H_2S在炎症反应调节中的作用研究进展

硫化氢(hydrogen sulfide,H_2S)是继一氧化氮(nitric oxide,NO)和一氧化碳(carbon monoxide,CO)之后的第三个气体分子信号,参与体内多种生理及病理过程,具有广泛的生物学效应。在炎症反应中,H_2S发挥促炎或抗炎的作用,其水平发生改变可影响炎症反应的进程。因此,研究H_2S与炎症的关系对探讨炎症性疾病的发生机制和治疗方法具有重要意义。     

硫化氢促进创面愈合的研究进展

硫化氢是继一氧化氮和一氧化碳之后所发现的第3种新型内源性气体信号分子。通过近几年对硫化氢的相关研究,证明其广泛参与了机体的各种病理生理过程。创面愈合是一个复杂的病理生理过程,也是临床上治疗急慢性创面的根本任务和最终目的,其效果关系着患者治疗的成败及后期生活质量的高低。根据影响创面愈合因素的不同,目前临床上使用的促进创面愈合的治疗方法和药物有很多。本文就硫化氢在创面愈合中所起的作用和相关机制进行简要综述,以期为相关临床治疗和研究提供一定参考。     

内源性气体信号分子和调节肽在特发性肺纤维化发病中的作用

特发性肺纤维化是一种病因不明的慢性进行性肺疾病,以纤维增殖、肺实质的破坏及细胞外基质的沉积为特征,其发病机制尚不明确。近几年的研究发现内源性气体信号分子(一氧化氮、一氧化碳和硫化氢)及调节肽(血管紧张素II、松弛素和尾加压素等)在调节肺纤维化,参与特发性肺纤维化的发病中发挥重要的作用。     

Mapping and signaling of neural pathways involved in the regulation of hydromineral homeostasis

Several forebrain and brainstem neurochemical circuitries interact with peripheral neural and humoral signals to collaboratively maintain both the volume and osmolality of extracellular fluids. Although much progress has been made over the past decades in the understanding of complex mechanisms underlying neuroendocrine control of hydromineral homeostasis, several issues still remain to be clarified. The use of techniques such as molecular biology, neuronal tracing, electrophysiology, immunohistochemistry, and microinfusions has significantly improved our ability to identify neuronal phenotypes and their signals, including those related to neuron-glia interactions. Accordingly, neurons have been shown to produce and release a large number of chemical mediators (neurotransmitters, neurohormones and neuromodulators) into the interstitial space, which include not only classic neurotransmitters, such as acetylcholine, amines (noradrenaline, serotonin) and amino acids (glutamate, GABA), but also gaseous (nitric oxide, carbon monoxide and hydrogen sulfide) and lipid-derived (endocannabinoids) mediators. This efferent response, initiated within the neuronal environment, recruits several peripheral effectors, such as hormones (glucocorticoids, angiotensin II, estrogen), which in turn modulate central nervous system responsiveness to systemic challenges. Therefore, in this review, we shall evaluate in an integrated manner the physiological control of body fluid homeostasis from the molecular aspects to the systemic and integrated responses.     

Gaseotransmitters: new frontiers for translational science

Translational research on endogenous gaseous mediators--nitric oxide, carbon monoxide, and hydrogen sulfide--has exploded over the past decade. Drugs that modulate either the gaseous mediators themselves or their related intracellular signaling pathways are already in use in the clinics, and still more are being tested in preclinical models and clinical trials. Discussed here are the chemical and pharmacological properties that present challenges for the translation of these potentially toxic molecules.     

Cross talk between carbon monoxide and nitric oxide

Carbon monoxide and nitric oxide are two endogenously produced gases that can act as second messenger molecules. Heme oxygenase and nitric oxide synthase are the enzyme systems responsible for generating carbon monoxide and nitric oxide, respectively. Both carbon monoxide and nitric oxide share similar properties, such as the ability to activate soluble guanylate cyclase to increase cyclic GMP. It is becoming increasingly clear that these two gases do not always work independently, but rather can modulate each other's activity. Although much is known about the heme oxygenase/carbon monoxide and nitric oxide synthase/nitric oxide pathways, how these two important systems interact is less well understood. This review attempts to define the current known relationship between carbon monoxide and nitric oxide as it relates to their production and physiological function.     

