Cascade Of Mediators Research Articles

Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy?

Influenza viruses (IVs) circulate seasonally and are a common cause of respiratory infections in pediatric and adult patients. Additionally, recurrent pandemics cause massive morbidity and mortality worldwide. Infection may result in rapid progressive viral pneumonia with fatal outcome. Since accurate treatment strategies are still missing, research refocuses attention to lung pathology and cellular crosstalk to develop new therapeutic options.Alveolar epithelial cells (AECs) play an important role in orchestrating the pulmonary antiviral host response. After IV infection they release a cascade of immune mediators, one of which is granulocyte and macrophage colony-stimulating factor (GM-CSF). GM-CSF is known to promote differentiation, activation and mobilization of myeloid cells. In the lung, GM-CSF drives immune functions of alveolar macrophages and dendritic cells (DCs) and also improves epithelial repair processes through direct interaction with AECs. During IV infection, AEC-derived GM-CSF shows a lung-protective effect that is also present after local GM-CSF application. This mini-review provides an overview on GM-CSF-modulated immune responses to IV pneumonia and its therapeutic potential in severe IV pneumonia.

Expression of Pentraxin 3 and Thrombospondin 1 in Gingival Crevicular Fluid during Wound Healing after Gingivectomy in Postorthodontic Patients.

Background. Wound healing is a tissue repair process after an injury, and two of its main components are inflammation and angiogenesis, in which course a cascade of mediators is involved. The aim of this research was to evaluate the involvement of Pentraxin 3 and Thrombospondin 1 in wound healing after periodontal surgery (gingivectomy) for gingival overgrowth during orthodontic treatment with or without magnification devices, by assessing their levels in GCF. Methods. From 19 patients with gingival overgrowth as a result of fixed orthodontic treatment, the overgrown gingiva was removed by gingivectomy, from one half of the mandibular arch without magnification and from the other under magnification. Pentraxin 3 and Thrombospondin 1 were determined from gingival crevicular fluid by ELISA tests. Results. Statistically significant differences (p < 0.05) and correlations between levels of the two biomarkers were analyzed. Statistically significant differences were established between levels of the two biomarkers at different time points, with significant positive correlation at the point of 24 hours. Conclusions. Within the limitations of this study, the results seem to sustain the involvement of Pentraxin 3 and Thrombospondin 1 in the processes of inflammation and angiogenesis in wound healing of patients with postorthodontic gingivectomy. The dynamics of Pentraxin 3 and Thrombospondin 1 levels could suggest a reduced inflammation and a faster angiogenesis using microsurgery.

Polyethylene glycols: An effective strategy for limiting liver ischemia reperfusion injury.

Liver ischemia-reperfusion injury (IRI) is an inherent feature of liver surgery and liver transplantation in which damage to a hypoxic organ (ischemia) is exacerbated following the return of oxygen delivery (reperfusion). IRI is a major cause of primary non-function after transplantation and may lead to graft rejection, regardless of immunological considerations. The immediate response involves the disruption of cellular mitochondrial oxidative phosphorylation and the accumulation of metabolic intermediates during the ischemic period, and oxidative stress during blood flow restoration. Moreover, a complex cascade of inflammatory mediators is generated during reperfusion, contributing to the extension of the damage and finally to organ failure. A variety of pharmacological interventions (antioxidants, anti-cytokines, etc.) have been proposed to alleviate graft injury but their usefulness is limited by the local and specific action of the drugs and by their potential undesirable toxic effects. Polyethylene glycols (PEGs), which are non-toxic water-soluble compounds approved by the FDA, have been widely used as a vehicle or a base in food, cosmetics and pharmaceuticals, and also as adjuvants for ameliorating drug pharmacokinetics. Some PEGs are also currently used as additives in organ preservation solutions prior to transplantation in order to limit the damage associated with cold ischemia reperfusion. More recently, the administration of PEGs of different molecular weights by intravenous injection has emerged as a new therapeutic tool to protect liver grafts from IRI. In this review, we summarize the current knowledge concerning the use of PEGs as a useful target for limiting liver IRI.

