Therapeutic Use of Carbon Monoxide in Ex-Vivo Lung Perfusion in Donor With Prolonged Cold Ischemia.

INTRODUCTION: Carbon monoxide (CO) has been shown to exert protective effects in multiple organs following ischemic injury, including the lung. The purpose of this study was to examine the effects of CO administration during ex vivo lung perfusion (EVLP) on lung grafts exposed to prolonged cold ischemia. METHODS: Ten porcine lungs were subjected to 18 h of cold ischemia followed by 6 h of EVLP. Lungs were randomized to EVLP alone (control, n = 5) or delivery of 500 ppm of CO during the 1st hour of EVLP (treatment, n = 5). Following EVLP, the left lungs were transplanted and reperfused for 4 h. RESULTS: At the end of EVLP, pulmonary vascular resistance (P = 0.007) and wet to dry lung weight ratios (P = 0.027) were significantly reduced in CO treated lungs. Posttransplant, lung graft PaO2/FiO2 (P = 0.032) and compliance (P = 0.024) were significantly higher and peak airway pressure (P = 0.032) and wet to dry ratios (P = 0.003) were significantly lower in CO treated lungs. Interleukin-6 was significantly reduced in plasma during reperfusion in the CO treated group (P = 0.040). CONCLUSIONS: In this preclinical porcine model, CO application during EVLP resulted in better graft performance and outcomes after reperfusion.

Elucidating the Molecular Pathways and Therapeutic Interventions of Gaseous Mediators in the Context of Fibrosis.

Fibrosis, a pathological alteration of the repair response, involves continuous organ damage, scar formation, and eventual functional failure in various chronic inflammatory disorders. Unfortunately, clinical practice offers limited treatment strategies, leading to high mortality rates in chronic diseases. As part of investigations into gaseous mediators, or gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), numerous studies have confirmed their beneficial roles in attenuating fibrosis. Their therapeutic mechanisms, which involve inhibiting oxidative stress, inflammation, apoptosis, and proliferation, have been increasingly elucidated. Additionally, novel gasotransmitters like hydrogen (H2) and sulfur dioxide (SO2) have emerged as promising options for fibrosis treatment. In this review, we primarily demonstrate and summarize the protective and therapeutic effects of gaseous mediators in the process of fibrosis, with a focus on elucidating the underlying molecular mechanisms involved in combating fibrosis.

Gases in Sepsis: Novel Mediators and Therapeutic Targets.

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.

Vasodilator effects of sulforaphane in cerebral circulation: A critical role of endogenously produced hydrogen sulfide and arteriolar smooth muscle KATP and BK channels in the brain.

We investigated the effects of sulforaphane (SFN), an isothiocyanate from cruciferous vegetables, in the regulation of cerebral blood flow using cranial windows in newborn pigs. SFN administered topically (10 µM-1 mM) or systemically (0.4 mg/kg ip) caused immediate and sustained dilation of pial arterioles concomitantly with elevated H2S in periarachnoid cortical cerebrospinal fluid. H2S is a potent vasodilator of cerebral arterioles. SFN is not a H2S donor but it acts via stimulating H2S generation in the brain catalyzed by cystathionine γ-lyase (CSE) and cystathionine ß-synthase (CBS). CSE/CBS inhibitors propargylglycine, ß-cyano-L-alanine, and aminooxyacetic acid blocked brain H2S generation and cerebral vasodilation caused by SFN. The SFN-elicited vasodilation requires activation of potassium channels in cerebral arterioles. The inhibitors of KATP and BK channels glibenclamide, paxilline, and iberiotoxin blocked the vasodilator effects of topical and systemic SFN, supporting the concept that H2S is the mediator of the vasodilator properties of SFN in cerebral circulation. Overall, we provide first evidence that SFN is a brain permeable compound that increases cerebral blood flow via a non-genomic mechanism that is mediated via activation of CSE/CBS-catalyzed H2S formation in neurovascular cells followed by H2S-induced activation of KATP and BK channels in arteriolar smooth muscle.

