Current Pharmaceutical Biotechnology - Volume 12, Issue 9, 2011

This special issue of Current Pharmaceutical Biotechnology is focused on the role of gaseous transmitters which have turned end for traditional concept of intercellular signalization. Unlike classical messengers, gaseous transmitters are not readily stored in vesicular structures, are re-synthesized as needed and affect cellular metabolism in a more immediate fashion. Two of them - nitric oxide (NO) and hydrogen sulfide (H2S) - have been proved as signaling molecules playing a unique role in the cardiovascular control. The discovery of important vasoactive role of NO originated from the research of Furchgott and colleagues who recognized that gentle rubbing off the intimal arterial surface eliminated the relaxant response to acetylcholine. The diffusible substance released from endothelium which was responsible for vasorelaxation of smooth muscle cells was called “endothelium-derived relaxing factor” and later it was identified that it is NO. NO has become one of the most researched molecules and in 1992 it was voted "Molecule of the Year". During years the research has uncovered basic physiological pathways and regulatory mechanisms which are behind the NO effects. NO is synthesized in the process of metabolism of L-arginine to L-citruline by enzyme NO-synthase (NOS). Three isoforms of NOS were discovered in the cardiovascular system: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS), and it has been suggested that each of them has the potential to regulate vascular tone and to alter blood pressure. New findings reviewed in the articles included into this special issue enrich the knowledge about NO and refresh the current concept of NO effects. The original theory of vasorelaxation mediated by NO released from endothelial cells has been step by step confronted by the growing evidences that vascular smooth muscle cells themselves are able to produce NO as it is reported in the review of Cacanyiova. Several studies revealed that different pathological interventions in endothelial function - such as oxidative stress or hypertension - were associated with NO generation in vascular media as physiologically relevant compensation of endothelial NO deficiency. Further, the review of Kristek demonstrates that nNOS inhibition induces completely different process compared to eNOS inhibition - the last was confirmed by hypertension, arterial and heart hypertrophy accompanied by changes in vasoactivity. The specificity of endothelial or neuronal NO function seems to be related to particular circulatory area and very probably is determined by mutual interactions with other regulatory systems (sympathoadrenergic, renin-angiotensin etc.). Research paper of Dashwood and colleagues suggests that reduced neuronal as well as endothelium-derived NO may play a role in developing erectile dysfunction. The importance of the study is that the human material is used. Authors showed nerve degeneration - nitrergic neuropathy - accompanied by decreased expression of nNOS in penile tissue of patients with erectile dysfunction so confirming the specific position of NO system in a modified vascular tissue - corpus cavernosum. Accumulating evidences emphasize the importance of the central nervous system and dysfunction in neurotransmission in the brain in the development of cardiovascular diseases. It has been shown repeatedly that there is close relationship between alterations in NO neurotransmission and central regulation of cardiovascular system. The review of Ufnal and Sikora is focused on gaseous transmitters in the brain. The brain NO system is affected by several currently used cardiovascular drugs and accordingly it has been suggested that central action of NO may contribute to their therapeutics effects. Pharmacological manipulation of the gaseous transmitters systems, such as NO, in the brain affects the sympathetic system activity, release and/ or action of the most essentials hormones involved in the regulation of the circulatory system and may present a possible novel therapeutic target in the future. The specific role of endothelial NO in the regulation of cerebral blood flow and vascular tone is discussed in the review of Atochin and Huang. The authors demonstrate that pharmacological and genetic manipulations of the endothelial NO system essentially affect the maintenance of vascular tone and cerebral perfusion under normal and pathological conditions such as ischemia and hyperoxia.....

