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PubMed2003

Inhibitory effects of the root cortex of Paeonia suffruticosa on interleukin-8 and macrophage chemoattractant protein-1 secretions in U937 cells.

In an effort to elucidate the mechanism of the anti-inflammatory effect of mudanpi, the root cortex of Paeonia suffruticosa Andrews (Ranunculaceae), we determined the effects of the methanolic extract of mudanpi (MEM) on the secretions of interleukin (IL)-8, a major mediator of acute neutrophil-mediated inflammation, and macrophage chemoattractant protein (MCP)-1, a major mediator of chronic macrophage-mediated inflammation, in human monocytic U937 cells stimulated with phorbol myristate acetate (PMA). MEM significantly inhibited PMA-induced secretions of IL-8 and MCP-1 proteins in a dose-dependent manner. The inhibition of these chemokines by MEM was due to its suppression of IL-8 and MCP-1 genes. In addition, 1,2,3,4,6-penta-O-galloyl-beta-D-glucose, one of major constituents isolated from MEM, inhibited PMA-induced secretions of IL-8 and MCP-1 proteins by its suppression of IL-8 and MCP-1 genes. Thus, one possible anti-inflammatory mechanism of mudanpi, an anti-inflammatory Chinese crude drug, may be to inhibit the secretions of inflammatory chemokines.

Anti-Inflammatory Agents↗
PubMed2002

Non-eosinophilic asthma: importance and possible mechanisms.

There is increasing evidence that inflammatory mechanisms other than eosinophilic inflammation may be involved in producing the final common pathway of enhanced bronchial reactivity and reversible airflow obstruction that characterises asthma. A review of the literature has shown that, at most, only 50% of asthma cases are attributable to eosinophilic airway inflammation. It is hypothesised that a major proportion of asthma is based on neutrophilic airway inflammation, possibly triggered by environmental exposure to bacterial endotoxin, particulate air pollution, and ozone, as well as viral infections. If there are indeed two (or more) subtypes of asthma, and if non-eosinophilic (neutrophil mediated) asthma is relatively common, this would have major consequences for the treatment and prevention of asthma since most treatment and prevention strategies are now almost entirely focused on allergic/eosinophilic asthma and allergen avoidance measures, respectively. It is therefore important to study the aetiology of asthma further, including the underlying inflammatory profiles.

Asthma↗
PubMed2003

Anti-angiogenic effects of dimethyl sulfoxide on endothelial cells.

Dimethyl sulfoxide (DMSO) has anti-inflammatory and analgesic properties and is the only intravesical agent approved by the FDA for the treatment of interstitial cystitis. While it is known that DMSO has numerous biological effects on cell differentiation and alteration of cell-surface carbohydrate structures, the anti-inflammatory mechanism of DMSO has been not clear yet. Therefore, further investigation of DMSO in terms of inflammation therapy is needed. This study assessed the in vitro anti-angiogenic effects of DMSO on human aorta endothelial cells to clarify one of the mechanisms of its anti-inflammatory activity. DMSO did not affect expression of E-selectin on endothelial cells in the presence of TNF-alpha. Furthermore, DMSO effectively inhibited capillary tube formation; this mechanism would be due to suppression of matrix metalloproteinase-2 (MMP-2) production. These results provide useful knowledge about the anti-inflammatory effects of DMSO and the regulatory mechanism of MMP-2.

Angiogenesis Inhibitors↗
PubMed2001

Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis.

