Mehrad B, Strieter R M, 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. 1999 Feb 1;162(3):1633-40.
Invasive pulmonary aspergillosis is a common and devastating complication of immunosuppression, whose incidence has increased dramatically in tandem with the increase in the number of immunocompromised patients. Given the role of TNF-alpha in other pulmonary infections, we hypothesized that TNF-alpha is an important proximal signal in murine invasive pulmonary aspergillosis. Intratracheal challenge with Aspergillus fumigatus conidia in both neutropenic (cyclophosphamide-treated) and nonneutropenic BALB/c mice resulted in the time-dependent increase in lung TNF-alpha levels, which correlated with the histologic development of a patchy, peribronchial infiltration of mononuclear and polymorphonuclear cells. Ab-mediated neutralization of TNF-alpha resulted in an increase in mortality in both normal and cyclophosphamide-treated animals, which was associated with increased lung fungal burden as determined by histology and as quantified by chitin content. Depletion of TNF-alpha resulted in a reduced lung neutrophil influx in both normal and cyclophosphamide-treated animals, which occurred in association with a decrease in lung levels of the C-X-C chemokine, macrophage inflammatory protein-2 and the C-C chemokines macrophage inflammatory protein-1alpha and JE. In cyclophosphamide-treated animals, intratracheal administration of a TNF-alpha agonist peptide (TNF70-80) 3 days before, but not concomitant with, the administration of Aspergillus conidia resulted in improved survival from 9% in control mice to 55% in TNF70-80-treated animals. These studies indicate that TNF-alpha is a critical component of innate immunity in both immunocompromised and immunocompetent hosts, and that pretreatment with a TNF-alpha agonist peptide in a compartmentalized fashion can significantly enhance resistance to A. fumigatus in neutropenic animals.
侵袭性肺曲霉病是免疫抑制常见且严重的并发症，其发病率随着免疫功能低下患者数量的增加而急剧上升。鉴于肿瘤坏死因子-α（TNF-α）在其他肺部感染中的作用，我们推测TNF-α是小鼠侵袭性肺曲霉病中一个重要的近端信号。在中性粒细胞减少（经环磷酰胺处理）和非中性粒细胞减少的BALB/c小鼠中气管内接种烟曲霉分生孢子，导致肺TNF-α水平随时间增加，这与单核细胞和多形核细胞的斑片状、支气管周围浸润的组织学发展相关。抗体介导的TNF-α中和导致正常和环磷酰胺处理动物的死亡率增加，这与组织学确定并通过几丁质含量量化的肺部真菌负荷增加有关。TNF-α的耗竭导致正常和环磷酰胺处理动物的肺中性粒细胞流入减少，这与肺中C-X-C趋化因子、巨噬细胞炎性蛋白-2以及C-C趋化因子巨噬细胞炎性蛋白-1α和JE水平的降低相关。在环磷酰胺处理的动物中，在接种烟曲霉分生孢子前3天而非同时气管内给予TNF-α激动剂肽（TNF70-80），使存活率从对照小鼠的9%提高到TNF70-80处理动物的55%。这些研究表明，TNF-α是免疫功能低下和免疫功能正常宿主先天免疫的关键组成部分，并且以分区方式用TNF-α激动剂肽预处理可显著增强中性粒细胞减少动物对烟曲霉的抵抗力。