Nitric oxide (NO) participates in the control of the cardiovascular system where two constitutive isoforms of NO-synthase were discovered: endothelial and neuronal. Both isoforms were observed in various cells, however, endothelial NO-synthase is predominantly present in the endothelium. Injury of the endothelium disturbs the balance between vasodilation and vasoconstriction and triggers different pathological alterations. In addition, whereas the intact endothelium protects vascular smooth muscle from oxidative attack, intervention in the vascular wall integrity increases the concentration of vascular superoxides, thus disturbing the effects of NO. To preserve NO-mediated vasorelaxation, different reserve mechanisms have developed. In case of damage of some endothelial receptor type, vasodilation could be ensured by activation of some other type of the present receptors. Moreover, morphological evidence demonstrated that both isoforms of NO-synthase were expressed also in smooth muscle cells and functional studies revealed that different pathological interventions in endothelial function (such as oxidative stress or hypertension) were associated with NO generation in the vascular media. In this case, the generation of NO by vascular smooth muscle may represent a physiologically relevant compensation of endothelial NO deficiency. Whereas long-term inhibition of endothelial NO-synthase resulted in an unequivocal pattern of cardiovascular changes, inhibition of neuronal NO-synthase led to opposite effects, suggesting a specific position of neuronal NO-synthase in the regulation of cardiovascular tone. The specificity of endothelial or neuronal NO function seems to be related to a particular circulatory area and it is presumably determined by mutual interactions with other regulatory systems (sympathoadrenergic, renin-angiotensin, etc.).

Long-term increase of blood pressure represents one of the most important risk factors triggering many cardiovascular diseases, and via counter-regulatory mechanisms it is itself modulated by them. Adequate perfusion of the respective areas with nutrients requires appropriate production of vasodilatory and vasoconstrictory agents. Disharmony among them has an important impact on mechanical properties of the arteries, resulting in pathological alterations in the cardiovascular system. Defective production of the vasodilatory agent nitric oxide (NO) has a pronounced effect on this delicate balance and can evoke functional and structural changes in the cardiovascular system leading to hypertension. This review is focused mainly on changes in the cardiovascular system of newborn and adult Wistar rats after long-term administration of two different types of NO-synthase inhibitors: nonspecific inhibitor NG-nitro-L-arginine methylester and specific inhibitor of neuronal NO-synthase 7-nitroindazole. A possible supplementation of decreased endogenous NO production by NO donors is discussed. Particular attention is given to the complex interplay among blood pressure, arterial geometry, including arterial wall thickness, cross-sectional area, inner diameter, and individual components of the arterial wall, as extracellular matrix, endothelial and smooth muscle cell trophicity. Some methodological remarks for determination of the arterial geometry are also presented. Better understanding of the interrelationship among the factors involved can help in explaining more accurately differences in functional manifestations of vessels in various types of hypertension. The review indicates that the current concept of NO production, effect of NO deficiency, substitution of the missing NO in failing NO production in the cardiovascular system appears to be oversimplified.

Erectile dysfunction (ED) commonly occurs in approximately 15% of men over 70 years old. A number of causes of this condition are recognised with the major mechanism of ED being an impaired relaxation of the corpus cavernosum (CC) smooth muscle and resulting reduction in penile blood flow. There are reports that ED is associated with a reduction in local levels of endothelium-derived nitric oxide (NO) with most studies focussing on the potential role of endothelial nitric oxide synthase (eNOS) in the erectile process. Since there is a recognised neurogenic component of ED we have studied altered nerve density and neuronal nitric oxide synthase (nNOS) distribution by immunohistochemistry and nNOS protein expression by western blot analysis in penises from patients with neurogenic ED and diabetes compared with control tissue obtained from patients undergoing gender reassignment. There was a significant reduction in nerve density in tissue from ED compared with control patients (P<0.05). Immunostaining for nNOS colocalised with nerves and was reduced in ED tissue, as were nNOS protein levels. We have shown that nerve degeneration observed in penile tissue from ED patients is accompanied by a decrease in nNOS suggesting that reduced neuronal- as well as endotheliumderived NO plays a role in this condition.

