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PubMed1999

New insights in the bronchodilatory and anti-inflammatory mechanisms of action of theophylline.

Phosphodiesterase (PDE) inhibition and adenosine antagonism have been identified as important underlying mechanisms for the bronchodilating and anti-inflammatory action of theophylline (CAS 58-55-9). The aim of the present study was to determine the effects of PDE inhibition by theophylline on cAMP and arachidonic acid (AA) metabolism, namely leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) production, in cultured monocytes in vitro. Monocytes obtained from healthy non-smoking subjects were incubated in adherence at 37 degrees C for 4 h in the presence of theophylline (0.18, 1.8 and 18 micrograms/ml, respectively) and stimulated with LPS (10 micrograms/ml). LTB4, PGE2 and cAMP were measured in the same culture supernatants by direct enzyme immunoassay. LPS-stimulated generation of cAMP increased significantly (+162%) in the presence of theophylline (18 micrograms/ml); production of LTB4 was suppressed (-42%) compared to the baseline, whereas PGE2 production increased significantly (+39%). Production of cAMP correlated with increased PGE2 production (r = 0.73, p = 0.025) and with suppression of LTB4 (r = 0.67, p = 0.016). These effects were mimicked by cell permeant nucleotides, such as dibutyryl-cAMP but not by dibutyryl-cGMP and could be abolished by ibuprofen. These results provide the first evidence that the clinical efficacy of theophylline may result from inhibition of leukotriene production and its capacity to stimulate PGE2 production. The underlying mechanism is suggested as feedback regulatory induction of COX-2 by a prostaglandin driven cAMP-mediated process.

Adult↗
PubMed2006

Immune and inflammatory mechanisms in neuropathic pain.

Tissue damage, inflammation or injury of the nervous system may result in chronic neuropathic pain characterised by increased sensitivity to painful stimuli (hyperalgesia), the perception of innocuous stimuli as painful (allodynia) and spontaneous pain. Neuropathic pain has been described in about 1% of the US population, is often severely debilitating and largely resistant to treatment. Animal models of peripheral neuropathic pain are now available in which the mechanisms underlying hyperalgesia and allodynia due to nerve injury or nerve inflammation can be analysed. Recently, it has become clear that inflammatory and immune mechanisms both in the periphery and the central nervous system play an important role in neuropathic pain. Infiltration of inflammatory cells, as well as activation of resident immune cells in response to nervous system damage, leads to subsequent production and secretion of various inflammatory mediators. These mediators promote neuroimmune activation and can sensitise primary afferent neurones and contribute to pain hypersensitivity. Inflammatory cells such as mast cells, neutrophils, macrophages and T lymphocytes have all been implicated, as have immune-like glial cells such as microglia and astrocytes. In addition, the immune response plays an important role in demyelinating neuropathies such as multiple sclerosis (MS), in which pain is a common symptom, and an animal model of MS-related pain has recently been demonstrated. Here, we will briefly review some of the milestones in research that have led to an increased awareness of the contribution of immune and inflammatory systems to neuropathic pain and then review in more detail the role of immune cells and inflammatory mediators.

Animals↗
PubMedDate not supplied

[Inflammatory mechanisms, arteriosclerosis and ischemic stroke: clinical data and perspectives].

OBJECTIVE: The atherosclerosis is the most common cause of death and disability in developed countries by causing ischemic cardiopathic and stroke. The ischemic atherotrombotic stroke is the most frequent form of the last one. In this sense we review herein the mechanisms underlying the artherosclerotic process. DEVELOPMENT: It is understood as an inflammatory disease, by taking into account the widely accepted hypothesis by Ross: it was firstly stated in structural terms, as macrophages and T/B linfocities were present in the arterial wall from the first stages of the disease (fatty streak) to the last and complicated ones. The starting point is a functional endothelial damage, secondary to mechanical or vascular risk factors and called response to injury hypothesis . The next step is an inflammatory cascade that involves humoral (citokines, growth factors) and cellular (increased quimiotaxis, adherece and infiltration of inflamatory cells) mechanisms. They interact among them, outbalanced and in a progresssive way that leads to the final fibroproliferative response. Every stage has his own inflammatory components and interactive pathways. The following elements are outstanding in this process: 1) Adhesion molecules, including E selectin, ICAM 1 and VCAM 1, that are increased locally in the plaques and as circulating elements; plaquetary receptors of the type IIb/IIIa are integrins wich belong to the same family; 2) Citokines with either proinflammatory activity like IL 1, the TNF a and linfocitary ligands like the CD 40, or with antiinflammatory activity like the gamma interpheron; 3) Growth factors, with plaquetary (PDGF) and fibroblastic (FGF) variants as the cornerstone; 4) Markers of systemic inflammation, overall plasma C reactive protein and fibrinogen, that predict the risk of stroke and cardiovascular death; IL 6, complement, thrombin and heat shock proteins (HSP) would act in a similar but less conclusive way. CONCLUSIONS: The evidences of the pivotal role of the inflammation in the stroke allow to develop therapeutical strategies to prevent the disease: fostering natural antiinflamatory mechanisms, or inhibiting inflammatory elements by selective (monoclonal antibodies) or non selective (IIb/IIIa receptors, antiinflammatory drugs) pathways are distinctily glimpsed, ongoing or fully developed.

