Acute Inflammatory Disorders Research Articles

ChemInform Abstract: The Frondosins: An Unusual Synthetic and Stereochemical Journey

AbstractReview: 58 refs.

ChemInform Abstract: Sulfated Glycans in Inflammation

AbstractReview: 131 refs.

Sulfated glycans in inflammation.

Sulfated glycans such as glycosaminoglycans on proteoglycans are key players in both molecular and cellular events of inflammation. They participate in leukocyte rolling along the endothelial surface of inflamed sites; chemokine regulation and its consequential functions in leukocyte guidance, migration and activation; leukocyte transendothelial migration; and structural assembly of the subendothelial basement membrane responsible to control tissue entry of cells. Due to these and other functions, exogenous sulfated glycans of various structures and origins can be used to interventionally down-regulate inflammation processes. In this review article, discussion is given primarily on the anti-inflammatory functions of mammalian heparins, heparan sulfate, chondroitin sulfate, dermatan sulfate and related compounds as well as the holothurian fucosylated chondroitin sulfate and the brown algal fucoidans. Understanding the underlying mechanisms of action of these sulfated glycans in inflammation, helps research programs involved in developing new carbohydrate-based drugs aimed to combat acute and chronic inflammatory disorders.

Anti-inflammatory potential of Agaricus in carrageenan-induced model of local inflammation in rats

Background: The concept of effects of Agaricus on inflammatory responses is still controversial. This study, therefore, was designed to assess the potential of the anti-inflammatory effect of Agaricus 100% extract on acute inflammation using the model of carrageenan-induced paw edema in rats. Methods: Four groups among five (six rats each) have been injected with carrageenan (0.1 mL of 3% solution), intra-plantar in the right hind paw; the first group was injected with saline instead in the same manner and kept as control. An hour earlier, rats received different treatments, either saline (inflamed control), or diclofenac (inflamed, standard-treated), or Agaricus extract (5 mL/kg as small dose or 10 mL/kg as a large dose). The volume of the developed paw edema has been measured at an hour interval fashion (1~6 hrs) and at 24 hrs. Results: Agaricus extract showed inhibitory effects on the carrageenan-induced edema in time- and dose-dependent manner, at the late phase (2~ hrs) of the inflammatory response (small dose) and at both early (~2 hrs) and late phases (large dose). The effects were comparable to those of diclofenac being 11.74, 08.46, 08.99, 09.72 and 09.89% at 2-6 hrs (small dose); 14.04, 23.91, 21.92, 17.99, 15.63 and 16.96% at 1-6 hrs (large dose); 16.85, 31.30, 35.38, 35.97, 34.72 and 34.63% (diclofenac). The anti-inflammatory effect of Agaricus could be attributed to its phytochemical content which may inhibit the inducible inflammatory mediators (as prostaglandins and nitric oxide) in the late phase (small dose) and/or inhibiting both early (histamine and oxygen free radicals) and late mediators (large dose). Conclusions: These data may indicate that Agaricus extract has the potential of anti-inflammatory activity that could be applied in acute inflammatory disorders.

Cytochrome p450 enzymes in the bioactivation of polyunsaturated Fatty acids and their role in cardiovascular disease.

Various members of the cytochrome P450 (CYP) superfamily have the capacity of metabolizing omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs). In most mammalian tissues, CYP2C and CYP2J enzymes are the major PUFA epoxygenases, whereas CYP4A and CYP4F subfamily members function as PUFA hydroxylases. The individual CYP enzymes differ in their substrate specificities as well as regio- and stereoselectivities and thus produce distinct sets of epoxy and/or hydroxy metabolites, collectively termed CYP eicosanoids. Nutrition has a major impact on the endogenous CYP-eicosanoid profile. "Western diets" rich in n-6 PUFAs result in a predominance of arachidonic acid-derived metabolites, whereas marine foodstuffs rich in n-3 PUFAs shift the profile to eicosapentaenoic and docosahexaenoic acid-derived metabolites. In general, CYP eicosanoids are formed as second messengers of numerous hormones, growth factors and cytokines regulating cardiovascular and renal function, and a variety of other physiological processes. Imbalances in the formation of individual CYP eicosanoids are linked to the development of hypertension, myocardial infarction, maladaptive cardiac hypertrophy, acute kidney injury, stroke and inflammatory disorders. The underlying mechanisms are increasingly understood and may provide novel targets for the prevention and treatment of these disease states. Suitable pharmacological agents are under development and first proofs of concept have been obtained in animal models.

