Abstract
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.
Highlights
Ventilator-associated pneumonia (VAP) is a common and life-threatening complication of mechanical ventilation and one of the most common causes of sepsis in hospitalized patients
We have shown that serum H2S levels above 5.3μM can discriminate survivors of P.aeruginosa related sepsis with high sensitivity and is correlated with reduced mortality
The protective role of endogenous H2S resides in the enhancement of neutrophil recruitment and the phagocytic activity of neutrophils, as well as by inhibiting the cell-to-cell communication system of P. aeruginosa, rendering it more vulnerable to phagocytosis
Summary
Ventilator-associated pneumonia (VAP) is a common and life-threatening complication of mechanical ventilation and one of the most common causes of sepsis in hospitalized patients. Klebsiella (K.) pneumoniae, Acinetobacter (A.) baumannii and Pseudomonas (P.) aeruginosa are responsible for more than 50% of VAP cases in Greece and are characterized by high rates of antimicrobial resistance [1]. This mandates the investigation of new strategies, which can tackle the problem of antimicrobial resistance and lead to resolution of VAP. The pro-inflammatory effects observed after inhibition of CSE led us study the levels of host H2S in cases of lower respiratory tract infections (LRTIs) including ventilator associated pneumonia (VAP) and pneumonia caused by the novel SARS-CoV-2 virus (COVID-19 disease). Results showed that plasma H2S levels are higher among survivors of LRTI by COVID-19; non-survivors were characterized by disability to increase plasma H2S over the first seven days of follow-up [6]
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