A number of neurotransmitters, including biologically active gases namely, nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) have been postulated to play an important role in the control of the cardiovascular system by the brain. The attention of researchers has been focused on NO in particular. It has been shown that pharmacological manipulation of NO concentration in the brain produces significant changes in circulatory parameters. Furthermore, significant alterations in the brain NO system have been found in animal models of human cardiovascular diseases. These findings imply that NO in the brain may become a promising target for new treatment strategies. Although H2S and CO have also been proved to serve as transmitters in the central nervous system, their role in the neurogenic regulation of the cardiovascular system remains more obscure. Interestingly, increased synthesis of NO, H2S and CO is found in inflammation and it appears that the gases mediate some of the circulatory responses to inflammatory stimuli. In this review we discuss the role of brain gaseous transmitters in the control of the circulatory system in health and disease.

Endothelial nitric oxide (NO) plays important roles in the vascular system. Animal models that show vascular dysfunction demonstrate the protective role of endothelial NO dependent pathways. This review focuses on the role of endothelial NO in the regulation of cerebral blood flow and vascular tone. We will discuss the importance of NO in cerebrovascular function using animal models with altered endothelial NO production under normal, ischemic and reperfusion conditions, as well as in hyperoxia. Pharmacological and genetic manipulations of the endothelial NO system demonstrate the essential roles of endothelial NO synthase in maintenance of vascular tone and cerebral perfusion under normal and pathological conditions.

The vascular endothelium plays a pivotal role in the maintenance of vessel wall integrity. In this regard, endothelial cells actively regulate vascular reactivity by responding to mechanical forces and neurohormonal mediators by releasing a variety of relaxing and contracting factors. Nitric oxide (NO), an endogenous gas synthesized by NO synthases (NOSs) is the main endothelium-derived vasodilator. Continuous production of NO by constitutive NOS maintains the vasculature in a state of vasodilation, whereas its phasic generation by inducible NOS can acutely dilate an artery in response to either physiological or pathological stimuli. Under homeostatic conditions, the endothelium maintains normal vascular tone and blood flow, and there is little or no expression of proinflammatory factors. However, both traditional and novel cardiovascular risk factors initiate a chronic inflammatory process that is accompanied by a loss of vasodilator and antithrombotic factors and an increase in vasoconstrictor and prothrombotic products. Furthermore, increased oxidative stress may result in a complete derangement of the NO system, with decreased NO bioavailability and a paradoxical NOS-related oxidant generation. Because of the antiatherogenic, antithrombotic properties of NO and the proatherogenic prothrombotic actions of endogenous oxidants, a decreased NO bioavailability with increased oxidative stress will result not only in impaired endothelium-dependent vasorelaxation but also in the acceleration of atherogenesis and onset of acute atherotrombotic events. The concepts of “endothelial dysfunction” and “endothelial activation” referring to different alterations in endothelial phenotype, may contribute to the development and clinical expression of atherosclerosis.

This mini-review takes into consideration the physiology, synthesis and mechanisms of action of the nitric oxide (NO) and, subsequently, the causes and effects of the NO bioavailability impairment. In diabetes mellitus the reduced NO bioavailability is caused by the increased free radicals production, secondary to hyperglycemia. The reactive oxygen species oxidize the cofactors of the nitric oxide synthase, diminishing their active forms and consequently leading to a decreased NO production. Furthermore the decreased concentration of reduced glutathione results in a diminished production of nitrosoglutathione. These molecules are important intermediates of the NO pathway and physiologically activate the soluble guanylate cyclase. Their decrease in oxidative states of the cell, therefore, leads to a reduced cGMP production which represents the principal molecule that carries out NO's major effects. Finally we considered the eventual therapeutic strategies to improve NO bioavailability by acting on the causes of its decrease. Therefore the treatments proposed are based on the possibility to counteract the oxidation and, in this context, the physiopathological mechanisms strongly support the treatment with thiols.

