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PubMedDate not supplied

Immunopharmacological studies on Picrorhiza kurroa Royle-ex-Benth. Part IV: Cellular mechanisms of anti-inflammatory action.

In this work abroagation of anti-inflammatory effect of Picrorhiza kurroa extract (PK) by beta-adrenergic blockade was confirmed, which suggests alteration in cell-surface biology by PK treatment. Blockade of protein synthesis by cycloheximide pretreatment reduced PK effect, suggesting protein mediation. Metabolic inhibitor dinitrophenol inhibited inflammatory cedema equally in control and PK treated animals, and masking of PK effect was concluded. Discriminations of anti-inflammatory mechanism(s) of PK and the latter two cytotoxic agents was inferred from these observations and from existing knowledge. Selective PK influence on membrane linked activation events in inflammatory effector cells could be the basis of anti-inflammatory and perhaps other biological activities reported with the herb.

2,4-Dinitrophenol↗
PubMed1976

[Mechanism of anti-inflammatory action of 2-(2-fluoro-4-biphenylyl) propionic acid (flurbiprofen)].

Anti-inflammatory mechanism of 2-(2-fluoro-4-biphenylyl) propionic acid (Flurbiprofen, FP-70) was studied by various analysis in comparison with other drugs. It was found in the test of rat edema induced by various phlogists that carrageenin and yeast-induced edemas were markedly inhibited by FP-70, whereas dextran, formalin, serotonin and bradykinin-induced edemas were scarcely inhibited by FP-70. The action of FP-70 was similar to that of soy bean trypsin inhibitor. However, FP-70 showed no effects on kinin synthetase and kininase. FP-70 showed a marked inhibition on prostaglandin synthesis. The inhibitory effect of FP-70 was 10.1, 96.5 and 2280.6 times as large as indomethacin, ibuprofen and acetylsalicylic acid, respectively. FP-70 did not inhibit the permeability of dye induced by prostaglandin E2 in the rat skin. FP-70 inhibited the acid phosphatase and beta-glucuronidase activities of isolated lysosome of rat liver and also suppressed the release of acid phosphatase from the lysosome. These effects were similar to those of indomethacin. On the other hand, FP-70 suppressed markedly the heat-induced hemolysis of dog erythrocytes. The effect was similar to that of indomethacin and was 10 times stronger than those of ibuprofen, ibufenac and phenylbutazone. Activation of rat liver mitochondrial ATPase by FP-70 at a concentration of 10 muM was 74.7%, while indomethacin showed 37.8% activation at the same concentration. FP-70 as well as ibuprofen and phenylbutazone uncoupled the oxidative phosphorylation in rat liver mitochondria. From the above and previously reported results, it is suggested that the potent anti-inflammatory action of FP-70 is the result of the following effects; inhibition on the protein and leucocyte migration, inhibition on the prostaglandin synthesis, stabilization of the cell membrane and activation of ATPase.

Animals↗
PubMed1997

Expression of the bumetanide-sensitive Na-K-Cl cotransporter BSC2 is differentially regulated by fluid mechanical and inflammatory cytokine stimuli in vascular endothelium.

In vascular endothelium, the electroneutral Na-K-Cl cotransport system is thought to function in the maintenance of a selective permeability barrier in certain vascular beds (e.g., brain), as well as in the preservation of endothelial homeostasis in the face of fluctuating osmotic conditions that may accompany certain pathophysiological conditions (e.g., diabetes mellitus). Here we demonstrate that the gene encoding the bumetanide-sensitive cotransporter BSC2, one of the two major isoforms of Na-K-Cl cotransporters present in mammalian cells, can be differentially regulated by inflammatory cytokines and fluid mechanical forces in cultured endothelium. Interleukin-1beta and tumor necrosis factor-alpha significantly upregulate expression of BSC2 mRNA and protein in human umbilical vein endothelial cells, a response that is inhibited by pretreatment with interferon-gamma. Steady laminar fluid shear stress, at a physiologic magnitude (10 dyn/cm2), is also able to induce and maintain elevated expression of BSC2 in cultured human umbilical vein endothelial cells, while a comparable time-averaged magnitude of turbulent fluid shear stress is not. In vivo, BSC2 mRNA is upregulated after intraperitoneal administration of bacterial endotoxin (LPS) in murine lung and kidney, but not in cardiac tissue. These results provide the first experimental evidence that the BSC2 gene can be selectively regulated by different inflammatory cytokine and fluid mechanical stimuli in endothelium, and support a role for BSC2 in vascular homeostasis and inflammation.