Hydrogen sulfide prevents apoptosis of human PMN via inhibition of p38 and caspase 3

Hydrogen sulfide, together with carbon monoxide and nitric oxide, is now considered a gasotransmitter able to induce specific cellular responses. As hydrogen sulfide is a component of several natural compounds known to be effective in many inflammatory pathologies, particularly of the respiratory tract, we studied its effects in vitro on the survival and bactericidal activity of purified human neutrophils. We found that (1) HS(-) ions promote the survival of granulocytes, but not that of lymphocytes or eosinophils, cultured in serum-free medium; (2) the pro-survival effect of HS(-) is due to inhibition of caspase-3 cleavage and p38 MAP kinase phosphorylation; (3) the bactericidal activity of neutrophils is not impaired by hydrogen sulfide. We conclude that HS(-) promotes the short-term survival of neutrophils potentially accelerating the resolution of inflammatory processes and preventing the occurrence of new ones.     

气体信号分子硫化氢调节细胞功能的作用与机制

背景：硫化氢作为第3种气体信号分子在细胞功能调节方面的研究越来越多,但是目前对其认识尚存在一些矛盾之处。 目的：总结硫化氢在细胞功能调节方面的作用机制及其研究进展。 方法：应用计算机检索1990至2013年PubMed数据库,以“hydrogen sulfide,gasotransmitter”为检索关键词进行检索,最终纳入54篇相关进行分析。 结果与结论：很多研究证明硫化氢在细胞功能的调节方面起到重要作用,其在细胞功能调节方面的作用机制较为复杂。传统的信号分子(如激素和神经介质)可通过一系列的级联反应来放大信号进行信号转导,但是气体信号分子可通过转录后修饰胞内靶向蛋白而更迅速的影响细胞代谢。大多数研究表明生理浓度下的硫化氢具有抗氧化、抗炎和抗凋亡的作用。但在炎症和凋亡方面的研究,部分研究却得到了不同的结果,也说明硫化氢对于某些细胞功能的调节可能存在双重性,因此对其作用机制的研究有待进一步加强。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

Role of neurotransmitter gases in the control of the carotid body in heart failure

The peripheral arterial chemoreflex, arising primarily from the carotid body in most species, plays an important role in the control of breathing and in autonomic control of cardiovascular function. The peripheral chemoreflex is enhanced in heart failure patients and animal models of heart failure and contributes to the sympathetic hyperactivity and breathing instability that exacerbates the progression of the disease. Studies in animal models have shown that carotid body chemoreceptor activity is enhanced under both normoxic and hypoxic conditions in heart failure due to disruption of local mediators that control carotid body function. This brief review highlights evidence that the alterations in the gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide in the carotid body contribute to the exaggerated carotid body function observed in heart failure.     

Nitric Oxide-Releasing Macromolecular Systems in Anticoagulant Therapeutics

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) are considered endogenous gaseous signaling molecules that play crucial roles in regulating physiological and pathological pathways. Among these molecules, NO has demonstrated unique advantages and clear efficacy in the treatment of blood coagulation in cardiovascular diseases. As a result, the development of NO-releasing materials for anticoagulant therapeutics has garnered significant attention. However, unlike traditional anticoagulant treatments such as heparin and oral anticoagulants, NO, a gaseous molecule under ambient conditions, cannot be administered orally, through injection, or via the skin. Consequently, researchers have focused on developing NO-releasing macromolecular systems by combining various donors with polymeric materials for use in anticoagulant therapeutics. This minireview aims to highlight the methods and advancements in constructing such NO-releasing macromolecular systems and exploring their applications in anticoagulant therapeutics.     

Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?

Except in rare cases, the stomach can withstand exposure to highly concentrated hydrochloric acid, refluxed bile salts, alcohol, and foodstuffs with a wide range of temperatures and osmolarity. This is attributed to a number of physiological responses by the mucosal lining to potentially harmful luminal agents, and to an ability to rapidly repair damage when it does occur. Since the discovery in 1971 that prostaglandin synthesis could be blocked by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), there has been great interest in the contribution of prostaglandins to gastric mucosal defense. Prostaglandins modulate virtually every aspect of mucosal defense, and the importance of this contribution is evident by the increased susceptibility of the stomach to injury following ingestion of an NSAID. With chronic ingestion of these drugs, the development of ulcers in the stomach is a significant clinical concern. Research over the past two decades has helped to identify some of the key events triggered by NSAIDs that contribute to ulcer formation and/or impair ulcer healing. Recent research has also highlighted the fact that the protective functions of prostaglandins in the stomach can be carried out by other mediators, in particular the gaseous mediators nitric oxide and hydrogen sulfide. Better understanding of the mechanisms through which the stomach is able to resist injury in the presence of luminal irritants is helping to drive the development of safer anti-inflammatory drugs, and therapies to accelerate and improve the quality of ulcer healing.     