Arteriosclerosis↗
PubMed2006

Anti-inflammatory mechanism of simvastatin in mouse allergic asthma model.

Statins have anti-inflammatory property and immunomodulatory activity. In this study we aimed to investigate the inhibitory mechanism of simvastatin in allergic asthmatic symptoms in mice. BALB/c mice were sensitized and challenged by ovalbumin to induce asthma. Ovalbumin-specific serum IgE levels were measured by enzyme-linked immunosorbent assay (ELISA), and the recruitment of inflammatory cells into bronchoalveolar lavage fluid or lung tissues was measured by Diff-Quik staining and hematoxylin and eosin (H&E) staining, respectively, the expressions of CD40, CD40 ligand (CD40L), and vascular cell adhesion molecule-1 (VCAM-1) by immunohistochemistry, the mRNA and protein expressions of cytokines in lung tissues by reverse transcriptase-polymerase chain reaction (RT-PCR) or ELISA, epithelial hyperplasia by periodic acid-Schiff (PAS) staining, activities of matrix metalloproteinases (MMPs) by zymography, the activities of small G proteins, mitogen-activated protein (MAP) kinases and nuclear factor-kappa B (NF-kappaB) in bronchoalveolar lavage cells and lung tissues by western blot and EMSA, respectively. Simvastatin reduced ovalbumin-specific IgE level, the number of total inflammatory cells, macrophages, neutrophils, and eosinophils into bronchoalveolar lavage fluid, the expressions of CD40, CD40L or VCAM-1, the mRNA and protein levels of interleukin (IL)-4, IL-13 and tumor necrosis factor (TNF)-alpha, the numbers of goblet cells, activities of MMPs, and further small G proteins, MAP kinases and NF-kappaB activities in bronchoalveolar lavage cells and lung tissues increased in ovalbumin-induced allergic asthma in mice. Our data suggest that simvastatin may be used as a therapeutic agent in asthma, based on reductions of various allergic responses via regulating small G proteins/MAP kinases/NF-kappaB in mouse allergic asthma.

Animals↗
PubMed1999

The importance of inflammatory mechanisms for the development of Alzheimer's disease.

A variety of inflammatory proteins has been identified in brains of patients with Alzheimer's disease. The current data suggest that the inflammatory processes are intimately involved in several crucial events in the pathological cascade. Immunohistochemical studies reveal that those parts of the brain wherein the amyloid-beta deposits are closely associated with a chronic inflammatory response are strongly related to the characteristic symptoms. An inflammation-based approach could also provide a valuable theoretical framework to study the influence of extracerebral factors (such as acute phase reactants) on the clinical course of Alzheimer's disease.

Acute-Phase Reaction↗
PubMed1994

[Inflammatory mechanisms in nervous system].

Experimental autoimmune encephalomyelitis (EAE), is a neuroautoimmune inflammatory disease, involving sensitization to central nervous system myelin basic protein (MBP). Our studies of the coagulation system and ensuing fibrinolysis implicate coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature, as events initiating the inflammation characterizing EAE. Among recipient rats injected with MBP-primed, cultured-activated lymph node cells, "opening" the blood-brain barrier (BBB) and deposition of perivascular fibrin within the spinal cord occur in parallel one day before onset of clinical signs of EAE. The critical event precipitating EAE is a binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of cerebrovascular endothelial cells. Coagulation and ensuring fibrinolysis occur at sites of binding of effector cells to cerebrovascular endothelium. Release of biologically active peptides, cleaved from fibrin, "open" the BBB. Once BBB is opened, even transiently, the stage is set for a complex cascade of immunologically-nonspecific inflammatory events, which plays an important role in the development of tissue damage, including demyelination.

