清除减弱，气道高反应性、嗜酸性粒细胞增多和支气管周围纤维化显著增加。在烟曲霉致敏小鼠中，通过腺病毒介导MCP-1/CCL2过表达，在分生孢子攻击后第7天，这些小鼠的分生孢子数量、气道炎症和气道高反应性显著降低。在分生孢子攻击后第14 - 30天，对烟曲霉致敏小鼠的MCP-1/CCL2水平进行免疫中和，与对照组相比，不影响分生孢子负荷，但显著降低气道高反应性肺IL-4水平和淋巴细胞向气道的募集。这些数据表明，MCP-1/CCL2参与了肺部对烟曲霉分生孢子的抗真菌和过敏反应。