Prooxidant and antioxidant functions of nitric oxide in liver toxicity

In response to tissue damage and inflammation induced by a variety of xenobiotics including acetaminophen, carbon tetrachloride, ethanol, galactosamine, and endotoxin, as well as disease states such as viral hepatitis, and postischemic and regenerative injury, the liver produces large quantities of nitric oxide. Indeed, nearly all cell types in the liver including hepatocytes, Kupffer cells, stellate cells, and endothelial cells have the capacity to generate nitric oxide. Thus, these cells, as well as infiltrating leukocytes, may indirectly augment tissue injury. In many models of liver damage, nitric oxide and its oxidation products such as peroxynitrite contribute to the injury process by directly damaging the tissue or by initiating additional immunologic reactions that result in damage. In some models, nitric oxide donors or peroxynitrite can mimic the cytotoxic actions of liver toxins. Moreover, agents that prevent the generation of nitric oxide or antioxidants that bind reactive nitrogen intermediates, or knockout mice with reduced capacity to produce nitric oxide, are protected from xenobiotic-induced tissue injury. In contrast, there have been reports that blocking nitric oxide production enhances xenobiotic-induced tissue injury. This has led to the concept that nitric oxide either inactivates proteins critical for xenobiotic-induced tissue injury or acts as an antioxidant, reducing cellular levels of cytotoxic reactive oxygen intermediates. Whether or not nitric oxide or secondary oxidants generated from nitric oxide act as mediators of tissue injury or protect against toxicity is likely to depend on the precise targets of these reactive nitrogen intermediates, as well as levels of superoxide anion present and the extent to which tissue injury is mediated by reactive oxygen intermediates. In addition, as toxicity is a complex process involving a variety of cell types and many soluble mediators, the contribution of each of these factors must be taken into account when considering the role of nitric oxide as a determinant of tissue injury.     

The resolution of inflammation: Principles and challenges

The concept that chemokines, cytokines and pro-inflammatory mediators act in a co-ordinated fashion to drive the initiation of the inflammatory reaction is well understood. The significance of such networks acting during the resolution of inflammation however is poorly appreciated. In recent years, specific pro-resolving mediators were discovered which activate resolution pathways to return tissues to homeostasis. These mediators are diverse in nature, and include specialized lipid mediators (lipoxins, resolvins, protectins and maresins) proteins (annexin A1, galectins) and peptides, gaseous mediators including hydrogen sulphide, a purine (adenosine), as well as neuromodulator release under the control of the vagus nerve. Functionally, they can act to limit further leukocyte recruitment, induce neutrophil apoptosis and enhance efferocytosis by macrophages. They can also switch macrophages from classical to alternatively activated cells, promote the return of non-apoptotic cells to the lymphatics and help initiate tissue repair mechanisms and healing. Within this review we highlight the essential cellular aspects required for successful tissue resolution, briefly discuss the pro-resolution mediators that drive these processes and consider potential challenges faced by researchers in the quest to discover how inflammation resolves and why chronic inflammation persists.     

