Renieris Georgios, Droggiti Dionysia-Eirini, Katrini Konstantina, Koufargyris Panagiotis, Gkavogianni Theologia, Karakike Eleni, Antonakos Nikolaos, Damoraki Georgia, Karageorgos Athanasios, Sabracos Labros, Katsouda Antonia, Jentho Elisa, Weis Sebastian, Wang Rui, Bauer Michael, Szabo Csaba, Platoni Kalliopi, Kouloulias Vasilios, Papapetropoulos Andreas, Giamarellos-Bourboulis Evangelos J
4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
PLoS Pathog. 2021 Mar 26;17(3):e1009473. doi: 10.1371/journal.ppat.1009473. eCollection 2021 Mar.
Hydrogen sulfide (H2S) has recently been recognized as a novel gaseous transmitter with several anti-inflammatory properties. The role of host- derived H2S in infections by Pseudomonas aeruginosa was investigated in clinical and mouse models. H2S concentrations and survival was assessed in septic patients with lung infection. Animal experiments using a model of severe systemic multidrug-resistant P. aeruginosa infection were performed using mice with a constitutive knock-out of cystathionine-γ lyase (Cse) gene (Cse-/-) and wild-type mice with a physiological expression (Cse+/+). Experiments were repeated in mice after a) treatment with cyclophosphamide; b) bone marrow transplantation (BMT) from a Cse+/+ donor; c) treatment with H2S synthesis inhibitor aminooxyacetic acid (ΑΟΑΑ) or propargylglycine (PAG) and d) H2S donor sodium thiosulfate (STS) or GYY3147. Bacterial loads and myeloperoxidase activity were measured in tissue samples. The expression of quorum sensing genes (QS) was determined in vivo and in vitro. Cytokine concentration was measured in serum and incubated splenocytes. Patients survivors at day 28 had significantly higher serum H2S compared to non-survivors. A cut- off point of 5.3 μΜ discriminated survivors with sensitivity 92.3%. Mortality after 28 days was 30.9% and 93.7% in patients with H2S higher and less than 5.3 μΜ (p = 7 x 10-6). In mice expression of Cse and application of STS afforded protection against infection with multidrug-resistant P. aeruginosa. Cyclophosphamide pretreatment eliminated the survival benefit of Cse+/+ mice, whereas BMT increased the survival of Cse-/- mice. Cse-/- mice had increased pathogen loads compared to Cse+/+ mice. Phagocytic activity of leukocytes from Cse-/- mice was reduced but was restored after H2S supplementation. An H2S dependent down- regulation of quorum sensing genes of P.aeruginosa could be demonstrated in vivo and in vitro. Endogenous H2S is a potential independent parameter correlating with the outcome of P. aeruginosa. H2S provides resistance to infection by MDR bacterial pathogens.
硫化氢（H₂S）最近被公认为是一种具有多种抗炎特性的新型气体递质。在临床和小鼠模型中研究了宿主来源的H₂S在铜绿假单胞菌感染中的作用。评估了肺部感染败血症患者的H₂S浓度和生存率。使用严重全身性多重耐药铜绿假单胞菌感染模型进行动物实验，实验对象为胱硫醚-γ裂解酶（Cse）基因组成型敲除的小鼠（Cse⁻/⁻）和具有生理表达的野生型小鼠（Cse⁺/⁺）。在小鼠接受以下处理后重复进行实验：a）用环磷酰胺处理；b）接受来自Cse⁺/⁺供体的骨髓移植（BMT）；c）用H₂S合成抑制剂氨基氧乙酸（AOAA）或炔丙基甘氨酸（PAG）处理；d）给予H₂S供体硫代硫酸钠（STS）或GYY3147。测量组织样本中的细菌载量和髓过氧化物酶活性。在体内和体外测定群体感应基因（QS）的表达。测量血清和培养的脾细胞中的细胞因子浓度。与未存活者相比，在第28天存活的患者血清H₂S水平显著更高。5.3μM的截断点对存活者的鉴别灵敏度为92.3%。H₂S水平高于和低于5.3μM的患者28天后的死亡率分别为30.9%和93.7%（p = 7×10⁻⁶）。在小鼠中，Cse的表达和STS的应用可提供针对多重耐药铜绿假单胞菌感染的保护作用。环磷酰胺预处理消除了Cse⁺/⁺小鼠的生存优势，而BMT提高了Cse⁻/⁻小鼠的生存率。与Cse⁺/⁺小鼠相比，Cse⁻/⁻小鼠的病原体载量增加。Cse⁻/⁻小鼠白细胞的吞噬活性降低，但在补充H₂S后恢复。在体内和体外均可证明H₂S对铜绿假单胞菌群体感应基因有依赖性下调作用。内源性H₂S是与铜绿假单胞菌感染结局相关的一个潜在独立参数。H₂S可提供对多重耐药细菌病原体感染的抵抗力。
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