OBJECTIVES: This study assessed the role of angiotensin II type 1 (AT1) receptor antagonists on inflammatory mechanisms involved in atherogenesis. Specific inflammatory markers included solubilized tumor necrosis factor-alpha receptor II (sTNF-alphaRII), vascular cell adhesion molecule-1 (VCAM-1) and superoxide. In addition, the AT1 receptor blocker irbesartan was evaluated for its ability to suppress these markers in individuals with atherosclerosis. BACKGROUND: Mechanisms involved in the complex process of atherogenesis include alterations in the inflammatory responses. The use of compounds that suppress these responses may reduce the degree of damage seen in atherosclerosis. METHODS: With a cross-sectional study design, 33 normotensive patients with stable coronary artery disease (CAD) were treated with irbesartan for a 24-week period. These patients were compared against a control population with no known coronary atherosclerosis. Marker levels were measured by enzyme-linked immunosorbent assay technique and lucigenin chemiluminescence assay and statistically evaluated by two-way repeated measures analysis of variance. RESULTS: All patients with coronary artery disease had increased levels of inflammatory molecules over those of control patients. Treatment with irbesartan in these patients significantly reduced levels of inflammatory molecules measured. Soluble VCAM-1 levels were reduced by 36%; soluble TNF-alpha levels were reduced by 54% and superoxide level decreased by 52%. Maximal suppression of inflammatory markers by irbesartan therapy in patients with CAD was seen at 12 weeks. CONCLUSIONS: The effect of irbesartan on each inflammatory marker is significant. Our results show that use of irbesartan may retard the inflammatory process seen in premature forms of atherosclerosis.

Adult↗
PubMed2003

Cutaneous venous dysfunction studied in vivo in the LPS-treated rabbit: implication of NO in saphenous vein hyporeactivity.

Superficial vein pathology involves both mechanical (hyperpressure and distension) and inflammatory mechanisms. Conflicting results exist about the role of NO in the venous hyporeactivity induced by inflammation. In order to clarify this point, we aimed to investigate the effects of sepsis on cutaneous vein responsiveness in vivo and the possible contributions of constitutive and inducible NOS to the changes of venous contractility. Saphenous vein diameter was recorded by an ultrasonic echo-tracking device in pentobarbital-anaesthetised rabbits. Bacterial lipopolysaccharide (LPS) was administered i.v. at 20 mg/kg/15 min, inducing a progressive fall in mean arterial blood pressure after 2-3 h. The effects of LPS on saphenous vein responsiveness to noradrenaline (2 microg/kg i.v.) were measured simultaneously. In some rabbits, veins were removed for immunochemistry to detect iNOS staining. The venoconstriction to noradrenaline was already significantly reduced at 30 min after LPS (6+/-1% instead of 19+/-1% before LPS) and was completely abolished 3 h after LPS. A reduction of the venoconstriction induced by sumatriptan, a 5-HT(1B/D) agonist, (100 microg/kg, 11+/-1% after saline n=5) was also observed 180 min after LPS infusion (3+/-1%, n=4). The venodilatations induced by acetylcholine or sodium nitroprusside injected locally into the vein were not altered by LPS. When administered 90 min after LPS infusion, the NOS inhibitor L-NAME but not the selective iNOS inhibitor L-NIL (10 mg/kg) induced a recovery of the venoconstriction. Preventive perfusion with L-NAME (10 mg/kg/2 h) reduced the initial hyporeactivity to noradrenaline (30 to 60 min), but accelerated the lethal fall in MAP. L-NIL (10 mg/kg/2 h), to a lesser extent than L-NAME, also reduced the initial hyporeactivity to noradrenaline; in contrast to L-NAME, L-NIL also delayed the complete loss of noradrenaline constriction and improved animal survival. In control animals, neither L-NAME nor L-NIL modified the venoconstriction induced by noradrenaline. iNOS staining was observed in the saphenous vein endothelium after LPS. The experimental model developed in these experiments allows the study of venous responsiveness during sepsis in vivo. Our results show that LPS administration reduces saphenous vein contractility to both adrenergic and serotoninergic constrictor agents. The data suggest that both endothelial and inducible NO are involved in the loss of venous reactivity but these enzymes exert contrasting effects on blood pressure changes.

Acetylcholine↗
PubMed1999

Expression of C5a receptor in mouse brain: role in signal transduction and neurodegeneration.

