Ojielo Charles I, Cooke Kenneth, Mancuso Pete, Standiford Theodore J, Olkiewicz Krystyna M, Clouthier Shawn, Corrion Leigh, Ballinger Megan N, Toews Galen B, Paine Robert, Moore Bethany B
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109-0642, USA.
J Immunol. 2003 Oct 15;171(8):4416-24. doi: 10.4049/jimmunol.171.8.4416.
Bone marrow transplantation (BMT) is an important therapeutic option for a variety of malignant and nonmalignant disorders. Unfortunately, BMT recipients are at increased risk of infection, and in particular, pulmonary complications occur frequently. Although the risk of infection is greatest during the neutropenic period immediately following transplant, patients are still vulnerable to pulmonary infections even after neutrophil engraftment. We evaluated the risk of infection in this postengraftment period by using a well-established mouse BMT model. Seven days after syngeneic BMT, B6D2F(1) mice are no longer neutropenic, and by 3 wk, they demonstrate complete reconstitution of the peripheral blood. However, these mice remain more susceptible throughout 8 wk to infection after intratracheal administration of Pseudomonas aeruginosa; increased mortality in the P. aeruginosa-infected BMT mice correlates with increased bacterial burden in the lungs as well as increased systemic dissemination. This heightened susceptibility to infection was not secondary to a defect in inflammatory cell recruitment to the lung. The inability to clear P. aeruginosa in the lung correlated with reduced phagocytosis of the bacteria by alveolar macrophages (AMs), but not neutrophils, decreased production of TNF-alpha by AMs, and decreased levels of TNF-alpha and IFN-gamma in the bronchoalveolar lavage fluid following infection. Expression of the beta(2) integrins CD11a and CD11c was reduced on AMs from BMT mice compared with wild-type mice. Thus, despite restoration of peripheral blood count, phagocytic defects in the AMs of BMT mice persist and may contribute to the increased risk of infection seen in the postengraftment period.
骨髓移植（BMT）是治疗多种恶性和非恶性疾病的重要选择。不幸的是，BMT受者感染风险增加，尤其是肺部并发症频繁发生。虽然移植后立即出现的中性粒细胞减少期感染风险最大，但即使中性粒细胞植入后，患者仍易发生肺部感染。我们使用成熟的小鼠BMT模型评估了植入后期的感染风险。同基因BMT后7天，B6D2F(1)小鼠不再处于中性粒细胞减少状态，到3周时，它们的外周血显示完全重建。然而，在气管内给予铜绿假单胞菌后，这些小鼠在8周内仍更容易感染；铜绿假单胞菌感染的BMT小鼠死亡率增加与肺部细菌负荷增加以及全身播散增加相关。这种对感染的易感性增加并非继发于炎症细胞向肺部募集的缺陷。肺部无法清除铜绿假单胞菌与肺泡巨噬细胞（AMs）而非中性粒细胞对细菌的吞噬作用降低、AMs产生肿瘤坏死因子-α（TNF-α）减少以及感染后支气管肺泡灌洗液中TNF-α和干扰素-γ（IFN-γ）水平降低有关。与野生型小鼠相比，BMT小鼠AMs上β(2)整合素CD11a和CD11c的表达降低。因此，尽管外周血细胞计数恢复，但BMT小鼠AMs中的吞噬缺陷仍然存在，这可能导致植入后期感染风险增加。