An Appraisal of Developments in Allium Sulfur Chemistry: Expanding the Pharmacopeia of Garlic.

Alliums and allied plant species are rich sources of sulfur compounds that have effects on vascular homeostasis and the control of metabolic systems linked to nutrient metabolism in mammals. In view of the multiple biological effects ascribed to these sulfur molecules, researchers are now using these compounds as inspiration for the synthesis and development of novel sulfur-based therapeutics. This research has led to the chemical synthesis and biological assessment of a diverse array of sulfur compounds representative of derivatives of S-alkenyl-l-cysteine sulfoxides, thiosulfinates, ajoene molecules, sulfides, and S-allylcysteine. Many of these synthetic derivatives have potent antimicrobial and anticancer properties when tested in preclinical models of disease. Therefore, the current review provides an overview of advances in the development and biological assessment of synthetic analogs of allium-derived sulfur compounds.

Redox-related gaseous mediators in the gastrointestinal tract.

Redox-related gaseous molecular species in the gastrointestinal tract are derived from the chemical oxidation-reduction reactions, enzymatic reactions, swallowing, and bacterial production. Recent studies have demonstrated the crucial roles of the microbiota and gaseous molecules in the pathogenesis of gastrointestinal inflammatory and functional diseases. Especially in the hypoxic condition of the large intestine, various bacteria produce acetic acid, methane, and hydrogen sulfide using hydrogen molecules generated by the fermentation reaction as an energy source. In this review, we summarized the recent advances in the biology of redox-related gaseous molecules in the gastrointestinal tract.

Garlic and Gaseous Mediators.

Garlic (Allium sativum) and allied plant species are rich sources of sulfur compounds. Major roles for garlic and its sulfur constituents include the regulation of vascular homeostasis and the control of metabolic systems linked to nutrient metabolism. Recent studies have indicated that some of these sulfur compounds, such as diallyl trisulfide (DATS), alter the levels of gaseous signalling molecules including nitric oxide (NO), hydrogen sulfide (H2S), and perhaps carbon monoxide (CO) in mammalian tissues. These gases are important in cellular processes associated with the cardiovascular system, inflammation, and neurological functions. Importantly, these studies build on the known biological effects of garlic and associated sulfur constituents. This review highlights our current understanding of the health benefits attributed to edible plants like garlic.

H2S is a key antisecretory molecule against cholera toxin-induced diarrhoea in mice: Evidence for non-involvement of the AC/cAMP/PKA pathway and AMPK.

Hydrogen sulphide (H2S) is a gasotransmitter that participates in various physiological and pathophysiological processes within the gastrointestinal tract. We studied the effects and possible mechanism of action of H2S in secretory diarrhoea caused by cholera toxin (CT). The possible mechanisms of action of H2S were investigated using an intestinal fluid secretion model in isolated intestinal loops on anaesthetized mice treated with CT. NaHS and Lawesson's reagent and l-cysteine showed antisecretory activity through reduction of intestinal fluid secretion and loss of Cl- induced by CT. Pretreatment with an inhibitor of cystathionine-γ-lyase (CSE), dl-propargylglycine (PAG), reversed the effect of l-cysteine and caused severe intestinal secretion. Co-treatment with PAG and a submaximal dose of CT increased intestinal fluid secretion, thus supporting the role of H2S in the pathophysiology of cholera. CT increased the expression of CSE and the production of H2S. Pretreatment with PAG did not reverse the effect of SQ 22536 (an AC inhibitor), bupivacaine (inhibitor of cAMP production), KT-5720 (a PKA inhibitor), and AICAR (an AMPK activator). The treatment with Forskolin does not reverse the effects of the H2S donors. Co-treatment with either NaHS or Lawesson's reagent and dorsomorphin (an AMPK inhibitor) did not reverse the effect of the H2S donors. H2S has antisecretory activity and is an essential molecule for protection against the intestinal secretion induced by CT. Thus, H2S donor drugs are promising candidates for cholera therapy. However, more studies are needed to elucidate the possible mechanism of action.