In this study we explored the potential role of the complement derived anaphylatoxin C5a and the expression of its receptor in mouse brain. Using in situ hybridization, we found that C5a receptor messenger RNA is expressed in mouse brain. In response to intraventricular kainic acid injection, there was marked increase in the C5a receptor messenger RNA expression, particularly in hippocampal formation and cerebral cortex. C5a ligand-binding autoradiography confirmed the functional expression and elevation of the C5a receptor post-lesioning. The expression of C5a receptor messenger RNA in brain was confirmed by northern blot hybridization of total RNA from neuronal and glial cells in vitro. Based on these findings we explored the role of C5a in mechanisms of signal transduction in brain cells. Treatment of primary cultures of mouse astrocytes with human recombinant C5a resulted in the activation of mitogen-activated extracellular signal-regulated protein kinase. This response appeared to be mediated by the C5a receptor since astrocyte cultures derived from C5a receptor knockout mice were not responsive to the treatment. Understanding the regulation of C5a receptor in brain and mechanisms by which pro-inflammatory C5a modulates specific signal transduction pathways in brain cells is crucial to studies of inflammatory mechanisms in neurodegeneration.

Animals↗
PubMed2006

Inhaled nitric oxide alleviates hyperoxia suppressed phosphatidylcholine synthesis in endotoxin-induced injury in mature rat lungs.

BACKGROUND: We investigated efficacy of inhaled nitric oxide (NO) in modulation of metabolism of phosphatidylcholine (PC) of pulmonary surfactant and in anti-inflammatory mechanism of mature lungs with inflammatory injury. METHODS: Healthy adult rats were divided into a group of lung inflammation induced by i.v. lipopolysaccharides (LPS) or a normal control (C) for 24 h, and then exposed to: room air (Air), 95% oxygen (O), NO (20 parts per million, NO), both O and NO (ONO) as subgroups, whereas [3H]-choline was injected i.v. for incorporation into PC of the lungs which were processed subsequently at 10 min, 4, 8, 12 and 24 h, respectively, for measurement of PC synthesis and proinflammatory cytokine production. RESULTS: LPS-NO subgroup had the lowest level of labeled PC in total phospholipids and disaturated PC in bronchoalveolar lavage fluid and lung tissue (decreased by 46-59%), along with the lowest activity of cytidine triphosphate: phosphocholine cytidylyltransferase (-14-18%) in the lungs, compared to all other subgroups at 4 h (p < 0.01), but not at 8 and 12 h. After 24-h, all LPS-subgroups had lower labeled PC than the corresponding C-subgroups (p < 0.05). LPS-ONO had higher labeled PC in total phospholipids and disaturated PC, activity of cytidylyltransferase, and lower activity of nuclear transcription factor-kappaB and expression of proinflammatory cytokine mRNA, than that in the LPS-O subgroup (p < 0.05). CONCLUSION: In LPS-induced lung inflammation in association with hyperoxia, depressed PC synthesis and enhanced proinflammatory cytokine production may be alleviated by iNO. NO alone only transiently suppressed the PC synthesis as a result of lower activity of cytidylyltransferase.

Administration, Inhalation↗
PubMed2003

Immunomodulation by antimicrobial drugs.

Immunomodulation aims at either enforcement of host defence mechanisms or dampening of the inflammatory response of the host. Thus, immunomodulatory drugs may enhance host defence by either stimulating the inflammatory response or inhibiting the counter-regulatory, anti-inflammatory response. On the other hand, the response of the host may be down-modulated through inhibition of the inflammatory response or induction of counter-regulatory, anti-inflammatory mechanisms. Antimicrobial drugs may have such immunomodulatory effects, but so far these effects have not been exploited clinically.

Adjuvants, Immunologic↗
PubMedDate not supplied

Neural stem cells in inflammatory CNS diseases: mechanisms and therapy.

