Sawa T, Kurahashi K, Ohara M, Gropper M A, Doshi V, Larrick J W, Wiener-Kronish J P
Departments of Anesthesia and Medicine, The University of California, San Francisco, California 94143, USA.
Antimicrob Agents Chemother. 1998 Dec;42(12):3269-75. doi: 10.1128/AAC.42.12.3269.
CAP18 (cationic antimicrobial protein; 18 kDa) is a neutrophil-derived protein that can bind to and inhibit various activities of lipopolysaccharide (LPS). The 37 C-terminal amino acids of CAP18 make up the LPS-binding domain. A truncated 32-amino-acid C-terminal fragment of CAP18 had potent activity against Pseudomonas aeruginosa in vitro. We studied the antimicrobial and LPS-neutralizing effects of this synthetic truncated CAP18 peptide (CAP18106-137) on lung injury in mice infected with cytotoxic P. aeruginosa. To determine its maximal effect, the CAP18106-137 peptide was mixed with bacteria just prior to tracheal instillation, and lung injury was evaluated by determining the amount of leakage of an alveolar protein tracer (125I-albumin) into the circulation and by the quantification of lung edema. The lung injury caused by the instillation of 5 x 10(5) CFU of P. aeruginosa was significantly reduced by the concomitant instillation of CAP18106-137. However, the administration of CAP18106-137 alone, without bacteria, induced lung edema, suggesting that it has some toxicity. Also, the peptide did not significantly reduce the number of bacteria that had been simultaneously instilled, nor did it significantly improve the survival of the infected mice. The addition of CAP18106-137 to aztreonam along with the bacteria did decrease the level of antibiotic-induced release of inflammatory mediators including tumor necrosis factor alpha, interleukin-6, and nitric oxide and also improved the survival of the mice. Therefore, more investigations are needed to confirm the toxicities and the therapeutic benefits of CAP18106-137 as an adjunctive therapy to antibiotics in the treatment of infections caused by gram-negative bacteria.
阳离子抗菌蛋白18（CAP18，18 kDa）是一种源自中性粒细胞的蛋白质，它能够结合并抑制脂多糖（LPS）的多种活性。CAP18的37个C末端氨基酸构成了LPS结合域。CAP18截短的32个氨基酸的C末端片段在体外对铜绿假单胞菌具有强大的活性。我们研究了这种合成的截短型CAP18肽（CAP18106 - 137）对感染细胞毒性铜绿假单胞菌的小鼠肺损伤的抗菌和LPS中和作用。为了确定其最大效果，在气管内滴注前将CAP18106 - 137肽与细菌混合，并通过测定肺泡蛋白示踪剂（125I - 白蛋白）进入循环的渗漏量以及定量肺水肿来评估肺损伤。伴随滴注CAP18106 - 137可显著减轻由滴注5×10(5) CFU铜绿假单胞菌所引起的肺损伤。然而，单独给予CAP18106 - 137（无细菌）会诱发肺水肿，表明它具有一定毒性。此外，该肽并未显著减少同时滴注的细菌数量，也未显著提高感染小鼠的存活率。在给予细菌的同时，将CAP18106 - 137添加到氨曲南中确实降低了抗生素诱导的包括肿瘤坏死因子α、白细胞介素 - 6和一氧化氮在内的炎症介质释放水平，并且提高了小鼠的存活率。因此，需要更多研究来证实CAP18106 - 137作为抗生素辅助疗法治疗革兰氏阴性菌感染的毒性和治疗益处。