Animals↗
PubMed1994

Induction of B1 receptors in vivo in a model of persistent inflammatory mechanical hyperalgesia in the rat.

The induction of mechanical hyperalgesia by B1 and B2 receptor agonists following an inflammatory insult has been studied in the rat. Intra-articular injection of bradykinin, but not desArg9 bradykinin, into naïve joints induced mechanical hyperalgesia with a reduction of up to 38% in load tolerated by the treated leg. Following intra-articular injection of Freund's complete adjuvant (FCA) the load tolerated by the treated leg was depressed for three days. The development of FCA-induced hyperalgesia was reduced by desArg9Leu8BK or Hoe 140. Bradykinin, desArg9BK and the metabolically stable B1 receptor agonist SarDPhe8desArg9BK were all hyperalgesic upon intra-articular administration 3 days after FCA administration. The hyperalgesia induced by desArg9BK and SarDPhe8desArg9BK was prevented by co-administration of desArg9Leu8BK but not by Hoe 140. At low doses (< 10 nmol) bradykinin-induced hyperalgesia was presented by Hoe 140 but not by desArg9Leu8BK. At higher doses of bradykinin (> 100 nmol) the hyperalgesia was reduced by both Hoe 140 and desArg9Leu8BK. These data suggest that following an inflammatory insult both bradykinin B1 and B2 receptor mechanisms are involved in the accompanying hyperalgesia.

Animals↗
PubMed2005

Anti-inflammatory mechanisms of glucocorticoids targeting granulocytes.

Asthmatic inflammation involves the recruitment and activation of inflammatory cells, and changes in the structural cells of the lung and asthma are characterized by an increased expression of components of the inflammatory cascade including cytokines, chemokines, growth factors, enzymes, receptors and adhesion molecules. The increased expression of these proteins seen in asthma is generally the result of enhanced gene transcription, since many of the genes are not expressed in normal cells but are induced in a cell-specific manner during the inflammatory process. There is clear evidence that neutrophils, long thought of as being transcriptionally inert, can respond to stimuli to induce inflammatory genes. Glucocorticoids are very effective in controlling the inflammation seen in asthmatic airways. Beyond their recognized actions on eosinophil and neutrophil apoptosis, glucocorticoids have profound effects on the chemotaxis, activation and release of mediators from granulocytes (eosinophils, neutrophils and basophils). Few mechanistic studies are available in these cells, but it appears that in granulocytes, glucocorticoids target the same signaling pathways, such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), that are important in other cells. We summarize these known mechanisms at the end of this review.

Animals↗
PubMed1999

[Inflammatory mechanisms of renal fibrosis: glomerulonephritis].

Studies of glomerulonephritis models have shown that inflammatory reaction is responsible for the development of glomerulosclerosis and tubulo-interstitial sclerosis and, hence, for the progression to end stage renal failure. That macrophage accumulation and fibrosis extension are frequently not closely related events suggests that macrophages are not involved in progression process. Glomerular sclerosis is rather associated with the release of mediators from resident cells-mainly growth factors such as platelet-derived growth factor and transforming growth factor-beta--the synthesis and bioactivity of which are enhanced by inflammatory mediators. Tubulo-interstitial sclerosis is induced by inflammatory lesions of the glomerulus that lead to proteinuria. Indeed, reabsorption of proteins in proximal tubule triggers epithelial cells to release proinflammatory and prosclerotic mediators into the interstitium. New therapeutic approaches including gene transfer strategies are directed at suppressing the efficiency of such mediators.

Fibrosis↗
PubMed2001

Interleukin-4 and tumour necrosis factor-alpha inhibit transforming growth factor-beta production in a human bronchial epithelial cell line: possible relevance to inflammatory mechanisms in chronic obstructive pulmonary disease.