Nitric oxide (NO) has been suggested to play a pivotal role in ischemic acute renal failure (ARF) but there are controversies about its role in hypertensive and non hypertensive ischemic kidney. Multiple strategies including administration of exogenous NO donors have been shown to protect the kidney against toxic or ischemic injury, suggesting endothelial dysfunction as impaired NO generation due to ischemia. However, in postischemic kidney, NO derived from inducible nitric oxide synthase (iNOS) has been considered to enhance the tissue damage while iNOS inhibition decreased the tubular damage. It is well known decrease in basal production of NO in essential hypertension and that long lasting hypertension damages medium size and small-size blood vessels, therefore predisposes nephroangiosclerosis patients to ARF. Many studies have shown that long term stimulation of NO release in normotension improves renal haemodymnamics and kidney function in ischemic form of ARF. On the other hand, there are studies that have shown that NO synthesis stimulation has no effect or even worsens tubular damage in postischemic hypertensive kidney. Therefore, it seems likely that NO supplementation plays different role in postischemic renal damage development, beneficial in well preserved normotensive kidney and limited in postischemic hypertensive kidney due to disturbed tubuloglomerular response, vasoreactivity and kidney vascular structure.

Nitric oxide (NO) has a role in many physiological processes and its decreased concentration can lead to several pathophysiological events, therefore it is of considerable importance to find and to characterize suitable NO-donors for clinical use. S-nitrosothiols (RSNOs) are promising candidates for such therapeutics because these molecules do not appear to induce tolerance and were shown to be effective in several disease models. One of the main endogenous nitrosothiols is S-nitrosoglutathione (GSNO), which was tested as a therapeutic agent in 15 human investigations with good results. Despite the proven benefits of GSNO this molecule is not yet present in any pharmaceutical composition. The problem with the use of nitrosothiols is their fast and often unpredictable rate of decomposition in aqueous solutions. In this article we review current developments in the field which relate to the clinical applications of GSNO and other nitrosothiols in indications such as asthma, cystic fibrosis, embolization prevention or diabetic leg ulcers. The review focuses on the chemical and biological data which support the therapeutic use of GSNO and highlights areas where further research is needed.

In the arterial wall nitric oxide (NO) is the key transmitter for endothelium-dependent regulation of vascular tone. It is produced in intact endothelial cells by endothelial NO synthase (eNOS) as the key enzyme from L-arginine. Endothelial NO generation is highly regulated by mechanical, humoral, and metabolic factors. The regulation of NO synthesis occurs at different levels: ENOS gene polymorphisms are related to eNOS expression and activity and may potentially increase coronary event rate, mRNA expression is influenced by estrogen status and shear stress, mRNA stability is enhanced by vascular endothelial growth factor (VEGF), and final enzyme activity is regulated by the phosphorylation status at serine/threonine residues. Released from endothelial cells NO is rapidly transported to the neighboring vascular smooth muscle cells (VSMCs), where it induces the production of cGMP as a second messenger. CGMP in turn increases Ca2+ uptake into intracellular calcium stores thereby lowering [Ca2+]i and inducing VSMC relaxation and vasodilation. On its way to the VSMCs NO may be prematurely degraded by reactive oxygen species. On the other hand, chronic endurance exercise with regular bouts of increased laminar flow along the endothelium has the potential to increase eNOS mRNA expression and phosphorylation via AKT (protein kinase B) and to reduce oxidative stress by improving antioxidative protection. The growing knowledge about the complex regulation of NO synthesis and degradation in cardiovascular diseases and its response to exercise has led to a new understanding of the protective effects of long-term habitual physical activity against atherosclerotic heart disease and vascular aging.

Recent research has shown that the endogenous gas hydrogen sulphide (H2S) is a signalling molecule of considerable biological potential and has been suggested to be involved in a vast number of physiological processes. In the vascular system, H2S is synthesized from cysteine by cystathionine-γ-lyase (CSE) in smooth muscle cells (SMC) and 3- mercaptopyruvate sulfuresterase (3MST) and CSE in the endothelial cells. In pulmonary and systemic arteries, H2S induces relaxation and/or contraction dependent on the concentration of H2S, type of vessel and species. H2S relaxes SMC through a direct effect on KATP-channels or Kv-channels causing hyperpolarization and closure of voltage-dependent Ca2+-channels followed by a reduction in intracellular calcium. H2S also relaxes SMC through the release of endothelium- derived hyperpolarizing factor (EDHF) and nitric oxide (NO) from the endothelium. H2S contracts SMC through a reduction in nitric oxide (NO) availability by reacting with NO forming a nitrosothiol compound and through an inhibitory effect on endothelial nitric oxide synthase (eNOS) as well as a reduction in SMC cyclic AMP concentration. Evidence supports a role for H2S in oxygen sensing. Furthermore, reduced endogenous H2S production may also play a role in ischemic heart diseases and hypertension, and treatment with H2S donors and cysteine analogues may be beneficial in treatment of cardiovascular disease.