Autoimmune inflammatory diseases of the central nervous system (CNS) are highly complex in their interaction of different cell populations. The main therapy focus in the last years has been the inhibition of the immune system. Recent progress has shown that endogenous as well as transplanted neural stem cells might positively influence the outcome of such diseases. In this review, we discuss the current concept of the underlying pathogenesis with a specific focus on local CNS cells and potential treatment options.

Cell Differentiation↗
PubMed2004

Monitoring the allergic inflammation.

Individual symptoms of allergy such as asthma, dermatitis, rhinitis have many different underlying mechanisms. The detailed characterization of the inflammatory mechanisms underlying symptom development in the individual patient is important in order to optimally control treatment. Measurement of eosinophil cationic protein (ECP) in sputum or blood and eosinophil protein X/eosinophil derived neurotoxin (EPX/EDN) in urine may be used to read the involvement of the eosinophil granulocyte in the process. An important information as eosinophil dominated processes seem to be particularly sensitive to corticosteroid treatment. The possibilities to measure the involvement of other inflammatory cells exist today, but are only used to a small extent. The dream would be that every patient with an inflammatory disease is characterized with respect to the profile of involving cells and mediators. Such information would provide us with a unique understanding of the underlying mechanisms of the development of disease symptoms and the possibilities of treating these.

Asthma↗
PubMed2004

Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases.

Commensal microflora (normal microflora, indigenous microbiota) consists of those micro-organisms, which are present on body surfaces covered by epithelial cells and are exposed to the external environment (gastrointestinal and respiratory tract, vagina, skin, etc.). The number of bacteria colonising mucosal and skin surfaces exceeds the number of cells forming human body. Commensal bacteria co-evolved with their hosts, however, under specific conditions they are able to overcome protective host responses and exert pathologic effects. Resident bacteria form complex ecosystems, whose diversity is enormous. The most abundant microflora is present in the distal parts of the gut; the majority of the intestinal bacteria are Gram-negative anaerobes. More than 50% of intestinal bacteria cannot be cultured by conventional microbiological techniques. Molecular biological methods help in analysing the structural and functional complexity of the microflora and in identifying its components. Resident microflora contains a number of components able to activate innate and adaptive immunity. Unlimited immune activation in response to signals from commensal bacteria could pose the risk of inflammation; immune responses to mucosal microbiota therefore require a precise regulatory control. The mucosal immune system has developed specialised regulatory, anti-inflammatory mechanisms for eliminating or tolerating non-dangerous, food and airborne antigens and commensal micro-organisms (oral, mucosal tolerance). However, at the same time the mucosal immune system must provide local defense mechanisms against environmental threats (e.g. invading pathogens). This important requirement is fulfilled by several mechanisms of mucosal immunity: strongly developed innate defense mechanisms ensuring appropriate function of the mucosal barrier, existence of unique types of lymphocytes and their products, transport of polymeric immunoglobulins through epithelial cells into secretions (sIgA) and migration and homing of cells originating from the mucosal organised tissues in mucosae and exocrine glands. The important role of commensal bacteria in development of optimally functioning mucosal immune system was demonstrated in germ-free animals (using gnotobiological techniques). Involvement of commensal microflora and its components with strong immunoactivating properties (e.g. LPS, peptidoglycans, superantigens, bacterial DNA, Hsp) in etiopathogenetic mechanism of various complex, multifactorial and multigenic diseases, including inflammatory bowel diseases, periodontal disease, rheumatoid arthritis, atherosclerosis, allergy, multiorgan failure, colon cancer has been recently suggested. Animal models of human diseases reared in defined gnotobiotic conditions are helping to elucidate the aetiology of these frequent disorders. An improved understanding of commensal bacteria-host interactions employing germ-free animal models with selective colonisation strategies combined with modern molecular techniques could bring new insights into the mechanisms of mucosal immunity and also into pathogenetic mechanisms of several infectious, inflammatory, autoimmune and neoplastic diseases. Regulation of microflora composition (e.g. by probiotics and prebiotics) offers the possibility to influence the development of mucosal and systemic immunity but it can play a role also in prevention and treatment of some diseases.

