Lechner A J, Ryerse J S, Matuschak G M
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Missouri 63104.
Microsc Res Tech. 1993 Dec 1;26(5):444-56. doi: 10.1002/jemt.1070260512.
We compared physiological and ultrastructural indices of acute lung injury (ALI) during septic shock caused by taxonomically diverse pathogens to distinguish ALI due to endogenous inflammatory mediators vs. microbial exotoxins or other factors. Conscious rats were infected i.v. with gram-negative Escherichia coli (EC, serotype 055:B5), exotoxin-C producing gram-positive Staphylococcus aureus (SA), or yeast-phase Candida albicans (CA, a clinical isolate). Viable inocula of 10(10) EC, 10(10) SA, or 10(9) CA caused lethal shock in < 24 h, but distinct types of ALI were noted after bacteria vs. fungi. Within 0.5 h of EC infection, leukocytes marginated in the lung vasculature; by death at 6-14 h, animals were hyperoxemic but not acidemic, and showed slight interstitial edema with increased wet/dry weight ratios (W/D = 5.22 +/- 0.10, mean +/- SE, vs. 4.86 +/- 0.07 in controls, P < 0.05). Similarly mild ALI occurred after 10(10) SA. In contrast, within 0.5 h of CA infection, yeast were visible within lung intravascular leukocytes. By death at 6-12 h, CA animals showed hyperoxic acidemia and moderate ALI with capillary obstruction, interstitial hemorrhage, and elevated lung W/D (5.52 +/- 0.13, P < 0.01 vs. controls) associated with yeast-mycelial transformation. Prior neutropenia accelerated mortality and worsened ALI after CA, with hypoxemic acidemia, increased lung W/D (7.23 +/- 0.34, P < 0.05 vs. other groups), capillary occlusion, perivascular and alveolar hemorrhage, and septal disruption by mycelia. Bacteremia induced large increases in serum tumor necrosis factor-alpha (TNF) and interleukin-1 alpha within 1.5 h, but these cytokines remained low in CA animals, even at death. Neither survival nor ALI after EC or CA was altered by pentoxifylline, which attentuated TNF production, or by cyclooxygenase inhibition with ibuprofen. Thus, overall ALI severity correlated with physiological indices of pulmonary function, but ultrastructural changes correlated better with pathogen type than circulating cytokine or eicosanoid mediators. Whereas lethal bacteremia induced early cytokinemia and mild ALI with or without bacterial exotoxins, moderate ALI apparently was mediated by fungal exotoxins during lethal candidemia, which worsened during neutropenia due to enhanced mycelial proliferation.
我们比较了由分类学上不同的病原体引起的脓毒性休克期间急性肺损伤（ALI）的生理和超微结构指标，以区分由内源性炎症介质引起的ALI与微生物外毒素或其他因素。清醒大鼠经静脉注射感染革兰氏阴性大肠杆菌（EC，血清型055:B5）、产外毒素C的革兰氏阳性金黄色葡萄球菌（SA）或酵母相白色念珠菌（CA，临床分离株）。10¹⁰个EC、10¹⁰个SA或10⁹个CA的活菌接种在<24小时内导致致死性休克，但细菌感染与真菌感染后的ALI类型不同。在EC感染后0.5小时内，白细胞在肺血管系统中靠边；到6 - 14小时死亡时，动物血氧过多但无酸血症，且表现出轻微的间质水肿，湿/干重比增加（W/D = 5.22±0.10，平均值±标准误，对照组为4.86±0.07，P<0.05）。10¹⁰个SA感染后也出现类似的轻度ALI。相比之下，在CA感染后0.5小时内，可见酵母存在于肺血管内白细胞中。到6 - 12小时死亡时，CA感染的动物表现出高氧性酸血症和中度ALI，伴有毛细血管阻塞、间质出血以及与酵母 - 菌丝体转化相关的肺W/D升高（5.52±0.13，与对照组相比P<0.01）。预先存在的中性粒细胞减少会加速死亡率并使CA感染后的ALI恶化，表现为低氧性酸血症、肺W/D增加（7.23±0.34，与其他组相比P<0.05）、毛细血管闭塞、血管周围和肺泡出血以及菌丝体导致的间隔破坏。菌血症在1.5小时内导致血清肿瘤坏死因子 - α（TNF）和白细胞介素 - 1α大幅增加，但这些细胞因子在CA感染的动物中即使在死亡时仍保持低水平。己酮可可碱（可减弱TNF产生）或布洛芬抑制环氧化酶均未改变EC或CA感染后的生存率或ALI。因此，总体ALI严重程度与肺功能的生理指标相关，但超微结构变化与病原体类型的相关性比与循环细胞因子或类花生酸介质的相关性更好。致死性菌血症诱导早期细胞因子血症以及伴有或不伴有细菌外毒素的轻度ALI，而中度ALI显然是由致死性念珠菌血症期间的真菌外毒素介导的，在中性粒细胞减少期间由于菌丝体增殖增强而恶化。
