Gases in Sepsis: Novel Mediators and Therapeutic Targets

Abstract

Sepsis, a potentially lethal condition resulting from failure to control the initial infection, is associated with a dysregulated host defense response to pathogens and their toxins. Sepsis remains a leading cause of morbidity, mortality and disability worldwide. The pathophysiology of sepsis is very complicated and is not yet fully understood. Worse still, the development of effective therapeutic agents is still an unmet need and a great challenge. Gases, including nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), are small-molecule biological mediators that are endogenously produced, mainly by enzyme-catalyzed reactions. Accumulating evidence suggests that these gaseous mediators are widely involved in the pathophysiology of sepsis. Many sepsis-associated alterations, such as the elimination of invasive pathogens, the resolution of disorganized inflammation and the preservation of the function of multiple organs and systems, are shaped by them. Increasing attention has been paid to developing therapeutic approaches targeting these molecules for sepsis/septic shock, taking advantage of the multiple actions played by NO, CO and H2S. Several preliminary studies have identified promising therapeutic strategies for gaseous-mediator-based treatments for sepsis. In this review article, we summarize the state-of-the-art knowledge on the pathophysiology of sepsis; the metabolism and physiological function of NO, CO and H2S; the crosstalk among these gaseous mediators; and their crucial effects on the development and progression of sepsis. In addition, we also briefly discuss the prospect of developing therapeutic interventions targeting these gaseous mediators for sepsis.

Antibiotic resistance: The challenges and some emerging strategies for tackling a global menace

“… 64 Along with nitric oxide and carbon monoxide, hydrogen sulfide has been identified as the third gasotransmitter in mammals and has been connected to a range of metabolic processes. 66 , 67 H 2 S is produced by cysteine degradation in mammals and bacteria via cystathionine‐lyase (CSE), cystathionine‐synthase (CBS), and 3‐mercaptopyruvate sulfurtransferase (3MST). 68 , 69 This implies that mammalian cells also synthesize H 2 S, and human cells rely on it.…”

“…Surprisingly, both effects are linked with either protection from or worsening oxidative damage and energy metabolism 64 . Along with nitric oxide and carbon monoxide, hydrogen sulfide has been identified as the third gasotransmitter in mammals and has been connected to a range of metabolic processes 66,67 . H 2 S is produced by cysteine degradation in mammals and bacteria via cystathionine‐lyase (CSE), cystathionine‐synthase (CBS), and 3‐mercaptopyruvate sulfurtransferase (3MST) 68,69 .…”

Hydrogen Sulfide: A Gaseous Mediator and Its Key Role in Programmed Cell Death, Oxidative Stress, Inflammation and Pulmonary Disease

“…H 2 S is a colorless and flammable gas and has a distinctive odor of rotten eggs. Similar to nitric oxide and carbon monoxide, H 2 S has been recognized as a gaseous mediator [ 26 , 27 ]. While H 2 S is toxic in moderate to high amounts, it plays a critical role in many cellular functions and biological processes at low concentrations [ 26 , 27 ].…”

“…The methylation of H 2 S to methanethiol by thiol- S -methyltransferase in the cytoplasm and the oxidation of H 2 S to thiosulfate and sulfate by sulfide quinone oxidoreductase, rhodanese and sulfite oxidase in the mitochondria are the major enzymatic pathways involved in the inactivation of H 2 S [ 31 , 32 , 33 ]. In addition, H 2 S can be directly exhaled from the airways or excreted from the kidney by binding with methemoglobin and metallo- or disulfide-containing molecules [ 27 , 34 ]. It is worth mentioning that polysulfide species might be involved in the biological and pathological effects of H 2 S as polysulfide species not only act as a natural source of H 2 S production, but also function as a major way to contribute to the elimination of H 2 S [ 35 ].…”

Hydrogen sulphide: Diabetic cardiomyopathy as the paradigm of its pleiotropic function

“…6 The secondary prevention of ischaemia/reperfusion injury is another promising field for H 2 S in both myocardial and cerebral flow 7,8 and sepsis as well. 9 As stated by the author, diabetes is an 'ideal' field for studying the potential application of H 2 S. Hyperglycaemia is indeed associated with superoxide excess with consequent NO activity impairment, lipid peroxidation and inflammation, all potential target of H 2 S.…”