Both endogenously produced and exogenously administered H2S exert numerous biological effects. However, the molecular mechanisms underlying these effects are not fully understood. This review surveys the biological effects of H2S and summarizes the molecular mechanisms of H2S action. It focuses on the role of H2S/HS--induced NO release from nitroso compounds, modulation of ion channels and the antioxidant and radical properties of H2S in the molecular mechanism of its effects. The potential involvement of H2S in nitroso signaling underlying its diverse biological effects is also discussed.

The functional relevance of nitric oxide (NO) in the cardiovascular system is well established since the end of the 80', when it was firstly proposed as a key controller of vasodilation. More recent evidences, still debated and partly conflicting, point to a role of NO in the angiogenic progression. On the other hand hydrogen sulfide is a new entry as a gasotransmitter in the cardiovascular system. The variety of its biological functions seems to grow day after day. The first to be described is surely its reversible and poisoning binding of the cytochrome c oxidase that leads to impairment of the respiratory chain in mitochondria. However, sub-toxic concentrations have been later proved to be essential to maintain fundamental physiological functions in several tissues. The basal production of H2S is determined by the activity of, at least, three constitutively expressed enzymes (CBS, CSE, and 3-MPT) with tissue specificity for CBS and CSE in the central nervous and cardiovascular system, respectively. The assumption of a pivotal role of H2S in regulating physiological function is supported by the demonstration that reduced production of this gaseous molecule by CSE induces hypertension in mice. The increasing number of studies showing the regulatory functions of H2S reveals that maintaining the normal blood pressure levels is only one of its multiple biological actions. In this review, we would like to explore the recent literature on NO and H2S roles on cardiovascular system and to elucidate potential outcomes in the use of pharmacological drugs interfering with their metabolism.

Hydrogen sulphide (H2S) is a recently discovered gasotransmitter that may regulate a growing number of endothelial functions, including nitric oxide (NO) release, proliferation, adhesion and migration, which are the key steps of angiogenesis. The mechanism whereby H2S impacts on endothelial physiology is still unclear: however, the aforementioned processes are driven by an increase in intracellular Ca2+ concentration ([Ca2+]i). In the present study, we exploited the excised rat aorta to gain insights into the regulation of [Ca2+]i by H2S within in situ endothelial cells (ECs). Sodium hydrosulphide (NaHS), a H2S donor, caused an elevation in [Ca2+]i, which disappeared in absence of extracellular Ca2+. NaHSinduced Ca2+ inflow was sensitive to high doses of Gd3+, but not BTP-2. Inhibition of the reverse-mode of the Na+-Ca2+ exchanger (NCX), with KB-R7943 or upon removal of extracellular Na+, abrogated the Ca2+ response to NaHS. Moreover, NaHS-elicited Ca2+ entry was significantly reduced by TEA and glybenclamide, which hinted at the involvement of ATP-dependent K+ (KATP) channels. Conversely, NaHS-evoked Ca2+ signal was not affected by the reducing agent, dithiothreitol. Acute addition of NaHS hindered both Ca2+ release and Ca2+ entry induced by ATP, a physiological agonist of ECs. Consistently, inhibition of endogenous H2S synthesis with DL-propargylglycine impaired ATP-induced Ca2+ inflow, whereas it did not affect Ca2+ mobilization. These data provide the first evidence that H2S may stimulate Ca2+ influx into ECs by recruiting the reverse-mode of NCX and KATP channels. In addition, they show that such gasotransmitter may modulate the Ca2+ signals elicited by physiological stimuli in intact endothelium.