Critical care management of systemic mastocytosis: when every wasp is a killer bee.

Since the critical care physician will most likely be involved in a life-threatening expression of systemic mastocytosis, recognition of this disease is of utmost importance in the critical care management of these patients. Mastocytosis is a severely under-recognized disease because it typically occurs secondary to another condition and thus may occur more frequently than assumed. In this article, we will review the current knowledge on the treatment of mastocytosis crises with an emphasis on critical care management. Mastocytosis is characterized by the clonal proliferation and accumulation of mast cells in different tissues. Mast cell mediators contain a wide range of biologically active substances that may lead to itching and hives but may ultimately lead to anaphylactic shock caused by the release of histamine and other mediators from mast cells. The mainstay of therapy is the avoidance of potential triggers of mast cell degranulation and, if unsuccessful, blocking the cascade of mast cell mediators. The critical care physician should be well aware of the special precautions which should be kept in mind throughout the management of a mastocytosis crisis to avoid massive mast cell degranulation. Histamine-releasing drugs and certain physical triggers like temperature change should be avoided.

IL-1 in Colon Inflammation, Colon Carcinogenesis and Invasiveness of Colon Cancer.

Interleukin-1 (IL-1) is a major "alarm" upstream pro-inflammatory cytokine that mainly acts by inducing cascades of cytokine and inflammation-promoting mediators. In the tumor arena, IL-1 is produced by both malignant and microenvironmental cells. IL-1α and IL-1β are the major agonists of IL-1, while IL-1Ra is a physiological inhibitor of pre-formed IL-1. IL-1α and IL-1β differ in their compartmentalization and in the producing cells. IL-1β is only active in its inflammasome dependent processed and secreted form and has been considered as the major mediator of inflammation. On the other hand, IL-1α is mainly cell-associated in tissue resident cells, being also active in its precursor form. The role of the IL-1 molecules in the unique microenvironment in the colon is largely unknown. Here, we described the role of IL-1α and IL-1β in colon homeostasis, colon inflammation, colon carcinogenesis and invasiveness of colorectal cancer. Understanding of the integrative role of IL-1α and IL-1β in these processes will facilitate the application of novel IL-1 modulating approaches.

A systems pharmacology approach to investigate the mechanisms of action of Semen Strychni and Tripterygium wilfordii Hook F for treatment of rheumatoid arthritis

Ethnopharmacology relevanceThe angiogenesis control at the initiation of rheumatoid arthritis (RA) that mainly blocks the inflammatory cascades expects to attenuate the action of angiogenic mediators, synovial angiogenesis, and to partially reverse the erosive bone damage. Two typical Chinese herbs, Semen Strychni and Tripterygium wilfordii Hook F (TwHF) have been used as a remedy to treat RA since ancient time. However, their functioning mechanisms are still unknown. Thus it is necessary to exploit their underlying mechanism for the treatment of RA. MethodsThis study was undertaken to analyze their underlying mechanism based on a systems biology platform. Firstly, active components of the two herbs were screened out from TcmSP database based on their OB and DL values. Then their potential targets were predicted by using Random Forest, Support Vector Machine, and validated via docking process. Finally, a network of compound-target was constructed. ResultsIn this work, 27 and 33 active compounds were screened out from Semen Strychni and TwHF, targeting 28 and 32 potential proteins, respectively. The results show that the two herbs modulate the angiogenesis mediators through both direct and indirect pathways, and 21 common targets shared by Semen Strychni and TwHF bear major responsibility for treating RA. ConclusionsThe underlying mechanism of Semen Strychni and TwHF in treatment of RA is through multiple targets interaction by their blocking of the angiogenesis mediator cascades. This may provide us a better understanding of the function of the two herbs for the treatment of RA, as well as a clue to unveil their possible treatment effects of other systemic diseases, and in this way, hopefully the screening models may facilitate the discovery of novel combined drugs.