OBJECTIVE: Human bronchial epithelial cells are known to secrete an array of inflammatory cytokines including tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-4, which may play a role in immune responses in lung diseases such as chronic obstructive pulmonary disease (COPD). However, the regulatory mechanisms governing cytokine production in bronchial epithelia in COPD are largely unknown. Transforming growth factor-beta (TGF-beta) is an anti-inflammatory cytokine and is involved in airway repair. The purpose of this study was to study the effect of TNF-alpha and IL-4 (pro-inflammatory cytokines known to be up-regulated in COPD), on the production of TGF-beta (a negative regulator of inflammation) by epithelial cells. METHODOLOGY: A bronchial epithelial cell line was used as an in vitro culture model (16HBE). Cell cultures were stimulated with various combinations of TNF-alpha and IL-4 (20 ng/mL) for 24 h. Transforming growth factor-beta production was measured by flow cytometry, enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Exposure to TNF-alpha significantly up-regulated production of IL-4 from cultured epithelial cells. Unstimulated cells spontaneously released TGF-beta. Exposure to TNF-alpha and IL-4 significantly inhibited production of TGF-beta. The inhibitory effects of TNF-alpha and IL-4 on TGF-beta synthesis were summative. CONCLUSIONS: The inhibitory effect of IL-4 and TNF-alpha on production of the regulatory cytokine TGF-beta in a bronchial epithelial cell line suggests that such mechanisms may contribute to the progression of the inflammatory response and compromise repair processes in inflammatory lung diseases such as COPD.

Bronchi↗
PubMed2003

Involvement of endogenous endothelins in thermal and mechanical inflammatory hyperalgesia in mice.

Endothelin receptors have been involved in inflammatory, neuropathic and tumoral pain. In the case of inflammatory hyperalgesia, some previous papers have pointed towards the involvement of ETB receptors, although the stimulation of ETA receptors seems to participate in the development of the inflammatory reaction. We have studied the effect of ETA and ETB receptor antagonists in the thermal and mechanical hyperalgesia induced in a model of acute (induced by carrageenan) and chronic (induced by complete Freund's adjuvant, CFA) inflammation in mice. The i.pl. administration of the selective ETA antagonist BQ-123 (1-10 nmol) antagonized the thermal hyperalgesia detected by the unilateral hot plate test, observed in both inflammatory models, whereas the i.pl. administration of the ETB selective antagonist BQ-788 (17.7 nmol) failed to modify this. In contrast, both BQ-123 (3-17.7 nmol) and BQ-788 (3-17.7 nmol) antagonized the mechanical hyperalgesia, as assessed by the Randall-Selitto test in carrageenan- and CFA-treated mice. Both BQ-123 and BQ-788 were able to antagonize the mechanical hyperalgesia induced by ET-1 (200 pmol; i.pl.) in the same dose range. Thus, ETA receptors are involved in both thermal and mechanical hyperalgesia whereas ETB receptors are only involved in mechanical hyperalgesia in these inflammatory models. In conclusion, the role of ETB receptors in inflammatory pain is further supported and new insights into the participation of ETA receptors in inflammatory hyperalgesia are given.

Animals↗
PubMed2004

Pre- and postnatal inflammatory mechanisms in chronic lung disease of preterm infants.

Epidemiological data suggest a strong association between chorioamnionitis and the development of chronic lung disease in preterm infants. Increased concentrations of proinflammatory cytokines present in the amniotic fluid and the systemic fetal circulation seem to be important mediators in the early inflammatory response by recruiting and activating inflammatory cells and by inducing pathways of lung injury. As a consequence vascular cell adhesion molecules are upregulated and a marked infiltration of neutrophils and macrophages as well as an increased expression of interleukin-8 mRNA in the bronchoalveolar epithelium and in the interstitial tissue takes place. These antenatal events may prime the lungs such that various injurious factors in the postnatal period provoke an excessive inflammatory response: oxygen toxicity, mechanical ventilation, inappropriate resuscitation, pulmonary and systemic infections, persistent ductus arteriosus. Besides proinflammatory cytokines, toxic oxygen radicals, lipid mediators and potent proteases may be responsible for acute and chronic lung injury. In general, an imbalance between pro- and anti-inflammatory factors can be considered as a hallmark of lung injury, and may considerably affect normal alveolarisation and pulmonary vascular development by inducing growth arrest of the immature lung.

Cell Adhesion Molecules↗
PubMed2004

Influence of inflammatory mechanisms on the redox balance in interstitial lung diseases.