Endothelial, but not smooth muscle, peroxisome proliferator-activated receptor β/δ regulates vascular permeability and anaphylaxis

Remodeling of quiescent vessels with increases in permeability, vasodilatation, and edema are hallmarks of inflammatory disorders. Factors involved in this type of remodeling represent potential therapeutic targets. We investigated whether the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) β/δ, a regulator of metabolism, fibrosis, and skin homeostasis, is involved in regulation of this type of remodeling. Wild-type and various Pparb/d mutant mice were used to monitor dermal acute vascular hyperpermeability (AVH) and passive systemic anaphylaxis-induced hypothermia and edema. PPARβ/δ-dependent kinase activation and remodeling of endothelial cell-cell junctions were addressed by using human endothelial cells. AVH and dilatation of dermal microvessels stimulated by vascular endothelial growth factor A, histamine, and thrombin are severely compromised in PPARβ/δ-deficient mice. Selective deletion of the Pparb/d-encoding gene in endothelial cells invivo similarly limits dermal AVH and vasodilatation, providing evidence that endothelial PPARβ/δ is the major player in regulating acute dermal microvessel remodeling. Furthermore, endothelial PPARβ/δ regulatory functions are not restricted to the skin vasculature because its deletion in the endothelium, but not in smooth muscle cells, also leads to reduced systemic anaphylaxis, the most severe form of allergic reaction, in which an acute vascular response plays a key role. PPARβ/δ-dependent AVH activation likely involves the activation of mitogen-activated protein kinase and Akt pathways and leads to downstream destabilization of endothelial cell-cell junctions. These results unveil not only a novel function of PPARβ/δ as a direct regulator of acute vessel permeability anddilatation but also provide evidence that antagonizing PPARβ/δ represents an important strategy to consider for moderating diseases with altered endothelial integrity, such as acute inflammatory and allergic disorders.

The Frondosins: An Unusual Synthetic and Stereochemical Journey

AbstractIsolated from the marine sponge Dysidea frondosa, the frondosin family of meroterpenoid natural products were shown to be antagonists of the binding of the cytokine interleukin‐8 to its receptor. With implications of interleukin‐8 management being associated with a wide range of acute and chronic inflammatory disorders, as well as tumor progression and/or metathesis, there have been a multitude of syntheses of these natural products in the hopes of developinging new pharmacological agents. However, assignment of the absolute configurations of these natural products became unclear, because the first two syntheses of frondosin B, by Danishefsky and by Trauner, produced conflicting assignments for the single stereogenic center at C8. Here we describe the initial stereochemical mystery surrounding the Danishefsky and Trauner syntheses and provide evidence through ensuing syntheses of frondosins B and A that resolve this issue. These subsequent asymmetric syntheses have established that (1) the natural product occurs as the R enantiomer, and (2) a late‐stage stereochemical inversion occurred during the Trauner and Wright syntheses of frondosin B.

Therapeutic Impact of Human Serum Albumin–Thioredoxin Fusion Protein on Influenza Virus-Induced Lung Injury Mice

Reactive oxygen species (ROS) are the primary pathogenic molecules produced in viral lung infections. We previously reported on the use of a recombinant human serum albumin (HSA)–thioredoxin 1 (Trx) fusion protein (HSA–Trx) for extending the half-life Trx, an endogenous protein with anti-oxidant properties. As a result, it was possible to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx. We hypothesized that HSA–Trx would attenuate the enhanced ROS production of species such as hydroxyl radicals by neutrophils during an influenza viral infection. The levels of 8-hydroxy-2′-deoxyguanosine and 3-nitrotyrosine were used as indices of the anti-oxidant activity of HSA–Trx. In addition, the cytoprotective effects of HSA–Trx were examined in PR8 (H1N1) influenza virus-induced lung injured mice. The findings show that HSA–Trx reduced the number of total cells, neutrophils, and total protein in BALF of influenza virus-induced lung injured mice. The HSA–Trx treatment significantly decreased the level of 8-hydroxy-2′-deoxyguanosine and 3-nitrotyrosine, but failed to inhibit inducible nitric oxide synthase expression, in the lungs of the virus-infected mice. On the other hand, Tamiflu® treatment also significantly suppressed the production of inflammatory cells and neutrophil infiltration, as well as the protein level in BALF and lung histopathological alterations caused by the influenza virus. The suppressive effect of Tamiflu® was slightly stronger than that of HSA–Trx. Interestingly, Tamiflu® significantly decreased virus proliferation, while HSA–Trx had no effect. These results indicate that HSA–Trx may be of therapeutic value for the treatment of various acute inflammatory disorders such as influenza-virus-induced pneumonia, by inhibiting inflammatory-cell responses and suppressing the overproduction of NO in the lung.