Autoimmune Diseases↗
PubMed2000

Inflammation in cystic fibrosis and its management.

Pulmonary complications are by far the most serious complications in cystic fibrosis (CF). In response to endobronchial bacterial infections, the long-term consequences of chronically activated polymorphonuclear leukocytes (neutrophils) are thought to cause loss of lung function and premature death. Effective anti-inflammatory therapy implies that we understand the complex networks of the immune response with its myriads of mediators on effector cells. We have many steps to go in this context, but science has already shed some light on inflammatory mechanisms in CF airways, and anti-inflammatory treatment strategies have been applied clinically with some success. The aim of this chapter is to review our present knowledge, and we will focus on early inflammation, bacterial persistence mechanisms, neutrophil activation, cytokines and nitric oxide together with anti-inflammatory treatment strategies in CF patients.

Animals↗
PubMedDate not supplied

Overview of neural mechanisms in asthma.

There is much evidence that neural mechanisms are involved in the mechanisms and symptoms of asthma. Afferent nerves may be activated and sensitized by inflammatory mechanisms, resulting in symptoms such as cough and chest tightness, in activation of cholinergic reflexes and in the release of inflammatory neuropeptides. Cholinergic mechanisms are the predominant bronchoconstrictor neural pathway and may be enhanced in asthma, particularly during exacerbations, through several mechanisms, including impaired function of muscarinic autoreceptors on cholinergic nerve terminals. There may also be abnormalities in adrenergic control and in the function of beta-adrenoceptors, particularly in severe asthma. The neurotransmitter of bronchodilator nerves is now identified as nitric oxide and this mechanism may be impaired during asthma exacerbations. Finally, neurogenic inflammation, due to release of neuropeptides from sensory nerves, may contribute and amplify the inflammation in asthmatic airways.

Animals↗
PubMed2004

"Vulnerable plaques"--ticking of the time bomb.

Atherosclerosis and its sequelae are one of the leading causes of morbidity and mortality, especially in the developed nations. Over the years, treatment protocols have changed with the changing understanding of the disease process. Inflammatory mechanisms have emerged as key players in the formation of the atherosclerotic plaque. For the majority of its life span, the plaque develops silently and only some exhibit overt clinical manifestations. The purpose of this review is to examine the inherent properties of some of these "vulnerable" or symptomatic plaques. Rupture of the plaque is related to the thickness of the fibrous cap overlying the necrotic lipid core. A thin cap is more likely to lead to rupture. Multiple factors broadly grouped as the "determinants of vulnerability" are responsible for directly or indirectly influencing the plaque dynamics. Apoptosis is considered an important underlying mechanism that contributes to plaque instability. Inflammatory reactions within the plaque trigger apoptosis by cell-cell contact and intra cellular death signaling. Once started, the apoptotic process affects all of the components that make up the plaque, including vascular smooth muscle cells, endothelial cells, and macrophages. Extensive research has identified many of the key cellular and molecular regulators that play a part in apoptosis within the atherosclerotic lesion. This information will help us to gain a better understanding of the underlying mechanisms at the cellular and molecular level and enable us to formulate better therapeutic strategies to combat this disease.

Animals↗
PubMed2002

Antibodies against Chlamydia pneumoniae and their relation to lymphocyte population levels.

Chlamydia pneumoniae infection has long been suspected as a possible cause of atherosclerosis and has been frequently detected in atheromatous plaques of the coronary arteries. Nevertheless, its distribution is not correlated to the severity or extent of the disease, but it would support the hypothesis that the organism may be an active factor in the pathogenesis of atherosclerosis. A group of patients with stable angina were examined as to whether or not the positivity of antibodies against Chlamydia pneumoniae modified cellular populations as mechanisms responsible for the alterations of inflammatory response. We concluded that the presence of IgG anti-C. pneumoniae antibodies do not participate in the activation of inflammatory mechanisms that may intervene in the genesis of atherosclerosis in patients with stable angina.

