不同免疫抑制剂对小鼠罹患侵袭性肺曲霉病的影响

Comparison of two immunosuppressive agents on the infection and inflammation of experimental invasive pulmonary aspergillosis mice models

目的比较两种免疫抑制状态造成侵袭性曲霉感染(IPA)后天然免疫反应的异同。方法清洁级雄性BALB/c小鼠,分别使用地塞米松(A组)及环磷酰胺(B组)预处理后气道接种烟曲霉孢子建立IPA模型。观察小鼠存活率,肺病理检查,评估肺部及肺外脏器真菌负荷;支气管肺泡灌洗液(BALF)检测促炎、抗炎细胞因子浓度。结果 A组小鼠平均生存期与B组比较有显著差异。病理提示A组小鼠肺组织有大量炎症细胞聚集;B组可见到典型的曲霉菌丝浸润性生长。B组小鼠肺部烟曲霉CFU、烟曲霉18srRNA较A组升高;B组肺外各脏器与A组比较均具有统计学差异。检测BALF中炎症因子:A组TNF-α未检测到,IL-10峰值在72h出现,IL-1α自第一天起即升高,第3天达峰值;B组TNF-α及IL-10在24h后均明显升高,于48h达峰值;IL-1α一直在低水平维持;B组与各组间比较,TNF-α、IL-1α及IL-10均有显著差异。A、B两组IL-1β表达在接种烟曲霉后均迅速升高,并一直在高水平维持,两组间无差异。结论不同预处理造成小鼠免疫抑制后建立IPA模型,激素组肺部出现明显的炎症反应;环磷酰胺组可出现显著的全身真菌播散。

Objective To establish an experimental immunosuppressed mice model of invasive pulmonary aspergillosis （IPA） ,to e- valuated various parameters of the innate immune response during the progression of IPA.Methods Immunosuppressed mice received the intratracheal administration of A.fumigatus conidia after two immunosuppressive treatments： a corticosteroid （group A） and a cyclophosphamidum agent （group B）.We compared host responses 24 h, 48 h and 72 h after infection in terms of survival,lung tissue histopathological analysis, fungal burden, pulmonary production of pro- and anti-inflammatory cytokines. Results The group A showed longer survival than group B did （5.33 vs 2.5 d, P 〈0.05）.Group A showed severe bleeding and congestive, and lung tissue granuloma formation; while group B showed visible A.fumigatus hyphae, tissue necrosis 48 h after infection.Through CFUs and A. fumigatus 18sRNA detections, fugal burdens were significantly lower in lungs of corticosteroid-treated mice than those of cyclophos- phamidum-treated mice.This difference was also observed in livers and kidneys,indicating that the level of fungal dissemination was higher in group B than that of group A.In group B mice,the IL-10 concentration increased by 48 h after infection and peaked at 72 h （86＋15 pg/mL）.No TNF-a production was detected. In group A mice, both TNF-α and IL-10 were detected at very high concentra- tions at 48 h （3 120±393,434 ±97 pg/mL）.IL-1α expression increased 24 h after infection in group A mice and continually increased within the 3 days.But in group B,IL-1α concentrations maintained with low level.In both group A and B,the expressions of IL-1β in- creased dramatically after infection.Conclusion Establishing the IPA animal models of the mice by corticosteroid and chemotherapy- treated, We found that IPA pathogenesis was difference between the two groups ： the inflammation response of lung was severe in cor- ticosteroid-treated mice than those in chemotherapy-treated mice, while chemotherapy-treated mice showing an adverse host response.