Endocannabinoids, through opioids and prostaglandins, contribute to fever induced by key pyrogenic mediators

This study aims to explore the contribution of endocannabinoids on the cascade of mediators involved in LPS-induced fever and to verify the participation of prostaglandins and endogenous opioids in fever induced by anandamide (AEA). Body temperature (Tc) of male Wistar rats was recorded over 6h, using a thermistor probe. Cerebrospinal fluid concentration of PGE2 and β-endorphin were measured by ELISA after the administration of AEA.Intracerebroventricular administration of the CB1 receptor antagonist AM251 (5μg, i.c.v.), reduced the fever induced by IL-1β (3ng, i.c.v.), TNF-α (250ng, i.c.v.), IL-6 (300ng, i.c.v.), corticotrophin release factor (CRH; 2.5μg, i.c.v.) and endothelin (ET)-1 (1pmol, i.c.v.), but not the fever induced by PGE2 (250ng, i.c.v.) or PGF2α (250ng, i.c.v.). Systemic administration of indomethacin (2mgkg−1, i.p.) or celecoxib (5mgkg−1, p.o.) reduced the fever induced by AEA (1μg, i.c.v.), while naloxone (1mgkg−1, s.c.) abolished it. The increases of PGE2 and β-endorphin concentration in the CSF induced by AEA were abolished by the pretreatment of rats with AM251.These results suggest that endocannabinoids are intrinsically involved in the pyretic activity of cytokines (IL-1β, TNF-α, IL-6), CRH and ET-1 but not the PGE2 or PGF2α induced fevers. However, anandamide via CB1 receptor activation induces fever that is dependent on the synthesis of prostaglandin and opioids.

ChemInform Abstract: Triflic Acid Mediated Cascade Cyclization of Aryldiynes for the Synthesis of Indeno[1,2‐c]chromenes: Application to Dye‐Sensitized Solar Cells.

AbstractSubstrates bearing an ortho‐anisole substituent are transformed to the heterocyclic title scaffold in the presence of TfOH (mechanism).

ChemInform Abstract: Synthesis of Dihydrobenzoheterocycles Through Al(OTf)3‐Mediated Cascade Cyclization and Ionic Hydrogenation.

A facile and versatile synthesis of dihydrobenzoheterocycles via Al(OTf)3-mediated cascade cyclization and ionic hydrogenation has been developed. The reaction is applicable to a wide range of substrates with various functional groups to afford the corresponding products in good yields.

Activation of Caspase-8 and Caspase-9 are Required for PC12 Cells Differentiation

Nerve growth factor- (NGF) induced potent activation of caspase-8, and caspase-9 in PC12 cells in a time-dependent manner. Peptide inhibition of caspase activity led to a potent reduction in neurite outgrowth in NGF-treated cells. Although NGF treatment resulted in cell-cycle G0/G1 arrest as detected by FACS cell-cycle analysis, caspase inhibitors (caspase-8 and caspase-9 inhibitors) could block the G0/G1 arrest in PC12 cells. We demonstrated the unique caspase cascade, caspase-8, caspase-3, and caspase-9 to occur, in this order. In conclusion, present results confirm a unique role for the caspase-8 and caspase-9 mediated signal cascade in the differentiation of PC12 cells.

Triflic acid mediated cascade cyclization of aryldiynes for the synthesis of indeno[1,2-c]chromenes: application to dye-sensitized solar cells.

A new triflic acid (TfOH)-mediated cascade cyclization of ortho-anisole-substituted aryldiynes is described for the construction of indeno[1,2-c]chromenes. The cascade cyclization proceeds through an unusual TfOH-induced alkyne-alkyne cyclization followed by nucleophilic attack of the methoxy group on the benzylidene cation, which is completely different to the cyclization of ortho-aniline- or ortho-thioanisole-substituted aryldiynes. A new class of organic dyes with the indeno[1,2-c]chromene framework as both donor and π-linker were synthesized. These compounds exhibit high photovoltaic performances in dye- sensitized solar cells (DSCs).

