Haynes Allan, Ruda Frank, Oliver Jeffrey, Hamood Abdul N, Griswold John A, Park Pyong Woo, Rumbaugh Kendra P
Texas Tech University Health Sciences Center, Department of Surgery, 3601 4th Street, Lubbock, TX 79430, USA.
Infect Immun. 2005 Dec;73(12):7914-21. doi: 10.1128/IAI.73.12.7914-7921.2005.
The innate immune system is comprised of many components that function coordinately to prevent bacterial sepsis. However, thermal injury suppresses many of these factors, and the opportunistic pathogen Pseudomonas aeruginosa takes advantage of this condition, making it one of the leading causes of morbidity and mortality in the setting of thermal injury. P. aeruginosa is extremely efficient at colonizing burn wounds, spreading systemically, and causing sepsis, which often results in a systemic inflammatory response, multiple-organ failure, and death. The pathogenicity of P. aeruginosa is due to the arsenal of virulence factors produced by the pathogen and the immunocompromised state of the host. Syndecan 1 is a major heparan sulfate proteoglycan present on many host cells involved in thermal injury. Syndecan 1 anchored to the cell surface can be cleaved in a process termed ectodomain shedding. Syndecan 1 shedding results in the release of intact, soluble proteoglycan ectodomains that have diverse roles in innate immunity. Here we show for the first time that thermal injury results in shedding of syndecan 1 from host tissue. Our data show that syndecan 1 null mice are significantly less susceptible to P. aeruginosa infection than their wild-type counterparts, as demonstrated by (i) significantly lower mortality; (ii) absence of systemic spread of P. aeruginosa; and (iii) significant reductions in some proinflammatory cytokines. These results suggest that shed syndecan 1 plays an important role in the pathogenesis of P. aeruginosa infection of thermal injury and that syndecan 1-neutralizing agents may be effective supplements to current P. aeruginosa treatments.
先天性免疫系统由许多协同发挥作用以预防细菌性败血症的成分组成。然而，热损伤会抑制其中许多因素，而机会致病菌铜绿假单胞菌利用这种情况，使其成为热损伤发病和死亡的主要原因之一。铜绿假单胞菌在烧伤创面定植、全身扩散并引发败血症方面极其高效，这往往会导致全身炎症反应、多器官衰竭和死亡。铜绿假单胞菌的致病性归因于该病原体产生的一系列毒力因子以及宿主的免疫受损状态。Syndecan 1是存在于许多参与热损伤的宿主细胞上的一种主要硫酸乙酰肝素蛋白聚糖。锚定在细胞表面的Syndecan 1可在一个称为胞外域脱落的过程中被切割。Syndecan 1的脱落导致完整的可溶性蛋白聚糖胞外域的释放，这些胞外域在先天性免疫中具有多种作用。在这里，我们首次表明热损伤会导致Syndecan 1从宿主组织中脱落。我们的数据表明，Syndecan 1基因敲除小鼠比野生型小鼠对铜绿假单胞菌感染的易感性显著降低，表现为：（i）死亡率显著降低；（ii）铜绿假单胞菌无全身扩散；（iii）一些促炎细胞因子显著减少。这些结果表明，脱落的Syndecan 1在热损伤铜绿假单胞菌感染的发病机制中起重要作用，并且Syndecan 1中和剂可能是当前铜绿假单胞菌治疗的有效补充。