Antibodies, Bacterial↗
PubMed2003

Apoptotic DNA binds to HLA class II molecules inhibiting antigen presentation and participating in the development of anti-inflammatory functional behavior of phagocytic macrophages.

Resident macrophages are mainly responsible for the clearance of apoptotic cells from tissue by phagocytosis. Phagocytosis of apoptotic cells is not accompanied by activation of inflammatory mechanisms, unlike what happens when necrotic phenomena occur. We analyzed the effect of phagocytosis of apoptotic bodies on macrophage cell functions. After phagocytosis of apoptotic cells macrophages were unable to present an exogenous antigen to autologous antigen-specific T-cell lines. The inhibition was mediated by different mechanisms including binding of apoptotic DNA to human leukocyte antigen (HLA) class II molecules of macrophages, decreased expression of co-stimulatory molecules and increased secretion of tumor growth factor beta (TGFbeta). When dendritic cells were cultured with macrophages phagocytosing apoptotic cells, or with their supernatant, impaired dendritic cell antigen presenting activity and reduced tumor necrosis factor alpha (TNFalpha) secretion were found. Our results suggest that: (1) the phagocytosis of apoptotic bodies inhibits macrophage antigen presentation; (2) such inhibition is mediated by the binding of apoptotic DNA to macrophage HLA class II molecules as well as by the activation of biological mechanisms that induce an anti-inflammatory functional behavior in macrophages; and (3) macrophages phagocytosing apoptotic cells inhibit antigen presentation of neighboring dendritic cells via TGFbeta secretion. These events are likely related to the preservation of healthy tissues from the onset of inflammation.

Antigen Presentation↗
PubMed1991

Circadian variations in the superoxide production, enzyme release and neutrophil aggregation in patients with rheumatoid arthritis and controls.

Patients with rheumatoid arthritis (RA) experience fluctuations of symptoms throughout the day. These could be due to mechanical changes or modification of the inflammatory mechanisms. In the present paper we studied fluctuations of superoxide production (O2), enzyme release (beta-glucuronidase and lysozyme) and neutrophil aggregation in the peripheral blood of eight healthy volunteers and eight patients with RA. Although enzyme release was greater in patients with RA, no significant difference was found throughout the day, neither in control nor in patients. Similar results were obtained when studying neutrophil aggregation. On the contrary, the superoxide production, determined at 8:00, 14:00, and 20:00 h, was 6.3 +/- 0.5, 4.40 +/- 0.4 and 6.26 +/- 0.3, respectively, in patients with RA and 6.65 +/- 0.7, 4.7 +/- 0.7 and 7.27 +/- 0.4 in the controls. The values obtained at 14:00 h were significantly lower (alpha = 0.01). There were no differences in the curve form between patients and controls.

Arthritis, Rheumatoid↗
PubMed1996

Bronchopulmonary dysplasia and corticosteroid therapy: a case review.

The use of corticosteroids as a treatment for chronic lung disease is increasing in newborn intensive care units. The anti-inflammatory mechanism of steroids suppresses the pulmonary inflammatory response, leading to improved pulmonary compliance and often a successful extubation. However, side effects, including sepsis, hypertension, glucosuria, and heme positive stools, have been reported. Caregivers must appreciate the multisystem biochemical effects of corticosteroids and anticipate the potential side effects when administering this medication. The article reviews the biochemical processes of dexamethasone, a synthetic corticosteroid, and presents a case study of an infant receiving dexamethasone. A question-and-answer format is interpolated throughout the case study and is intended to challenge the reader's knowledge of the pathophysiology of chronic lung disease and the biochemical actions of corticosteroids. Implications for nursing assessment and management of infants receiving this medication are reviewed.

Anti-Inflammatory Agents↗