Observation of Mediated Cascade Energy Transfer in Europium-Doped ZnO Nanowalls by 1,10-Phenanthroline

Embedding rare earth ions into a host material such as alkali halides, semiconductors, and metal oxides has been extensively studied, with the goal to improve performance in light emitting devices and biomedicine. Here, Europium-embedded ZnO nanowall structures have been achieved by a facile electrochemical deposition method. Upon Eu embedment, the nanowalls were found to become thicker and stacked. X-ray photoemission study revealed that Zn(OH)2 was more dominant than ZnO near the surface and it confirmed that Eu(III) was uniformly distributed in the ZnO−Zn(OH)2 core−shell structure. We also measured the photo- luminescence spectra of as-grown, heat-treated and 1,10-phenanthroline surface-functionalized ZnO nanowalls samples, which led us to propose a unique cascade energy transfer model between ZnO, 1,10-phenanthroline, and Eu 3+ ion.

ABCA1 Expression in Macrophages of Allogeneic Hematopoietic Stem Cell Transplantation Patients with Severe Infection Undergoing Continuous Blood Purification

Excessive activation of the inflammatory mediator cascade after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients is associated with high mortality. Many studies have shown that continuous blood purification (CBP) could improve the prognosis of allo-HSCT patients with severe infection. However, the exact mechanism remains unclear. The aim of this study was to observe the effect of CBP on the expression of ATP-binding cassette transporter A1 (ABCA1) in macrophages, and to investigate the interventional effects of CBP on serum cytokine in allo-HSCT patients with severe infection. A total of 26 allo-HSCT patients with severe infection were included in this study. Before CBP and after CBP, blood samples were collected to observe hepatic and renal function, and the serum levels of TNF-α, IL-1, IL-6, and IL-10 were detected via ELISA. The THP-1 macrophages were exposed to serum samples obtained from patients at specific time points during CBP to test the changes of ABCA1 in macrophages by real-timePCR and Western blotting. Serum creatinine, alanine aminotransferase, and C reaction protein (CRP) levels decreased significantly after CBP. Moreover, TNF-α, IL-1, and IL-6 serum levels decreased significantly, but IL-10 level increased significantly after CBP (P<.05). After CBP, ABCA1 expression levels were higher than those before CBP, and ABCA1 expression was significantly increased with the supplementation of CBP (P<.05). CBP improved the condition of allo-HSCT patients with severe infection. CBP may be a potent up-regulator of the ABCA1 levels in macrophages of allo-HSCT patients with severe infection.

English

Vernal keratoconjunctivitis (VKC) is a recurrent seasonal disease of childhood, characterized by severe bilateral inflammation of the conjunctiva and by giant papillae of the superior tarsal conjunctiva, gelatinous hypertrophy of the limbus, and keratopathy. Clinical and immunohistochemical studies suggest that IgE-dependent (type I allergic) and IgE-independent (type IV allergic) mechanisms are involved in the immunopathogenesis of VKC, in which various inflammatory cells, including different T cell subpopulations play an active role via a cascade of chemical mediators. Endocrine, genetic, neurogenic, environmental and socioeconomic risk factors have been identified. The clinical course of this disease is usually benign and self-limiting, but a minority of patients will face very debilitating and sight threatening complications. The variety of currently available drugs to treat VKC include anti-histamines, mast-cell stabilizers, dual acting agents, corticosteroids and immunomodulators but none is enough to treat all aspects of the multifaceted pathophysiology of VKC. More selective drugs like anti-chemokine receptor antibodies and leukotriene receptor antagonists are under evaluation. Cyclosporine has been shown to be effective in the treatment of VKC but further randomized control trials are required to establish the minimum effective concentration. The purpose of this paper is to describe the clinical expression of VKC, to discuss its pathogenic mechanisms, and to suggest novel therapeutic strategies.