Hydrogen sulfide: a novel mediator of leukocyte activation

Accumulating evidence has suggested that hydrogen sulfide (H(2)S) is endogenously generated in many types of mammalian cells. Since H(2)S plays an important role in cardiovascular, central nervous and gastrointestinal systems, it is currently considered to be the third gaseous mediator. Recently, more and more attention has been paid to the biological functions of H(2)S in inflammation. In various animal models of inflammatory diseases (such as acute pancreatitis, sepsis and endotoxemia), endogenous H(2)S has been shown to be overproduced and participate in regulating the severity of inflammatory response and associated organ injury. Inhibition of H(2)S formation is likely to protect animals against these inflammatory diseases. H(2)S may exert its effect on inflammation via regulating the function of leukocytes, leukocyte trafficking and immune cell survival. Furthermore, H(2)S has been suggested to induce the release or production of neuropeptides (substance P and calcitonin gene-related peptide), which are considered to be pro-inflammatory mediators, and therefore contribute to inflammatory response. In addition, some studies reported that low doses of sodium hydrosulfide (NaHS, an H(2)S donor) exhibited some anti-inflammatory effect on local inflammation (such as non-steroidal anti-inflammatory drug-induced gastric injury). Taken together, all these findings demonstrate that in addition to the vasodilation and neuromodulation activity of H(2)S, it may contribute to the pathogenesis of inflammatory diseases via regulating the activation of leukocytes.     

Endogenous nitric oxide in allergic airway disease

There has been intense research into the role nitric oxide (NO) plays in physiologic and pathologic mechanisms. The presence of NO in exhaled breath and the high concentrations in nasal airways stimulated many studies examining exhaled and nasal NO as potential markers of airway inflammation, enabling repeated monitoring of airway inflammation not possible with invasive tests (eg, bronchoscopy). In airway inflammation, NO is not merely a marker but may have anti-inflammatory and proinflammatory effects. Nasal NO measurement may be used in the noninvasive diagnosis and monitoring of nasal disease. This review was compiled by speakers who gave presentations on NO at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in 1999 on exhaled and nasal NO, in vitro studies of NO, the chemistry of airway NO formation, and standardized measurement of exhaled mediators.     

Emerging role of carbon monoxide in physiologic and pathophysiologic states

The discovery of nitric oxide in the 1980s unraveled the novel concept then that an endogenous production of a gaseous substance such as nitric oxide can impart critical physiologic functions in a variety of biological and pathological processes. Interestingly though, we have known for a longer period of time that there exists another gaseous molecule, carbon monoxide (CO), that can be generated endogenously. The heme oxygenase enzyme system generates the majority, if not, all of the endogenous CO. Accumulating data in recent years have lent an intriguing supposition that we need to regard CO beyond the old paradigm that it imparts only toxicity and lethality to organisms. Instead, we need to consider CO, at low physiologic concentration, to play critical physiologic roles in various pathophysiologic states. This forum will review this double-edge sword of CO.     

Regulation of heart function by endogenous gaseous mediators-crosstalk between nitric oxide and hydrogen sulfide

Both nitric oxide (NO) and hydrogen sulfide (H(2)S) are two important gaseous mediators regulating heart function. The present study examined the interaction between these two biological gases and its role in the heart. We found that l-arginine, a substrate of NO synthase, decreased the amplitudes of myocyte contraction and electrically induced calcium transients. Sodium hydrogen sulfide (an H(2)S donor), which alone had minor effect, reversed the negative inotropic effects of l-arginine. The effect of l-arginine + sodium hydrogen sulfide was abolished by three thiols (l-cysteine, N-acetyl-cysteine, and glutathione), suggesting that the effect of H(2)S + NO is thiol sensitive. The stimulatory effect on heart contractility was also induced by GYY4137, a slow-releasing H(2)S donor, when used together with sodium nitroprusside, an NO-releasing donor. More importantly, enzymatic generation of H(2)S from recombinant cystathionine-γ-lyase protein also interacted with endogenous NO generated from l-arginine to stimulate heart contraction. In summary, our data suggest that endogenous NO may interact with H(2)S to produce a new biological mediator that produces positive inotropic effect. The crosstalk between H(2)S and NO also suggests an intriguing potential for the endogenous formation of a thiol-sensitive molecule, which may be of physiological significance in the heart.     

Exhaled markers of inflammation

Exhaled markers of inflammation allow completely noninvasive monitoring of inflammation and oxidative stress in the respiratory tract in inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis and interstitial lung diseases. Such noninvasive techniques are simple to perform, may be repeated frequently and can be applied in children, including neonates and patients with severe disease in whom more invasive procedures are not possible. Several volatile chemicals can be measured in the breath (nitric oxide, carbon monoxide, hydrocarbons), and many nonvolatile molecules (mediators, oxidation and nitration products, proteins) may be measured in exhaled breath condensate.     

Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications

The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.