Self-assembling lipid modified glycol-split heparin nanoparticles suppress lipopolysaccharide-induced inflammation through TLR4–NF-κB signaling

Self-assembling heparin nanoparticles have attracted much attention as promising drug carriers for various drugs, genes and imaging agents. In the present investigation, we found that heparin nanoparticles are selective Toll-like receptor 4 (TLR-4) antagonists and have a much greater anti-inflammatory effect than native heparin. More specifically, we developed self-assembling nanoparticles composed of glycol-split heparin/d-erythro-sphingosine conjugates (NAHNP), characterized their physicochemical properties and anti-inflammatory effect in vitro. Unlike native heparin, NAHNP significantly inhibited lipopolysaccharide-induced activation of MyD88-dependent NF-κB signaling pathway and production of pro-inflammatory cytokines such as TNF-alpha from mouse macrophages with IC50=0.019mg/mL. Furthermore, we investigated the structure–activity relationship of the conjugates and identified the length of attached alkyl chains of d-erythro-sphingosine to be critical for anti-inflammatory effect. Decrease in alkyl chain length of NAHNP resulted in loss of inhibitory activity. In line with these findings, 6-O-sulfate groups of d-glucosamine residue were essential for effective inhibition, while removal of 2-O-sulfo and 3-O-sulfo groups as well as replacement of N-sulfo groups with N-acetyl did not alter anti-inflammatory activity. Therefore, NAHNP would be a promising candidate in acute and chronic inflammatory disorders, in addition to the nature of a drug carrier.

CXCR2 receptor antagonists: a medicinal chemistry perspective.

Dysregulated leukocyte recruitment is believed to be a key contributor to various acute and chronic inflammatory disorders which can lead to serious pathological consequences. Chemokines are small molecular weight proteins that have been shown to be imperative in the direction of leukocytes to the sites of inflammation. In humans, several of these chemokines (CXCL8 and CXCL1) are elevated in inflammatory disorders such as asthma, arthritis, and chronic obstructive pulmonary disease (COPD). These chemokines modulate their downstream effects thru G-protein coupled receptors, such as CXCR2, making the identification of small-molecule antagonists of this receptor attractive towards developing novel therapies to treat inflammatory conditions. Since the first report of a CXCR2 receptor antagonist in 1998, there has been a considerable effort conducted mainly in the pharmaceutical industry to identify novel classes of CXCR2 receptor antagonists. Over a dozen distinct classes of CXCR2 receptor antagonists have been reported in the literature to date with a number of these compounds having reached mid-stage clinical trials. This review will provide a broad overview the medicinal chemistry efforts over the past 15 years towards the identification of CXCR2 receptor antagonists. The discussion will focus upon the early preclinical space covering the structure activity relationships (SAR), pharmacology, as well in preclinical in vivo evaluation for the different series of CXCR2 receptor antagonists. In addition, the available clinical data for the most advanced compounds in the clinic will be discussed and along with a perspective of the area moving forward.

Efficacy and safety of inhaled and intranasal corticosteroids.

Inflammation is an important phenomenon in allergic disorders and corticosteroid drugs since their anti inflammatory properties have a pivotal role in improvement, control and relieving the symptoms and signs of asthma, allergic rhinitis, atopic dermatitis and many other inflammatory disorders. Nevertheless, the prescription of these drugs might be associated with some unwanted reactions such as hyperglycemia, hypertension, Cushing's syndrome, adrenal insufficiency and growth failure. In recent decades administration of intranasal and inhaled corticosteroids instead of systemic parenteral or oral drugs reduced some of these concerns during treatment of patients and enable them to receive the effective and safer kind of therapy in acute or chronic inflammatory disorders of nose and airways. In this article the properties of inhaler (ICS) and intranasal corticosteroids (INCS) were reviewed.

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.

A1.39 Modulation of atp:adenosine balance by exosome and rain (Recombinant Anti-Inflammatory Fusion Protein) delivery of CD39 and CD73 is effective in reducing pro-inflammatory cytokine and chemokine production

Background and ObjectivesThe conversion of ATP to adenosine is an important mechanism of immune suppression by Tregs, and this is done by expression of CD39 and CD73. CD39 is a...