0329. Beneficial effects of azithromycin combined with ceftazidime without activity against P. aeruginosa in a murine sepsis model of peritonitis by Pseudomonas aeruginosa

Despite a proper management, the mortality of patients with severe sepsis and septic shock is very high. During sepsis, an uncontrolled cascade of inflammatory mediators is triggered, leading to tissue damage that can cause death. Macrolides, apart from their antibiotic properties, are capable of modulating inflammatory response. Macrolides inhibit the production and secretion of pro-inflammatory cytokines (IL-1, IL-6, IL-8 and TNF-α) levels and increase anti-inflammatory cytokines such as IL-10.

ChemInform Abstract: Copper/Silver‐Mediated Cascade Reactions for the Construction of 2‐Sulfonylbenzo[b]furans from trans‐2‐Hydroxycinnamic Acids and Sodium Sulfinates.

AbstractAn unprecedented synthetic protocol for the efficient construction of 2‐sulfonylbenzofurans via a protodecarboxylation/C—S bond formation/C—O bond formation cascade is developed.

Waist-to-height ratio distinguish obstructive sleep apnea from primary snoring in obese children.

Sleep-disordered breathing is caused by the interaction of multiple factors, including tonsillar hypertrophy, retrognathia, maxillary atresia, neuromuscular abnormalities, activation of inflammatory mediator cascades, and obesity. The prevalence and severity of obesity among children and adolescents increased worldwide during recent decades and has thus become a public health concern. The aim of this study is to assess the metabolic and anthropometric changes associated with sleep-disordered breathing in obese children. Prospective assessment of prepubertal obese children followed at a pediatric endocrinology outpatient clinic that had history of frequent snoring. Children were submitted to polysomnography, measurements of body weight, height, blood pressure, neck circumference, and waist circumference. BMI, neck-to-height, and waist-to-height ratios were calculated. Laboratory tests included a complete blood count, liver function tests, lipid profile, and glucose metabolism assessment. Additionally, the presence of metabolic syndrome was assessed. Differences between obstructive sleep apnea and primary snoring groups were calculated using unpaired t-test, Fisher's exact test or Mann-Whitney test (p < 0.05). The sample included 20 children with primary snoring and nine with obstructive sleep apnea. The two groups did not differ with regard to age, gender, BMI, or BMI z-score, serum lipids, glucose metabolism, cell count, liver function, or arterial blood pressure. Anthropometric data did not differ between groups. The waist-to-height ratio was greater among children with obstructive sleep apnea, compared to those with primary snoring. In the present study, the waist-to-height ratio was greater in children with obstructive sleep apnea and, thus, could distinguish these children from those with primary snoring.

Does Epigenetic Regulation Plays a Critical Role in Acute Lung Injury?

Acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) are severe respiratory conditions that remain as significant public health concerns, with ARDS mortality as high at 30-40% [1-4]. ALI/ARDS is primarily caused by pneumonia, it is also caused by a variety of other clinical disorders including pulmonary or non-pulmonary sepsis, major trauma, inhalation injury such as aspiration of gastric or oropharyngeal contents, drug over use, and blood products. ALI/ARDS features with widespread damage to the various types of cells in the lung and the structures of alveolar capillary membrane. The pathogenesis of ALI/ARDS involves three major overlapping phases, inflammatory phase, proliferative phase, and fibrotic phase. Pathological stimuli cause cytokine secretion and inflammatory cell infiltration to the injured site followed by the activation of pro-inflammatory mediator cascades. Many proinflammatory mediators including pro-inflammatory cytokines and chemokines are involved in the pathogenesis of ALI/ARDS. Increased amount of TNF-α, IL-1β, IL-6, and IL-8 are reported in BAL fluid and plasma of patients with ARDS, orchestrating with the low levels of inflammatory inhibitors such as IL-1α, IL-4, and IL-10. Inflammation in ALI/ARDS results in cell death, alveolar epithelial membrane leaking, and dysfunction of surfactant secretion. The followed injury repair mediates fibro proliferative response further impaired lung function.

