Johansen H K
APMIS Suppl. 1996;63:5-42. doi: 10.1111/j.1600-0463.1996.tb05581.x.
In patients with cystic fibrosis (CF), respiratory tract infections caused by Staphylococcus aureus and Haemophilus influenzae are followed by Pseudomonas aeruginosa with increasing age. Chronic endobronchial lung infection with P. aeruginosa is the leading cause of morbidity and mortality. In Danish CF patients we noted that both onset of initial colonization and chronic lung infection with P. aeruginosa peaked during the winter months which is the season for respiratory virus infections. Virus may therefore pave the way for P. aeruginosa. We established a chronic P. aeruginosa lung infection in rats by embedding mucoid bacteria in seaweed alginate and installing the beads intratracheally into the lower part of the left lung. Although the rats did not suffer from CF, the antibody responses and the pathologic changes of the lungs mimicked the findings in CF patients. By using this model in normal and athymic rats we showed that the T-cell response during the "natural" course of the infection played no major role. In a model of acute P. aeruginosa pneumonia we found that the macroscopic inflammatory response of the lungs was immense and that the natural capacity to clear P. aeruginosa was very efficient and could not be improved by immunization, although high serum levels of IgM, IgG and IgA antibodies to P. aeruginosa alginate, LPS, exotoxin A and sonicate were induced. We developed a method for collecting and measuring IgA in saliva and noted that mucosal IgA antibodies were induced by vaccination; they did not significantly prevent inflammation, however. In the chronic rat model we succeeded to improve the survival significantly and to change the inflammatory response subsequent to vaccination from an acute type inflammation dominated by polymorphonuclear leukocytes (PMNs) as in CF patients to a chronic type inflammation dominated by mononuclear leukocytes. Furthermore, we found that rats immunized with an alginate containing vaccine had a significantly earlier cellular shift to a chronic type inflammation as well as a significant reduction in the severity of the macroscopic inflammation compared to two other vaccine groups and to nonimmunized controls. Similar results were obtained in rats treated with the TH1 cytokine, interferon-gamma (IFN-gamma). Several authors have shown that the lung tissue damage during chronic infection in CF patients is caused by a type III hypersensitivity reaction leading to release of elastase by PMNs surrounding the bacterial microcolonies. The cellular shift we have induced by vaccination and by IFN-gamma treatment therefore offers a possible new strategy for improving the clinical course in chronically infected CF patients.
在囊性纤维化（CF）患者中，随着年龄增长，由金黄色葡萄球菌和流感嗜血杆菌引起的呼吸道感染之后会出现铜绿假单胞菌感染。铜绿假单胞菌引起的慢性支气管内肺部感染是发病和死亡的主要原因。在丹麦的CF患者中，我们注意到铜绿假单胞菌的初始定植和慢性肺部感染的发病高峰均出现在冬季，而冬季是呼吸道病毒感染的季节。因此，病毒可能为铜绿假单胞菌感染铺平道路。我们通过将黏液样细菌包埋在海藻酸盐中，并将珠子经气管内植入左肺下部，在大鼠中建立了慢性铜绿假单胞菌肺部感染。尽管大鼠没有患CF，但抗体反应和肺部的病理变化与CF患者的表现相似。通过在正常大鼠和无胸腺大鼠中使用该模型，我们发现感染“自然”过程中的T细胞反应没有起主要作用。在急性铜绿假单胞菌肺炎模型中，我们发现肺部的宏观炎症反应很强烈，清除铜绿假单胞菌的天然能力非常有效，并且尽管诱导了针对铜绿假单胞菌藻酸盐、脂多糖、外毒素A和超声处理产物的高血清水平的IgM、IgG和IgA抗体，但免疫并不能改善这种清除能力。我们开发了一种收集和测量唾液中IgA的方法，并注意到接种疫苗可诱导黏膜IgA抗体；然而，它们并不能显著预防炎症。在慢性大鼠模型中，我们成功地显著提高了生存率，并将接种疫苗后的炎症反应从CF患者中以多形核白细胞（PMN）为主的急性炎症类型转变为以单核白细胞为主的慢性炎症类型。此外，我们发现与其他两个疫苗组和未免疫对照组相比，用含藻酸盐疫苗免疫的大鼠细胞向慢性炎症类型的转变明显更早，并且宏观炎症的严重程度显著降低。在用TH1细胞因子干扰素-γ（IFN-γ）治疗的大鼠中也获得了类似的结果。几位作者已经表明，CF患者慢性感染期间的肺组织损伤是由III型超敏反应引起的，导致围绕细菌微菌落的PMN释放弹性蛋白酶。因此，我们通过接种疫苗和IFN-γ治疗诱导的细胞转变为改善慢性感染的CF患者的临床病程提供了一种可能的新策略。
