Yu H, Hanes M, Chrisp C E, Boucher J C, Deretic V
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor 48109, USA.
Infect Immun. 1998 Jan;66(1):280-8. doi: 10.1128/IAI.66.1.280-288.1998.
Chronic endobronchiolitis compounded by recurring Pseudomonas aeruginosa infections is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). In this study, a mouse model of repeated respiratory exposure to P. aeruginosa was established to facilitate investigations of factors contributing to P. aeruginosa persistence and associated inflammatory processes in the lung. While a single exposure to P. aeruginosa aerosols resulted in only mild histopathological changes, repeated exposure caused significant lung pathology in C57BL/6J mice. The peak of histopathological changes and inflammation in C57BL/6J mice was characterized by subacute lymphohistiocytic bronchopneumonia and persistent elevation of tumor necrosis factor alpha and macrophage inflammatory protein 2 in the lung but not in the serum. When isogenic nonmucoid (mucA+) and mucoid (mucA22) P. aeruginosa strains were compared, the mucoid cells were cleared several-fold less efficiently than the parental nonmucoid strain during the initial stages of the aerosol exposure regimen. However, the microscopic pathology findings and proinflammatory cytokine levels were similar in mice exposed to nonmucoid and mucoid P. aeruginosa throughout the infection. We also tested lung histopathology and proinflammatory cytokines in interleukin 10 (IL-10)-deficient transgenic (IL-10T) mice. Significant mortality was seen in IL-10T mice on initial challenge with P. aeruginosa, although no histopathological differences could be observed in the lungs of C57BL/6J and surviving IL-10T mice after a single exposure. However, increased pathology was detected in IL-10T mice relative to C57BL/6J after repeated challenge with P. aeruginosa. This observation supports the proposals that anti-inflammatory cytokines may play a role in suppressing P. aeruginosa-induced tissue damage during chronic infection.
慢性细支气管炎合并反复的铜绿假单胞菌感染是囊性纤维化（CF）患者发病和死亡的主要原因。在本研究中，建立了小鼠反复呼吸道暴露于铜绿假单胞菌的模型，以促进对导致铜绿假单胞菌在肺部持续存在及相关炎症过程的因素的研究。虽然单次暴露于铜绿假单胞菌气雾剂仅导致轻微的组织病理学变化，但反复暴露在C57BL/6J小鼠中引起了显著的肺部病变。C57BL/6J小鼠组织病理学变化和炎症的高峰表现为亚急性淋巴细胞组织细胞性支气管肺炎，以及肺中肿瘤坏死因子α和巨噬细胞炎性蛋白2持续升高，但血清中未升高。当比较同基因非黏液型（mucA+）和黏液型（mucA22）铜绿假单胞菌菌株时，在气雾剂暴露方案的初始阶段，黏液型细胞的清除效率比亲代非黏液型菌株低几倍。然而，在整个感染过程中，暴露于非黏液型和黏液型铜绿假单胞菌的小鼠的微观病理学发现和促炎细胞因子水平相似。我们还在白细胞介素10（IL-10）缺陷转基因（IL-10T）小鼠中测试了肺组织病理学和促炎细胞因子。IL-10T小鼠在初次感染铜绿假单胞菌时出现显著死亡，尽管单次暴露后在C57BL/6J小鼠和存活的IL-10T小鼠的肺中未观察到组织病理学差异。然而，在反复感染铜绿假单胞菌后，相对于C57BL/6J小鼠，IL-10T小鼠中检测到病理学增加。这一观察结果支持了抗炎细胞因子可能在慢性感染期间抑制铜绿假单胞菌诱导的组织损伤中起作用的观点。