Chronische Entzündung und Atherosklerose

The increasing gain of knowledge regarding the mechanistic details of the pathogenesis of chronic inflammatory diseases e. g. of rheumatic origin, chronic viral infections and atherosclerosis have revealed in conjunction with detailed insights in acute inflammation interesting similarities and differences. Cytokines such as IL-1 and tumour necrosis factor-α are proximal components of inflammatory cascades of systemic mediators activating the endothelium which leads to an endothelial dysfunction and moreover alter the balance within lymphocytic subpopulations containing distinct arsenals of secretory mediators such as interferons, interleukins and chemokines. Proinflammatory lymphocyte subtypes are TH1 und TH17 cells whereas Treg and TH2 cells are anti-inflammatory opponents. Since several years, interleukin-1- and TNF-antagonists have expanded the spectrum of drugs against rheumatic diseases and are currently studied in the setting of cardiovascular prevention with positive results on surrogate parameters. On the other hand efforts are undertaken to test the hypothesis if the pleiotropic effects of statins may have a positive influence on rheumatoid arthritis.

Continuous Blood Purification Ameliorates Endothelial Hyperpermeability in SAP Patients with MODS by Regulating Tight Junction Proteins via ROCK

Excessive activation of inflammatory mediator cascade during severe acute pancreatitis (SAP) is a major cause of multiple organ dysfunction and is associated with a high mortality. Recently, more and more studies have shown that continuous blood purification (CBP) could improve the prognosis of patients with multiple organ dysfunction syndrome (MODS), but the exact mechanism is still unclear. Many researchers have found that the disruption of tight junction barrier was an important factor for endothelial hyperpermeability, which played a key role in the pathogenesis of MODS. Previously, we found CBP could attenuate endothelial hyperpermeability in SAP patients with lung injury through regulating cytoskeleton reorganization mediated by RhoA/ROCK. However, the effect of CBP on the change of tight junction proteins in SAP patients with MODS was still unknown. This study aimed to investigate the role of tight junctions in endothelial hyperpermeability in SAP patients with MODS using an in vitro model, and the effect of CBP on tight junction barrier. Before CBP and after CBP, blood samples were collected to observe hepatic and renal function, and arterial blood gas, while the APACHE II score was calculated to evaluate the severity of patients. To test whether RhoA/ROCK signaling pathway was involved, human umbilical vein endothelial cells (HUVECs) were exposed to serum samples taken from patients at specific time points during CBP, or preincubated with ROCK inhibitor, Y-27632, followed by treatment with serum. Then, the changes in endothelial cell permeability and the expression and distribution of tight junction proteins occludin and claudin-1 were observed. Compared with before CBP, the APACHE II score, serum creatinine and alanine aminotransferase decreased significantly, while PaO2/FiO2 increased significantly after CBP. Meanwhile, endothelial permeability induced by serum from patients significantly increased, while the expression of tight junction proteins occludin and claudin-1 significantly decreased, and severe disruption of occludin and claudin-1 was found in these cells. However, pretreated with Rho-kinase inhibitor, Y-27632 could lessen all of these abnormalities, and in a dose-dependent way. Endothelial hyperpermeability, the abnormal expression and distribution of occludin and claudin-1 were attenuated in HUVECs treated with serum from patients after CBP treatment. The abnormality of tight junctions mediated by ROCK was an important mechanism for endothelial hyperpermeability induced by serum from SAP patients with MODS. CBP could ameliorate the disorganization and redistribution of tight junction proteins, hence improve the endothelial permeability.