Objective: This study aimed to explore the effect of onion extract on endogenous hydrogen sulfide (H2S) and adrenomedulin (ADM) and on atherosclerotic progression in rats with atherosclerosis (AS). Methods And Results: Male Sprague-Dawley rats were randomly divided into control, AS and AS+onion groups. Ultrastructure of aorta and atherosclerotic lesions both in aorta and in coronary artery were detected. Plasma and aortic H2S were detected by using a sulfide- sensitive electrode. Plasma and aortic ADM was determined with radioimmunoassay. Cystathionine-γ-lyase (CSE), calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP1, RAMP2 and RAMP3) mRNA expressions were analysed. Glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and NO synthase (NOS) contents in plasma, SOD1, SOD2 and ICAM-1 expressions in aorta were detected. Rats in the AS group showed marked atherosclerotic lesions both in aorta and in coronary artery but decreased aortic H2S production. Decreased plasma and aortic ADM content, but increased levels of aortic CRLR, RAMP2 and RAMP3 mRNAs were observed. Plasma GSH-PX and SOD were reduced but MDA elevated. Plasma ICAM-1 and NO contents and iNOS activity were increased. Onion extract, however, lessened atherosclerotic lesions and increased endogenous aortic H2S production, but decreased plasma ADM content, aortic ADM content and aortic CRLR, RAMP2 and RAMP3 mRNAs. In addition, it increased plasma GSH-PX level and SOD activities but reduced MDA; it decreased inflammatory response but increased plasma eNOS activity and NO content. Conclusions: Onion extract exerted a marked antiatherogenic effect in association with the up-regulation of the endogenous CSE/H2S pathway but down-regulation of the ADM/CRLR family in atherosclerotic rats.

Although blood maintains a fluid state under physiologic conditions, clot formation is an immediate response to injury. The immediacy of the response is accomplished by the continuous circulation of hemostatic factors as zymogens, inactive precursors, and by the sequestration of active factors by the vessel wall, accessible only when vascular damage breaches this divide. Clot resolution, achieved by anti-coagulant and fibrinolytic factors, is central to complete restoration following injury. This balance between pro-coagulant and fibrinolytic factors is disrupted in a diverse set of pathologies, including liver and pulmonary fibrosis, sepsis, the metabolic syndrome, rheumatoid arthritis, acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Factors within the coagulation cascade and their downstream mediators are emerging as pre-clinical and clinical targets in each of these pathologies yet with varied efficacy. The emphasis for this edition will be on therapies directed at the alteration in hemostatic factors in each of these disease states, including evaluation of current and proposed therapeutics directed at factors within the coagulation cascade, their immediate downstream effectors, and cell signaling regulators of factors within the cascade. Hemostatic factors can contribute to a wide range of pathologies due in part to the circulating nature of the components and to the etiology of a number of these pathologies as a dysregulated response to injury. In this regard, therapeutic strategies directed toward hemostatic factors may have broad applicability across pathologies. This possibility is highlighted by Liang-I Kang and Wendy Mars in “Fibrinolytic factors in liver fibrosis” as they focus on the fibrinolytic side of the hemostatic equation. The authors present recent pre-clinical evidence supporting the development of fibrinolytic factors as potential therapeutics in the reversal of fibrotic liver disease, arguing from the demonstrated usefulness of such factors in the resolution of acute myocardial infarct and ischemic damage. Similar fibrotic resolution might be achievable within the lung. In their review entitled “Use of transgenic mouse models to understand the origins of familial pulmonary fibrosis”, Al Senft and Steve Glasser describe available murine models for slow-onset, slow-resolving pulmonary fibrotic disease that could prove to be useful in assessing whether a similar therapeutic regimen might provide benefit in the resolution of pulmonary fibrosis. The work from Henry Akinbi's group, “Simvastatin is protective during Staphylococcus aureus pneumonia”, demonstrates in vivo the potential for statin drugs in ameliorating dysregulated coagulation status during sepsis. Such an approach that targets multiple pathways through well-characterized pharmacology may be especially useful in the treatment of the metabolic syndrome, a complex interplay of systems that is covered in the review by Laura Michael, Veena Rao, Patrick McCollam, Mark Kowala, and John Wetterau, in “Opportunities for pharmacotherapy at the intersection of metabolic syndrome and hemostasis”. Novel therapeutics also are in need of development as reported in the review “Therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome” by Sara Sebag, Julie Bastarache, and Lorraine Ware, wherein they note that clinical benefit has yet to be demonstrated in the treatment of ARDS/ALI. Harini Raghu and Matthew Flick in “Targeting the coagulation factor fibrinogen for arthritis therapy” further examine the contribution of coagulation factors in the pathogenesis and etiology of inflammatory disease. Hemostatic factors have served as biomarkers for this range of pathologies, yet their contribution to the onset of each is an emerging concept that indicates their potential usefulness as therapeutic targets. This collection of reviews examines the alternative use of well-characterized pharmacologic agents and the need for the development of novel therapeutics directed toward pro-coagulant and fibrinolytic factors as they contribute to the increasingly burdensome personal and economic impact of these disease states.

