Welling M M, Hiemstra P S, van den Barselaar M T, Paulusma-Annema A, Nibbering P H, Pauwels E K, Calame W
Department of Radiology, Division of Nuclear Medicine, Leiden University Medical Center, Leiden, The Netherlands.
J Clin Invest. 1998 Oct 15;102(8):1583-90. doi: 10.1172/JCI3664.
Neutrophil defensins (or human neutrophil peptides-HNP) are major constituents of the azurophilic granules of human neutrophils and have been shown to display broad-spectrum antimicrobial activity. Other activities of these defensins, which are released from stimulated neutrophils, include cytotoxic, stimulatory, and chemotactic activities toward a variety of target cells. We studied the potential use of HNP-1 for antibacterial therapy of experimental bacterial infections in mice. In experimental peritoneal Klebsiella pneumoniae infections in mice, HNP-1 injection was shown to markedly reduce bacterial numbers in the infected peritoneal cavity 24 h after infection. This antibacterial effect was found to be associated with an increased influx of macrophages, granulocytes, and lymphocytes into the peritoneal cavity. These leukocytes appeared to be a requirement for the antibacterial effect, since in leukocytopenic mice administration of HNP-1 did not display antibacterial activity. HNP-1 treatment also reduced bacterial numbers in experimental K. pneumoniae or Staphylococcus aureus thigh muscle infections. In this model, radiolabeled HNP-1 was found to accumulate at the site of infection, whereas most of the injected HNP-1 was rapidly removed from the circulation via renal excretion. These results demonstrate that neutrophil defensins display marked in vivo antibacterial activity in experimental infections in mice and that this activity appears to be mediated, at least in part, by local leukocyte accumulation.
中性粒细胞防御素（或人中性粒细胞肽-HNP）是人类中性粒细胞嗜天青颗粒的主要成分，已被证明具有广谱抗菌活性。这些防御素从受刺激的中性粒细胞中释放出来，其其他活性包括对多种靶细胞的细胞毒性、刺激和趋化活性。我们研究了HNP-1在小鼠实验性细菌感染抗菌治疗中的潜在用途。在小鼠实验性肺炎克雷伯菌腹腔感染中，感染后24小时注射HNP-1可显著降低感染腹腔内的细菌数量。发现这种抗菌作用与巨噬细胞、粒细胞和淋巴细胞向腹腔内的流入增加有关。这些白细胞似乎是抗菌作用所必需的，因为在白细胞减少的小鼠中，给予HNP-1没有显示出抗菌活性。HNP-1治疗也减少了实验性肺炎克雷伯菌或金黄色葡萄球菌大腿肌肉感染中的细菌数量。在这个模型中，发现放射性标记的HNP-1在感染部位积聚，而大部分注射的HNP-1通过肾脏排泄迅速从循环中清除。这些结果表明，中性粒细胞防御素在小鼠实验性感染中显示出显著的体内抗菌活性，并且这种活性似乎至少部分地由局部白细胞积聚介导。