Animals↗
PubMed1990

[Possible mechanisms of the anti-inflammatory action of polyamines].

Carrageenin paw edema of rats was inhibited in a dose-dependent manner by subcutaneous administration of polyamines. The latter had to be administered at least 2 hr before carrageenin challenge to achieve such inhibition. Moreover, inhibition was blocked by the simultaneous injection of actinomycin D. Polyamines also inhibited local bluing reactions to histamine in rats and similarly had to be administered 3 hr previously to achieve inhibition. Polyamines were shown to be glucocorticoid-type anti-inflammatory drugs, and may be glucocorticoids mediators of the synthesis of the postulated vascular permeability inhibitory protein that do not inhibit phospholipase A2 activity. Neutrophil chemotaxis was inhibited by polyamines in a concentration-dependent manner. In contrast to the experience with carrageenin paw edema, simultaneous addition to actinomycin D did not block the inhibitory action of polyamines on neutrophil chemotaxis. These results suggest that polyamines possess at least 2 different anti-inflammatory mechanisms. The first is mediated by the synthesis of an anti-inflammatory protein, and the second consist of direct action on leukocytes.

Animals↗
PubMed2005

Enhancing anti-inflammatory cytokine IL-10 may be beneficial for acute coronary syndrome.

Inflammation is one of the basic biological responses against vascular injury. It has been demonstrated, however, that inflammation is an important pathogenic feature in atherosclerotic lesions. Previous data showed that pro-inflammatory cytokines played an important role in acute coronary events. A complex intravascular inflammatory response is also an integral component of atherosclerotic plaque dynamic instability, and the imbalance between anti-inflammatory mechanisms and pro-inflammatory factors, in favor of the pro-inflammatory factors, will result in rupture of atherosclerotic plaque. Interluekine-10 (IL-10), which is produced by various inflammatory cells, especially macrophages, has multifaceted anti-inflammatory properties, including inhibition of the prototypic pro-inflammatory transcription factor nuclear factor-kappaB, leading to suppressed cytokine production, inhibition of matrix degrading metalloproteinase production, reduction of tissue factor expression, inhibition of apoptosis of macrophages and monocytes after infection, and promotion of the phenotypic switch of lymphocytes into the Th2 phenotype. All these inflammatory mechanisms have been shown to play a pivotal role for atheroslerotic lesion development and progression, indicating a potential regulatory role of IL-10. More recent data showed that decreased plasma concentration of anti-inflammatory cytokine IL-10 was associated with acute coronary syndrome. Therefore, we hypotheses that enhancing anti-inflammatory cytokine IL-10 may be a promising approach for the therapy of acute coronary diseases.

Acute Disease↗
PubMed1998

[Pain analysis is vital in rheumatic diseases. Pain often causes much worry to patients].

The article consists of a synthesis of a rheumatic pain symposium held at the annual meeting of the Swedish Medical Association in 1996. Various aspects of pain in rheumatic diseases were discussed, such as physiological, neurohumoral and neurogenic mechanisms, sensory stimulation treatment, differentiation of mechanical and inflammatory pain, quality enhancement by improved co-operation between primary and tertiary care facilities, pharmacological treatment with (centrally and peripherally acting) opioids, selective cyclo-oxygenase inhibitors, and NMDA (N-methyl-D-aspartate) receptor antagonists. For patients with rheumatic disorders exacerbated by pain problems, as for other patients, a pain diagnosis is of fundamental importance. This can be achieved by analysis of the social, psychological, physiological and medical factors contributing to the cause and degree of pain and to pain behaviour, and of the extent to which the pain may be nociceptive (i.e., inflammatory, mechanical, or ischaemic in origin), neurogenic or idiopathic. Pain analysis should be followed by individualised treatment focused on the patient's most crucial problems, thus enhancing the prospect of optimal treatment outcome.

Analgesics↗
PubMed2000

CD137 activation abrogates granulocyte-macrophage colony-stimulating factor-mediated anti-apoptosis in neutrophils.