Dysregulation of coagulation and fibrinolytic factors is now being recognized as not just a late-stage sequelae of liver disease, but in fact one of the potential contributing risk factors for liver cirrhosis. Recent molecular and animal studies have uncovered intriguing roles for plasmin and the plasminogen activators in protecting the liver from fibrosis development in a manner that is largely fibrin-independent. These pleiotropic effects may be explained by functions of their other proteolytic targets (e.g. hepatocyte growth factor) and receptor-mediated signaling. This review features salient basic science research which shows the immense potential of promoting the hepatic activity of plasmin and its activators in the prevention and treatment of liver cirrhosis in humans.

Pulmonary fibrosis is an unremitting degenerative lung disease that has an associated high mortality. The major pathological features include the growth of fibroblasts, emergence of myofibroblasts and their production of extracellular matrix that distorts the peripheral lung tissue and impairs respiratory function. Efforts to pharmacologically reduce inflammation, inhibit fibroblast growth, or matrix synthesis have not been successful in ameliorating disease. Genetic mutations associated with rare hereditary forms of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF) link definitive causes to this enigmatic group of diseases. The generation of mouse models with similar genetic lesions or deficiencies is providing insight into the mechanisms that lead to fibrosis. Mutations that alter components of pulmonary surfactant or surfactant homeostasis have been associated with specific forms of ILD and/or IPF. This small but growing collection of IPF related surfactant dysfunction mutations implicate respiratory epithelial cell injury as an early event in the molecular pathogenesis and progression of fibrosis. Determining the mechanisms for genetically defined examples of IPF should be informative for investigating the larger segment of IPF where the underlying cause remains obscure.

Epidemiologic studies suggest that the incidence and severity of sepsis are ameliorated in patients on statins (3- hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) for cholesterol lowering indications. We sought to understand the mechanism underlying such protection and hypothesized that simvastatin would be protective in mice against acute infection with Staphylococcus aureus, the primary etiologic agent in sepsis. Mice were treated with simvastatin or buffer for two weeks and were subsequently challenged with S. aureus intratracheally or intravenously. Relative to buffer-treated mice, bacterial killing was enhanced 4-fold (p=0.02), systemic dissemination was reduced, and lethality was decreased (hazard ratio 8.8, 95% CI 2.5 to 31.3, p=0.001) in mice that were pretreated with simvastatin for two weeks. Systemic inflammatory response was abrogated and the local elaboration of inflammatory mediators was diminished. Serum concentrations of pro-fibrinolytic protein C were elevated (p=0.034), while the concentration of pro-coagulant tissue factor in bronchoalveolar lavage fluids was attenuated (reduced 25%), p=0.001, in simvastatin-treated mice. Taken together, these data indicate that extended treatment with simvastatin is protective during infection with S. aureus through enhanced bacterial clearance, anti-inflammatory, and anti-coagulant activities. These studies provide insights into the mechanism by which statins confer protection in acute infection, support the notion that statins may be effective adjuncts in the treatment of sepsis, and provide a rationale for randomized control trials in patients that are at a high risk for infection characterized by coagulopathy.