Lechner A J, Rouben L R, Potthoff L H, Tredway T L, Matuschak G M
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, MO 63104.
Circ Shock. 1993 Apr;39(4):306-15.
Lethal circulatory shock during microbial sepsis is thought to be initiated by early molecular events, including production of tumor necrosis factor (TNF) and cytokine-mediated upregulation of neutrophil (PMN) function, irrespective of the causative organism. The phosphodiesterase inhibitor pentoxifylline (PTX) inhibits TNF gene transcription and modulates PMN function, and has been shown to improve outcome in experimental sepsis. We hypothesized that PTX would attenuate gram-negative and fungal septic shock by different mechanisms: reduced TNF production in Escherichia coli (EC) sepsis vs. enhanced PMN-mediated defense during Candida albicans (CA) fungemia. Conscious chronically catheterized rats received PTX (25 mg/kg, i.v.) before i.v. challenge with 10(10) viable EC (serotype 055:B5), 10(9) viable serotype A yeast-phase CA (each the LD100 in < 24 hr in naive rats), or normal sterile saline (NSS), and then PTX posttreatment (6.5 mg/hr x 4.5 hr). Treatment controls received NSS before and after challenge. Serum TNF peaked 1.5 hr after EC infection in NSS-treated animals (1654 +/- 390 U/ml, mean +/- SE), and was significantly reduced by PTX (120 +/- 32 U/ml, P < 0.01), but PTX did not improve 24 hr survival. PTX also aggravated systemic hypotension after EC, and did not modify neutropenia, thrombocytopenia, or microvascular permeability assessed by organ wet/dry weight (W/D) ratios. Peak serum TNF in CA + NSS animals (130 +/- 45 U/ml) was delayed 8 hr compared to EC animals, and were not reduced by PTX (67 +/- 25 U/ml, P = NS). Moreover, PTX did not alter CA-induced mortality, hypothermia, hypotension, neutropenia, increased lung W/D, or interstitial and alveolar hemorrhage. We conclude that PTX-induced suppression of endogenous TNF production does not prevent gram-negative shock in this model, possibly due to impaired TNF-mediated antibacterial host defense. Since fungal septic shock with acute disseminated candidiasis evolves prior to significant increases in circulating TNF, PTX also appears ineffective in its treatment.
微生物败血症期间的致死性循环性休克被认为是由早期分子事件引发的，包括肿瘤坏死因子（TNF）的产生以及细胞因子介导的中性粒细胞（PMN）功能上调，而与致病微生物无关。磷酸二酯酶抑制剂己酮可可碱（PTX）可抑制TNF基因转录并调节PMN功能，并且已证明其可改善实验性败血症的预后。我们假设PTX会通过不同机制减轻革兰氏阴性菌和真菌性败血症休克：在大肠杆菌（EC）败血症中减少TNF产生，而在白色念珠菌（CA）菌血症期间增强PMN介导的防御。有意识的慢性插管大鼠在静脉注射10(10) 个活的EC（血清型055:B5）、10(9) 个活的血清型A酵母相CA（每种在未处理大鼠中<24小时内的致死剂量为LD100）或正常无菌生理盐水（NSS）进行静脉攻击之前接受PTX（25mg/kg，静脉注射），然后进行PTX后处理（6.5mg/小时×4.5小时）。治疗对照组在攻击前后接受NSS。在NSS处理的动物中，血清TNF在EC感染后1.5小时达到峰值（1654±390U/ml，平均值±标准误），PTX使其显著降低（120±32U/ml，P<0.01），但PTX并未改善24小时生存率。PTX还加重了EC感染后的全身性低血压，并且未改变通过器官湿/干重（W/D）比值评估的中性粒细胞减少、血小板减少或微血管通透性。与EC动物相比，CA+NSS动物的血清TNF峰值（130±45U/ml）延迟了8小时，并且未被PTX降低（67±25U/ml，P=无显著性差异）。此外，PTX并未改变CA诱导的死亡率、体温过低、低血压、中性粒细胞减少、肺W/D增加或间质和肺泡出血。我们得出结论，在该模型中，PTX诱导的内源性TNF产生抑制并不能预防革兰氏阴性菌休克，这可能是由于TNF介导的抗菌宿主防御受损。由于急性播散性念珠菌病的真菌性败血症休克在循环TNF显著增加之前就已发展，PTX在其治疗中似乎也无效。
