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黏附分子在感染和炎症过程中中性粒细胞与内皮细胞的早期相互作用中起重要作用。一些临床前研究表明，在与脓毒症等疾病相关的全身炎症期间，抑制选择素功能可能是有益的。然而，选择素在将中性粒细胞招募到细菌感染部位是重要的，它们的抑制在脓毒症中可能会产生有害的影响。此外，给脓毒症患者注射选择素导向的单抗(MAb)也是无益的。然而，在全身炎症期间使用抗黏附分子策略的兴趣仍在继续，目前正在研究整合素导向的单抗在创伤患者中的应用。为了进一步评价在感染和脓毒症中抑制选择素分子功能的作用，我们研究了细菌感染部位和感染剂量两个因素对针对L-选择素的单抗作用的影响。在本研究中，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。血管内感染时，单抗可显著提高存活率。肺炎，尽管减少了早期的肺损伤，但单抗显著恶化了存活率和后来的肺修复。这些研究表明，抑制选择素功能可能有益于主要发生在血管内间隙的感染和炎症。然而，在血管外感染的患者中，这种抑制可能会恶化宿主的防御和预后。进一步的研究正在进行中，以确定L-选择素单抗在这些研究中的可变作用基础。此外，还计划利用该单抗的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.