CD137 (ILA / 4-1BB) is a member of the TNF / NGF receptor family, and has previously been suggested to be involved in T cell activation and differentiation. Here, we demonstrate that blood neutrophils from control individuals and patients with cystic fibrosis express CD137 mRNA and surface protein. In contrast, lung neutrophils derived from patients with cystic fibrosis did not express detectable CD137 levels. Such CD137-deficient neutrophils could also be generated from normal neutrophils by TNF-alpha stimulation in vitro. TNF-alpha was found to be highly expressed in epithelial cells from cystic fibrosis but not normal lungs, suggesting that TNF-alpha might account for reduced neutrophil CD137 levels under inflammatory conditions in vivo. To investigate whether CD137 is involved in the regulation of apoptosis, neutrophils were activated with functional anti-CD137 antibody in the presence or absence of different neutrophil survival factors in vitro. Activation of CD137 abrogated GM-CSF-mediated anti-apoptosis in normal but not in CD137-deficient neutrophils. Moreover, G-CSF- and IFN-gamma-mediated neutrophil anti-apoptosis was not affected by anti-CD137 antibody treatment. In conclusion, these data suggest that CD137 activation may limit GM-CSF-mediated anti-apoptosis of neutrophils. The absence of this anti-inflammatory mechanism in inflammatory responses might be associated with massive neutrophil accumulation and consequent tissue damage.

Antigens, CD↗
PubMed1995

Modulation of rat vascular smooth muscle cell (VSMC) proliferation by cysteinyl leukotriene D4: a role for mediation of interleukin 1.

Recent studies suggest the involvement of inflammatory mechanisms in the progression of atherosclerosis. Cysteinyl leukotrienes and cytokines could orchestrate this progression by acting on the proliferation of vascular smooth muscle cells (VSMC). In cultures of rat VSMC, proliferation was modulated by cysteinyl leukotriene C4 (LTC4) and LTD4, but not LTE4. Co-culturing LTD4 with VSMC produced an increased cell proliferation as assessed by [3H]thymidine incorporation studies (200%) as well as cell counts (70%), using LTD4 at 10(-6)M compared to controls. LTD4 exerted its effect through an interleukin 1 (IL-1)-dependent autocrine regulatory mechanism. When IL-1 was inhibited by using a receptor antagonist (IL-1ra) and a polyclonal antibody to IL-1, we found an inhibition of VSMC proliferation. The increase of VSMC proliferation was associated with the autocrine production of interleukin-1 (IL-1) concomitant to LTD4 stimulation (55.5 +/- 2.5 pg/ml in controls and 177 +/- 0.5 pg/ml in 10(-6)M LTD4). These results may shed new light on the mechanism of inflammatory involvement during atherogenesis, suggesting that the control of cysteinyl leukotrienes may be important in inflammatory processes involving IL-1.

Animals↗
PubMed1989

Sampling of the bovine teat for studies of defence mechanisms and inflammatory reactions based on a surgical procedure separating the teat and udder cisterns.

A surgical procedure to separate the teat and udder cisterns in the udder quarter was described. The sampling method used and its influence on the somatic cell count and bacteriological status of the teat samples were determined. The surgical procedure resulted in complete separation of the teat cistern from the udder cistern in nine out of fourteen teats in six cows. An increase in SCC was seen in one of nine teats during the sampling period of 4 to 8 days. Coagulase-negative staphylococci were isolated in samples from three of six teats at the end of the sampling period. The described methods could be of considerable importance in future studies of inflammatory reactions and defence mechanisms in the bovine teat.

Animals↗
PubMed2003

Alerting and tuning the immune response by extracellular nucleotides.

The interplay between pro- and anti-inflammatory mechanisms during inflammatory and immune responses is critical for avoiding excessive tissue damage. Extracellular nucleotides (e.g., adenosine 5'-triphosphate) may represent constitutive signals that can alert the immune system of abnormal cell death. Relatively high doses of nucleotides induce rapid release of proinflammatory mediators and favor pathogen killing. However, recent findings on antigen presenting cells, particularly dendritic cells, revealed a more complex role for these molecules. Chronic exposure to low-dose nucleotides can redirect cellular responses to prototypic activation stimuli, leading to suppressed inflammation and immune deviation.

Animals↗
PubMed1998

[Pain analysis is vital in rheumatic diseases. The pain is often the patient's worst problem].

