Mehrad B, Moore T A, Standiford T J
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
J Immunol. 2000 Jul 15;165(2):962-8. doi: 10.4049/jimmunol.165.2.962.
Invasive pulmonary aspergillosis is a devastating complication of immunosuppression that usually occurs in neutropenic patients. In this setting, augmentation of the antifungal activity of available immune cells may improve the outcome of the infection. Macrophage inflammatory protein-1 alpha (MIP-1 alpha) is a CC chemokine with potent chemotactic activity for various subsets of mononuclear leukocytes. We therefore tested the hypothesis that the influx of mononuclear cells into the lung in invasive pulmonary aspergillosis is in part mediated by MIP-1 alpha, and the manipulation of this ligand alters the outcome of the infection. We found that in both immunocompetent and neutropenic mice, MIP-1 alpha was induced in the lungs in response to intratracheal administration of Aspergillus fumigatus conidia. In neutrophil-depleted mice challenged with intratracheal conidia, there was evidence of invasive fungal pneumonia associated with a predominantly mononuclear leukocyte infiltrate. Ab-mediated depletion of MIP-1 alpha resulted in a 6-fold increase in mortality in neutropenic mice, which was associated with a 12-fold increase in lung fungal burden. Studies of single-cell suspensions of whole lungs revealed a 36% decrease in total lung leukocyte infiltration as a result of MIP-1 alpha neutralization. Flow cytometry on whole lung suspensions showed a 41% reduction in lung monocyte/macrophages as a result of MIP-1 alpha neutralization, but no difference in other lung leukocyte subsets. These studies indicate that MIP-1 alpha is a critical mediator of host defense against A. fumigatus in the setting of neutropenia and may be an important target in devising future therapeutic strategies against invasive aspergillosis.
侵袭性肺曲霉病是免疫抑制的一种毁灭性并发症，通常发生在中性粒细胞减少的患者中。在这种情况下，增强现有免疫细胞的抗真菌活性可能会改善感染的结局。巨噬细胞炎性蛋白-1α（MIP-1α）是一种CC趋化因子，对单核白细胞的各个亚群具有强大的趋化活性。因此，我们检验了以下假设：侵袭性肺曲霉病中单核细胞流入肺部部分是由MIP-1α介导的，并且对该配体的操控会改变感染的结局。我们发现，在免疫功能正常和中性粒细胞减少的小鼠中，气管内给予烟曲霉菌分生孢子后，肺部都会诱导产生MIP-1α。在用气管内分生孢子攻击的中性粒细胞减少的小鼠中，有证据表明存在侵袭性真菌性肺炎，伴有以单核白细胞为主的浸润。抗体介导的MIP-1α缺失导致中性粒细胞减少的小鼠死亡率增加6倍，这与肺部真菌负荷增加12倍有关。对全肺单细胞悬液的研究表明，由于MIP-1α中和，全肺白细胞浸润减少了36%。对全肺悬液进行的流式细胞术分析显示，由于MIP-1α中和，肺单核细胞/巨噬细胞减少了41%，但其他肺白细胞亚群没有差异。这些研究表明，MIP-1α是中性粒细胞减少情况下宿主抵御烟曲霉的关键介质，可能是设计未来抗侵袭性曲霉病治疗策略的重要靶点。