Efficacy and safety of a herbal medicinal product containing myrrh, chamomile and coffee charcoal for the treatment of gastrointestinal disorders: a non-interventional study

ObjectiveThis prospective observational postmarketing multicentre study was performed to collect data on the clinical efficacy, safety and tolerability of a licensed herbal combination of myrrh, coffee charcoal and chamomile extracts...

Cysteinyl leukotriene receptor-1 antagonists as modulators of innate immune cell function.

Cysteinyl leukotrienes (cysLTs) are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and monocytes/macrophages. Notwithstanding potent bronchoconstrictor activity, cysLTs are also proinflammatory consequent to their autocrine and paracrine interactions with G-protein-coupled receptors expressed not only on the aforementioned cell types, but also on Th2 lymphocytes, as well as structural cells, and to a lesser extent neutrophils and CD8+ cells. Recognition of the involvement of cysLTs in the immunopathogenesis of various types of acute and chronic inflammatory disorders, especially bronchial asthma, prompted the development of selective cysLT receptor-1 (cysLTR1) antagonists, specifically montelukast, pranlukast, and zafirlukast. More recently these agents have also been reported to possess secondary anti-inflammatory activities, distinct from cysLTR1 antagonism, which appear to be particularly effective in targeting neutrophils and monocytes/macrophages. Underlying mechanisms include interference with cyclic nucleotide phosphodiesterases, 5′-lipoxygenase, and the proinflammatory transcription factor, nuclear factor kappa B. These and other secondary anti-inflammatory mechanisms of the commonly used cysLTR1 antagonists are the major focus of the current review, which also includes a comparison of the anti-inflammatory effects of montelukast, pranlukast, and zafirlukast on human neutrophils in vitro, as well as an overview of both the current clinical applications of these agents and potential future applications based on preclinical and early clinical studies.

Immune functions of platelets.

This review collects evidence about immune and inflammatory functions of platelets from a clinician's point of view. A focus on clinically relevant immune functions aims at stimulating further research, because the complexity of platelet immunity is incompletely understood and not yet translated into patient care. Platelets promote chronic inflammatory reactions (e.g. in atherosclerosis), modulate acute inflammatory disorders such as sepsis and other infections (participating in the host defense against pathogens), and contribute to exacerbations of autoimmune conditions (like asthma or arthritis). It would hence be obsolete to restrict a description of platelet functions to thrombosis and haemostasis--platelets clearly are the most abundant cells with immune functions in the circulation.

석결명(石決明)의 항염증효과(抗炎症效果)

Objectives : Haliotidis Concha has been used to treat various human diseases such as liver dysfunction and inflammatory disorder. Although it has been shown the effects of Haliotidis Concha on the various diseases, it has almost not been studied about the anti-inflammatory effects of the Haliotidis Concha and its mechanisms. Methods : This research investigated the effects of the Haliotidis Concha ethanol extract (HCE) on the production of nitric oxide (NO) and prostaglandin <TEX>$E_2$</TEX> (<TEX>$PGE_2$</TEX>) as well as tumor necrosis factor-alpha (TNF-<TEX>${\alpha}$</TEX>). The protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were assayed by immunoblot analyses, and the productions of NO, <TEX>$PGE_2$</TEX> and TNF-<TEX>${\alpha}$</TEX> were assessed by ELISA. Results : Haliotidis Concha decreased the production of NO and <TEX>$PGE_2$</TEX>, and inhibited the expression iNOS and COX-2 proteins in a concentration-dependent manner in LPS-treated Raw 264.7 cells. HCE suppressed the ability of LPS to activate the signaling pathways of nuclear factor kappa B (NF-<TEX>${\kappa}B$</TEX>) as indicated by HCE inhibited nuclear NF-<TEX>${\kappa}B$</TEX> level and I-<TEX>${\kappa}B{\alpha}$</TEX> phosphorylation. Also, HCE inhibited mitogen-activated protein kinases (MAPKs). Conclusions : HCE repressed the production of LPS-inducible NO, <TEX>$PGE_2$</TEX> and TNF-<TEX>${\alpha}$</TEX>, which may be mediated by inhibition of NF-<TEX>${\kappa}B$</TEX> translocation. This study suggest the use for the treatment of acute inflammatory disorders.

