Matuschak G M, Lechner A J
Department of Internal Medicine, Saint Louis University Health Sciences Center, USA.
Crit Care Med. 1997 Jan;25(1):111-20. doi: 10.1097/00003246-199701000-00022.
Dimorphic Candida albicans spp. increasingly cause lethal septic shock and disseminated infection in the critically ill. Following candidemia, production of specific fungal exotoxins coincident with the yeast to hyphal phenotypic transition is believed to be important in the pathogenesis of Candida septic shock. However, overexpression of the pleiotropic cytokine tumor necrosis factor (TNF)-alpha by the host following hyphal germination is also thought to be a mechanism of Candida-related cardiopulmonary dysfunction, as well as of bacteremic shock. In this study, we hypothesized that increases in circulating TNF-alpha coinciding with the yeast to hyphal transition modulate the onset and progression of shock with multiple organ injury early after hematogenous candidiasis.
Prospective, controlled laboratory animal study.
University hospital animal research facility.
Pathogen-free, male Sprague-Dawley rats (n = 26).
Conscious, antibiotic-treated animals with chronic indwelling carotid arterial and jugular venous catheters were intravenously infected with 10(9) viable blastoconidia of the C. albicans clinical pathogen, CA-MEN (n = 10), over 30 mins and ending at t = 0 hr, compared with an equivalent inoculum of its viable agerminative mutant, CA-MM2002 n = 11), or an intravenous infusion of 0.9% sodium chloride (n = 5).
Mean arterial pressure (MAP), pulse rate, respiratory frequency, rectal temperature, acid-base status, quantitative blood cultures, circulating alanine aminotransferase (ALT), and bioactive TNF-alpha were serially measured in all three groups over 24 hrs or until death. Organ cultures, wet/dry weight ratios, and histopathologic changes in the lungs, heart, liver, and kidneys were determined in Candida-infected and 0.9% sodium chloride (normal saline)-infused subgroups at 6 and 24 hrs. Animals hematogenously infected with the C. albicans clinical isolate developed lethal nonendotoxemic shock in < or = 6 hrs (MAP 49 +/- 7 mm Hg [SEM]; p < .05 vs. t = 0 hr), and at death (7.0 +/- 0.3 hrs) were acidotic, hypocapnic, and hypothermic (rectal temperature 33.2 +/- 0.7 degrees C). Despite similar peak concentrations of circulating fungal colony-forming units (cfu) and kinetics of vascular clearance in both Candida-infected groups, survival and MAP in rats challenged with the agerminative C. albicans mutant were unchanged for > 8 hrs, as were pH, Pco2, and rectal temperature. No germination of the agerminative fungal strain occurred in vivo over 6 hrs. Serum TNF was nearly undetectable at t = 0 hr in all three groups. Although shock developed soon after fungemia with the C. albicans clinical isolate, TNF-alpha concentrations did not increase above normal saline values in either candidemic group at t = 1.5, 4.5, or 6 hrs (17 +/- 7 vs. 14 +/- 1 U/mL in the parent C. albicans organism vs. its agerminative mutant at t = 6 hrs). Greater numbers of agerminative C. albicans than its dimorphic parent strain were recovered from the lungs (5.41 +/- 1.0 vs. 2.02 +/- 0.38 x 10(7) cfu/g, respectively; p < .05) and kidneys (p < .01). By 24 hrs, modest germination of the mutant Candida strain was observed in the tissues. However, lung wet/dry ratios, intrapulmonary hyphal proliferation, and alveolar hemorrhage were all greater after infection with the parent fungal isolate. Likewise, myocardial necrosis and hepatic glycogen depletion with vacuolization were more severe after infection with the C. albicans clinical isolate vs. candidemia with its agerminative mutant, although serum ALT values did not differ between these groups.
Lethal C. albicans sepsis with lung injury and multiple organ damage are temporally associated with the in vivo yeast to hyphal transition in this model. However, this candidemic septic shock syndrome is modulated by circulating fungal virulence factors or host mediators other than TNF-alpha, a cytokine considered essen
二态性白色念珠菌在危重症患者中越来越多地导致致命性感染性休克和播散性感染。念珠菌血症发生后，与酵母型向菌丝型表型转变同时出现的特定真菌外毒素的产生，被认为在念珠菌感染性休克的发病机制中起重要作用。然而，宿主在菌丝萌发后多效性细胞因子肿瘤坏死因子（TNF）-α的过度表达，也被认为是念珠菌相关心肺功能障碍以及菌血症性休克的一种机制。在本研究中，我们假设血源性念珠菌病早期，与酵母型向菌丝型转变同时出现的循环TNF-α升高，会调节伴有多器官损伤的休克的发生和进展。
前瞻性对照实验室动物研究。
大学医院动物研究设施。
无病原体的雄性Sprague-Dawley大鼠（n = 26）。
对有意识、经抗生素治疗且留置慢性颈动脉和颈静脉导管的动物，在30分钟内静脉注射10⁹个白色念珠菌临床病原体CA-MEN的活芽生孢子（n = 10），于t = 0小时结束，与其等量接种其无芽生突变体CA-MM2002（n = 11）或静脉输注0.9%氯化钠（n = 5）进行比较。
在24小时内或直至死亡，对所有三组连续测量平均动脉压（MAP）、脉搏率、呼吸频率、直肠温度、酸碱状态、定量血培养、循环丙氨酸氨基转移酶（ALT）和生物活性TNF-α。在6小时和24小时时，对念珠菌感染组和输注0.9%氯化钠（生理盐水）组的肺、心脏、肝脏和肾脏进行器官培养、湿/干重比和组织病理学变化测定。血源性感染白色念珠菌临床分离株的动物在≤6小时内发生致命性非内毒素性休克（MAP 49±7 mmHg [SEM]；与t = 0小时相比，p < 0.05），死亡时（7.0±0.3小时）出现酸中毒、低碳酸血症和体温过低（直肠温度33.2±0.7℃）。尽管两个念珠菌感染组的循环真菌集落形成单位（cfu）峰值浓度和血管清除动力学相似，但用无芽生白色念珠菌突变体攻击的大鼠的存活率和MAP在> 8小时内未改变，pH、Pco₂和直肠温度也未改变。无芽生真菌菌株在体内6小时内未发生萌发。所有三组在t = 0小时时血清TNF几乎检测不到。尽管白色念珠菌临床分离株菌血症后很快发生休克，但在t = 1.5、4.5或6小时时，两个念珠菌血症组的TNF-α浓度均未高于生理盐水值（白色念珠菌亲本菌株在t = 6小时时为17±7 U/mL，其无芽生突变体为14±1 U/mL）。从肺（分别为5.41±1.0与2.02±0.38×10⁷ cfu/g；p < 0.05）和肾脏（p < 0.01）中回收的无芽生白色念珠菌数量多于其二态性亲本菌株。到24小时时，在组织中观察到突变念珠菌菌株有适度萌发。然而，用亲本真菌分离株感染后，肺湿/干比、肺内菌丝增殖和肺泡出血均更严重。同样，与无芽生突变体念珠菌血症相比，白色念珠菌临床分离株感染后心肌坏死和肝糖原耗竭伴空泡化更严重，尽管这些组之间血清ALT值无差异。
在该模型中，致命性白色念珠菌败血症伴肺损伤和多器官损害在时间上与体内酵母型向菌丝型转变相关。然而，这种念珠菌血症性感染性休克综合征是由循环真菌毒力因子或除TNF-α之外的宿主介质调节的，TNF-α是一种被认为至关重要的细胞因子。