The article consists of a synthesis of a rheumatic pain symposium held at the annual meeting of the Swedish Medical Association in 1996. Various aspects of pain in rheumatic diseases were discussed, such as physiological, neurohumoral and neurogenic mechanisms, sensory stimulation treatment, differentiation of mechanical and inflammatory pain, quality enhancement by improved cooperation between primary and tertiary care facilities, pharmacological treatment with (centrally and peripherally acting) opioids, selective cyclo-oxygenase inhibitors, and NMDA (N-methyl-D-aspartate) receptor antagonists. The aim of the symposium, with its focus on the manifest pain problem, was to improve our knowledge and skill in the understanding and treatment of this large patient category. For patients with rheumatic disorders exacerbated by pain problems, as for other patients, a pain diagnosis is of fundamental importance. This can be achieved by analysis of the social, psychological, physiological and medical factors contributing to the cause and degree of pain and to pain behaviour, and of the extent to which the pain may be nociceptive (i.e., inflammatory, mechanical, or ischaemic in origin), neurogenic or idiopathic. Pain analysis should be followed by individualised treatment focused on the patient's most crucial problems, thus enhancing the prospect of optimal treatment outcome.

Analgesia↗
PubMed1998

Lung inflammatory response in pneumonia.

In normal conditions, alveolar macrophages (AMs) are the main cells that respond to bacteria that reach lower airways. However, if the microbial inoculum is too high or too virulent to be stopped by AM alone, these cells recruit polymorphonuclear neutrophils (PMN) into the alveoli from the vascular compartment. Cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-beta), interleukin-6 (IL-6), and interleukin-8 (IL-8), secreted by the AM are able to attract PMN enhanced for phagocytosis, ready to destroy the invading pathogens. However, excessive cytokine production has deleterious effects, with a systemic inflammatory response (sepsis) that can lead to multiorganic failure and death. Other cytokines, such as interleukin-10 (IL-10) balance this response, attenuating several inflammatory mechanisms. The inflammatory lung response in pneumonia has been well studied in animals, and more recently in humans, using bronchoalveolar lavage to measure some inflammatory mediators (TNF-alpha, IL-1 beta, IL-6, IL-8). From these studies, it seems that: 1) the inflammatory response to pneumonia is compartmentalized for most cytokines (in contrast to adult respiratory distress syndrome (ARDS)), except for IL-6 which is a general marker of inflammation. On the other hand, C-reactive-protein is an acute-phase protein synthesized by the liver through the stimulus of IL-6 that may also be an easy-to-measure marker of inflammation that is directly related to IL-6; 2) some of these cytokines may be useful as prognostic indices; 3) there is no clear relationship between the local lung bacterial burden and the intensity of the inflammatory response; and 4) the administration of granulocyte colony-stimulating factor (G-CSF) is a promising therapeutic approach that is still under clinical investigation. In the future, it is probable that the therapeutic goal in severe pneumonia will be to find the exact point at which inflammation is beneficial but not deleterious. The measurement of the inflammatory response may serve for this purpose.

Bronchoalveolar Lavage Fluid↗
PubMed1993

Cellular mechanisms in inflammatory myopathies.

Cell-mediated immune mechanisms play a prominent role in inclusion body myositis (IBM) and polymyositis (PM). In both IBM and PM, CD8+ cytotoxic T cells expressing the alpha/beta receptor surround and focally invade non-necrotic muscle fibres. This lesion can be considered the hallmark of cell-mediated myocytotoxicity. Essentially the same type of lesion is observed in a variant form of PM, in which CD4-CD8- T cells bearing the gamma/delta receptor surround and invade non-necrotic muscle fibres. In both IBM and PM, all of the invaded and some of the non-invaded muscle fibres strongly express HLA class I molecules. This is consistent with the hypothesis that the CD8+ autoinvasive cytotoxic T cells recognize antigenic peptide(s) bound to HLA class I molecules on the muscle fibre surface. According to the rules of antigen processing, these peptides derive from proteins synthesized in the muscle fibre. Theoretically, the proteins could be viral components or self proteins that resemble viral components. Most attempts to demonstrate viral antigens or genome in muscle fibres have failed. On the other hand, the majority of HLA class I molecules expressed on the surface of any cell are loaded with endogenous self peptides. It seems plausible that muscle-specific autoantigen(s) could be recognized by autoaggressive T cells in the inflammatory myopathies, but the precise reasons for the recognition event remains elusive. Recently, it has become possible to study the interactions of muscle cells and cytotoxic effector cells in vitro. Myoblasts and myotubes can be induced to express a variety of immunologically relevant histocompatibility and cell adhesion molecules. Myotubes are highly susceptible to lysis by allogeneic CD8+ cytotoxic T cells sensitized against HLA class I alloantigens. Interestingly, cultured myotubes are also susceptible to lysis by antigen-nonspecific natural killer cells. Further, myoblasts stimulated by IFN gamma express HLA class II and acquire the full potential to process and present complex protein antigens to CD4+ T cells. This may indicate that myoblasts can actively participate in local immune reactions by presenting (auto) antigens to helper/inducer T cells. In different inflammatory myopathies, CD8+ T cells have been expanded directly from muscle and their interactions with autologous myotubes have been investigated in vitro. In several cases, a low but significant autoreactive cytotoxic effect was observed. This is consistent with the hypothesis that some cytotoxic effector T cells recognize an autoantigen on myotubes. One of the major goals for future studies is to define the autoantigens that are relevant in the pathogenesis of the inflammatory myopathies.