Ulinastatin attenuates experimental autoimmune encephalomyelitis by enhancing anti-inflammatory responses

Multiple sclerosis (MS) is a common inflammatory and demyelinating neurological disease. Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, has been widely used to test MS treatment methods. Ulinastatin (UTI), a drug used to treat acute inflammatory disorders, has been tested in animal models of autoimmune inflammatory diseases, such as ulcerative colitis and crescentic glomerulonephritis. We recently found that UTI has a neuroprotective effect on EAE by reducing oligodendrocyte apoptosis and demyelination. The anti-inflammatory effects of UTI on EAE/MS, however, have never been investigated. We have therefore evaluated the anti-inflammatory effects of UTI in EAE and explored the mechanisms underlying this effect. EAE was induced in mice with and without UTI treatment. Inflammation and demyelination of spinal cords were evaluated by staining with hematoxylin and eosin and with Luxol fast blue, respectively. Inflammatory markers in serum were analyzed by the Luminex method, and spinal cords were evaluated by immunofluorescence and Western blotting. UTI significantly lowered the clinical and pathological scores and the serum concentrations of the inflammatory cytokines interleukin (IL)-1β, IL-6, and matrix metal protease-9 (MMP-9). UTI also reduced the expression of tumor necrosis factor-alpha (TNF-α)/nuclear factor kappaB (NF-κB)/inducible nitric oxide synthase (iNOS) proteins and decreased CD11b+ cells in spinal cord lesions. UTI may protect against EAE in mice by suppressing inflammatory responses. We think that UTI might be a potential therapeutic agent for MS.

Can the anti-inflammatory activities of &amp;beta;2-agonists be harnessed in the clinical setting?

Beta2-adrenoreceptor agonists (β2-agonists) are primarily bronchodilators, targeting airway smooth muscle and providing critical symptomatic relief in conditions such as bronchial asthma and chronic obstructive pulmonary disease. These agents also possess broad-spectrum, secondary, anti-inflammatory properties. These are mediated largely, though not exclusively, via interactions with adenylyl cyclase-coupled β2-adrenoreceptors on a range of immune and inflammatory cells involved in the immunopathogenesis of acute and chronic inflammatory disorders of the airways. The clinical relevance of the anti-inflammatory actions of β2-agonists, although often effective in the experimental setting, remains contentious. The primary objectives of the current review are: firstly, to assess the mechanisms, both molecular and cell-associated, that may limit the anti-inflammatory efficacy of β2-agonists; secondly, to evaluate pharmacological strategies, several of which are recent and innovative, that may overcome these limitations. These are preceded by a consideration of the various types of β2-agonists, their clinical applications, and spectrum of anti-inflammatory activities, particularly those involving adenosine 3′,5′-cyclic adenosine monophosphate-activated protein kinase-mediated clearance of cytosolic calcium, and altered gene expression in immune and inflammatory cells.

A mouse is not a rat is not a man: species-specific metabolic responses to sepsis - a nail in the coffin of murine models for critical care research?

Sepsis and consequent multi-organ failure are the leading causes of mortality in critically ill patients. Numerous therapeutic strategies, which yielded promising results in preclinical studies, have failed to show any efficacy in clinical trials. Historically, most of our (patho)physiological understanding of cardiovascular regulation in health and disease has been established in larger mammals, e.g., dog, pig, and sheep. However, a very large body of the literature collected over recent decades originates from investigations in rodents. Despite their small size, which makes surgery difficult and limits repetitive blood sampling, murine models have been widely used, not because they are more faithful to adult human pathophysiology than larger mammals but because they are inexpensive, easy to handle and care for, and with availability of gene knockout and overexpression strains. Investigators have performed studies without necessarily having a good appreciation of some fundamental differences in the physiology of rodents. These have been long established by comparative physiologists, yet have never been taught in any medical school. One can query the logic of inferring information on mechanisms involved in septic shock using species capable of decreasing their high resting metabolic rate both rapidly and massively, and with the associated circulatory and respiratory responses. Mouse models of acute inflammatory disorders have recently been questioned by Seok et al. [1] who found that “genomic responses to different acute inflammatory stresses are highly similar in humans”, whereas “these responses are not reproduced in current mouse models”. In this context, Zolfaghari et al. [2] compared the metabolic responses to polymicrobial sepsis in rats and mice. Their main findings were that mice presented with a progressive drop in whole body O2 uptake and a concurrent fall in body temperature, which was only partially restored by external warming. This marked metabolic depression coincided with pronounced impairment of left heart systolic contractility. In sharp contrast, only severely ill rats showed a comparably decreased cardiac output, and the metabolic depression was only present during the late premortem period. How can we explain these findings by Zolfaghari et al. [2]? The authors have the merit of raising an issue of crucial importance for critical care research, i.e., whether or