THE INFLUENCE OF SITE AND SEVERITY OF INFECTION

中性粒细胞和内皮细胞上存在的选择素粘附分子在感染和炎症期间的早期嗜中性粒细胞-内皮细胞相互作用中是重要的。一些临床前研究表明，抑制选择素功能可能是有益的全身炎症与条件，如败血症。然而，选择素在将中性粒细胞招募到细菌感染部位方面非常重要，并且它们的抑制可能会在败血症期间产生有害影响。此外，选择素定向单克隆抗体（MAb）的管理与败血症患者是没有好处的。然而，在全身性炎症期间使用抗粘附分子策略的兴趣仍在继续，并且整合素定向的单克隆抗体目前正在创伤患者中进行研究。为了进一步评估在感染和脓毒症期间抑制选择素分子功能的作用，我们研究了两种因素的影响，即，细菌感染的部位和剂量对抗L-选择素单克隆抗体的影响。在这项研究中，细菌攻击的部位而不是剂量从根本上改变了L-选择素单抗的作用。对于血管内感染，MAb显著提高了生存率。对于肺炎，尽管减少了早期肺损伤，但MAb显著恶化了生存率和后期肺修复。这些研究表明，抑制选择素功能可能对主要发生在血管内的感染和炎症有益。然而，在血管外感染患者中，这种抑制可能会恶化宿主防御和结局。正在进行其他研究，以确定L-选择素单克隆抗体在这些研究中的可变效应的基础。此外，还计划使用该单克隆抗体的FAB片段进行研究。

Selectin adhesion molecules present on both neutrophils and endothelial cells are important in early neutrophil-endothelial interactions during infection and inflammation. Some preclinical studies suggest that inhibiting selectin function may be beneficial during systemic inflammation associated with conditions such as sepsis. However, selectins are important in recruiting neutrophils to sites of bacterial infection and their inhibition could have detrimental effects during sepsis. Furthermore, administration of a selectin directed monoclonal antibody (MAb) to patients with sepsis was not beneficial. Interest continues in the use of anti-adhesion molecule strategies during systemic inflammation however, and an integrin directed monoclonal antibody is presently under study in patients with trauma. In order to further assess the effects of inhibiting selectin molecule function during infection and sepsis, we investigated the influence of two factors, i.e., site and dose of bacterial infection, on the effects of MAbs directed against L-selectin. In this study, site but not dose of bacterial challenge fundamentally altered the effects of L-selectin MAb. With intravascular infection, MAb significantly improved survival. With pneumonia, despite reducing early lung injury, MAb significantly worsened survival and later lung repair. These studies sug-gest that inhibiting selectin function may be beneficial with infection and inflammation occurring primarily in the intravascular space. However, in patients with extravascular infection, this inhibition may worsen host defense and outcome. Additional studies are underway to determine the basis for the variable effects of L-selectin MAb in these stud-ies. In addition, studies are planned which will employ FAB fragments of this MAb.