Antibody-Dependent Cell Cytotoxicity↗
PubMed2006

Inflammation and bronchopulmonary dysplasia: a continuing story.

Increasing evidence indicates that bronchopulmonary dysplasia (BPD) results, at least in part, from an imbalance between pro-inflammatory and anti-inflammatory mechanisms, with a persistent imbalance that favours pro-inflammatory mechanisms. The inflammatory response is characterised by an accumulation of neutrophils and macrophages in the airways and pulmonary tissue of preterm infants and, moreover, by an arsenal of pro-inflammatory mediators which affect the alveolar capillary unit and tissue integrity. As well as pro-inflammatory cytokines and toxic oxygen radicals, various lipid mediators as well as potent proteases may be responsible for acute lung injury. During the last decade it has become evident that multiple pre- and postnatal events contribute to the development of BPD in preterm infants. Chorioamnionitis and cytokine exposure in utero, plus sequential lung injury caused by postnatal resuscitation, oxygen toxicity, volu-, barotrauma and infection all lead to a pulmonary inflammatory response which is most probably associated with aberrant wound healing and an inhibition of alveolarisation as well as vascular development in the immature lungs of very preterm infants, causing the 'new BPD'.

Bronchopulmonary Dysplasia↗
PubMed2000

Rheumatoid arthritis synovial stromal cells inhibit apoptosis and up-regulate Bcl-xL expression by B cells in a CD49/CD29-CD106-dependent mechanism.

Inflammatory sites, such as rheumatoid arthritis (RA) synovial tissue, contain large numbers of activated B cells and plasma cells. However, the mechanisms maintaining B cell viability and promoting their differentiation are not known, but interactions with stromal cells may play a role. To examine this, purified human peripheral B cells were cultured with a stromal cell line (SCL) derived from RA synovial tissue, and the effects on apoptosis and expression of Bcl-2-related proteins were analyzed. As a control, B cells were also cultured with SCL from osteoarthritis synovium or skin fibroblasts. B cells cultured with medium alone underwent spontaneous apoptosis. However, B cells cultured with RA SCL cells exhibited less apoptosis and greater viability. Although SCL from osteoarthritis synovium and skin fibroblasts also rescued B cells from apoptosis, they were less effective than RA SCL. B cell expression of Bcl-xL was markedly increased by RA SCL in a contact-dependent manner, whereas B cell expression of Bcl-2 was unaffected. Protection of B cells from apoptosis and up-regulation of Bcl-xL by RA SCL were both blocked by mAbs to CD106 (VCAM-1), but not CD54 (ICAM-1). Furthermore, cross-linking of CD49d/CD29 (very late Ag-4) on the surface of B cells rescued them from apoptosis and up-regulated Bcl-xL expression. These results indicate that SCL derived from RA synovial tissue play a role in promoting B cell survival by inducing Bcl-xL expression and blocking B cell apoptosis in a CD49d/CD29-CD106-dependent manner.

Adult↗
PubMed1978

[Phagocytosis--a central mechanism in inflammatory reaction (author's transl)].

It is attempted to describe the complex pathogenesis of the inflammatory reaction by analysing the mechanisms of several reactions involved. Phagocytosis is a central phenomenon of host defense mechanisms responding to an invasion of foreign bodies. The induction of secondary reactions following phagocytosis is looked at. Several pathogenetic mechanisms responsible for a switch from acute to chronic inflammation are suggested. Known principles of the autonomous regulation of cell effector functions are discussed in relation to their participation in inflammatory reactions.

Acute Disease↗