This study investigated the hypothesis that inflammatory, regulatory and antioxidant systems control the redox balance in interstitial lung diseases. Spontaneous mRNA expression of inflammatory cytokines and redox-active enzymes was examined in bronchoalveolar lavage (BAL) cells from patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis (SARC) using RT-PCR analysis. Pulmonary oxidative stress was characterized by carbonyl-levels in the soluble BAL-fluid protein. Protein carbonyls were normal in SARC, but 2.4-fold increased in IPF. Here, the protein carbonyls correlated inversely with glutathione peroxidase mRNA. The message for IL-8 increased 14-fold in IPF and was accompanied by a marked influx of PMN, while these parameters were not altered in SARC. Levels of IL-10 transcripts increased in both diseases, but stronger in SARC (33-fold) than in IPF (22-fold), contributing to a high IL-10/IL-8 mRNA ratio in SARC (0.86) in comparison to IPF (0.07) and controls (0.04). In SARC but not in IPF, IFN-gamma mRNA was expressed at high levels and correlated inversely with the carbonyl levels. In both diseases, IL-1beta, TNF-alpha, and IL-6 mRNA transcripts remained at baseline level. In summary, a low IL-10/IL-8 mRNA ratio was paralleled with significant oxidative stress in IPF, while a high IL-10/IL-8 ratio and enhanced IFN-gamma expression went along with a physiological redox-balance in SARC.

Adult↗
PubMed1999

Anti-inflammatory mechanism of alminoprofen: action on the phospholipid metabolism pathway.

Alminoprofen is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylpropionic acid class. It has anti-inflammatory properties different from the classical NSAID. Using both in vitro systems of cells in culture and in vivo models of inflammation, we report here that alminoprofen possesses both antiphospholipase A2 (PLA2) activity and anti-cycloxygenase (COX) activity. The PLA2 targeted by alminoprofen is likely the secretory phospholipase A2 (sPLA2) while the COX targeted is the COX-2.

Animals↗
PubMed2002

Aprotinin: antifibrinolytic and anti-inflammatory mechanisms of action in cardiac surgery with cardiopulmonary bypass.

Cardiopulmonary bypass results in activation of the coagulation, fibrinolytic, inflammatory, and complement cascades. These activated cascades result in a decrease in the number of circulating coagulation factors, hyperfibrinolysis, thrombocytopenia, platelet defects, coagulopathies, and an acute inflammatory response. Patients experiencing cardiac surgery with cardiopulmonary bypass are at risk for many potential problems. The use of aprotinin, an antifibrinolytic agent, has multiple effects that tend to reduce hematological defects and blunts the inflammatory response that is associated with cardiac surgery. The pathophysiological consequences of cellular activation associated with cardiopulmonary bypass, basic mechanisms of action of aprotinin, pharmacodynamic and pharmacokinetic properties, dosing, adverse reactions, and cost/benefit ratio are discussed in this article. Critical care nurses need to know about aprotinin to understand its role in reducing blood loss and transfusions during and after cardiac surgery.

Aprotinin↗
PubMed2002

Distinct inflammatory mechanisms mediate early versus late colitis in mice.

BACKGROUND & AIMS: Progression from the acute to chronic phase of inflammatory bowel disease cannot be easily evaluated in patients and has not been characterized in animal models. We report a longitudinal study investigating changes in the mucosal immune response in an experimental model of colitis. METHODS: Severity of colitis, body mass, stool consistency and blood content, serum amyloid A, and tissue histology were examined in interleukin (IL)-10-deficient mice over 35 weeks. The corresponding production of IL-12, IL-18, interferon gamma, tumor necrosis factor alpha, IL-4, and IL-13 by lamina propria mononuclear cells in the inflamed intestine was measured. Administration of neutralizing antibody to IL-12 at distinct times during disease progression permitted evaluation of its therapeutic potential. RESULTS: The clinical manifestations and intestinal inflammation delineated an early phase of colitis (10-24 weeks), characterized by a progressive increase in disease severity, followed by a late phase (>25 weeks), in which chronic inflammation persisted indefinitely. Lamina propria mononuclear cells from mice with early disease synthesized progressively greater quantities of IL-12 and interferon gamma, whereas production of both cytokines dramatically declined and returned to pre-disease levels in the late phase of colitis. Consistent with this pattern, neutralizing antibody to IL-12 reversed early, but not late, disease. In contrast, IL-4 and IL-13 production increased progressively from pre- to early to late disease. CONCLUSIONS: Colitis that develops in IL-10-deficient mice evolves into 2 distinct phases. IL-12 plays a pivotal role in early colitis, whereas its absence and the synthesis of IL-4 and IL-13 in late disease indicate that other immune mechanisms sustain chronic inflammation.

Acute Disease↗