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At least 253 records · Page 14Linked to original sources
PubMed2005

Histone deacetylation: an important mechanism in inflammatory lung diseases.

Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as NF-kappaB. Gene expression is regulated by modifications such as acetylation of core histones through the concerted action of coactivators such as CBP (cAMP-response element binding protein (CREB)-binding protein) which have intrinsic histone acetyltransferase (HAT) activity and are able to recruit other HAT enzymes. Conversely gene repression is mediated via histone deacetylases (HDAC) and other corepressors. In biopsies from asthmatic subjects there is an increase in HAT activity and some reduction in HDAC activity. Both of these changes are partially reversed by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through a combination of a direct inhibition of HAT activity and by the recruitment of HDAC2 to the activated NF-kappaB-stimulated inflammatory gene complex. In chronic obstructive pulmonary disease (COPD), a corticosteroid insensitive disease, there is a reduction in HDAC activity and HDAC2 expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation. This may also occur to differing degrees in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen within latent adenovirus infections. The reduction in HDAC activity induced by oxidative stress can be restored by theophylline, acting through specific kinases, which may be able to reverse steroid resistance in COPD and other inflammatory lung diseases. The modulation of HAT/HDAC activity may lead to the development of novel anti-inflammatory approaches to inflammatory lung diseases that are currently difficult to treat.

Acetylation↗
PubMed2004

Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gp120.

Chronic brain inflammation is the common final pathway in the majority of neurodegenerative diseases and central to this phenomenon is the immunological activation of brain mononuclear phagocyte cells, called microglia. This inflammatory mechanism is a central component of HIV-associated dementia (HAD). In the healthy state, there are endogenous signals from neurons and astrocytes, which limit excessive central nervous system (CNS) inflammation. However, the signals controlling this process have not been fully elucidated. Studies on the peripheral nervous system suggest that a cholinergic anti-inflammatory pathway regulates systemic inflammatory response by way of acetylcholine acting at the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) found on blood-borne macrophages. Recent data from our laboratory indicates that cultured microglial cells also express this same receptor and that microglial anti-inflammatory properties are mediated through it and the p44/42 mitogen-activated protein kinase (MAPK) system. Here we report for the first time the creation of an in vitro model of HAD composed of cultured microglial cells synergistically activated by the addition of IFN-gamma and the HIV-1 coat glycoprotein, gp120. Furthermore, this activation, as measured by TNF-alpha and nitric oxide (NO) release, is synergistically attenuated through the alpha7 nAChR and p44/42 MAPK system by pretreatment with nicotine, and the cholinesterase inhibitor, galantamine. Our findings suggest a novel therapeutic combination to treat or prevent the onset of HAD through this modulation of the microglia inflammatory mechanism.

Analysis of Variance↗
PubMed1998

Cytokines and cell adhesion molecules in cerebral ischemia: experimental bases and therapeutic perspectives.

The possibility of reopening an occluded cerebral artery by means of thrombolysis has renewed interest in a number of the several mechanisms that are active during acute cerebral ischemia. Over recent years, it has become apparent that leukocytes play a central role not only during the healing stage of brain infarction but also during the early phases of cerebral ischemia, when it is postulated that these cells produce harmful effects, particularly in the presence of reperfusion. This review is based on the critical analysis of more than 150 publications dealing with the role of leukocytes and some inflammatory mediators (cytokines, chemokines, and adhesion molecules) in cerebral ischemia. Animal studies indicate that leukocyte involvement is promoted by a variety of inflammatory molecules produced immediately after the onset of cerebral ischemia. Considerable experimental evidence suggests that these mediators play a key role in the progression from ischemia to irreversible injury (ie, cellular death and necrosis). However, the precise role of each molecule alone remains to be further elucidated as well as in relation to the complex network existing among different mediators. Progress in our understanding of the inflammatory mechanisms operating in cerebral ischemia has enabled the testing of new compounds with promising results in animals; in contrast, one recent controlled trial of an anti-leukocyte molecule in acute stroke patients showed negative results. This discrepancy may derive in part from our incomplete understanding of the complexity of the inflammatory mechanisms involved in cerebral ischemia. Our analysis suggests that until sufficient knowledge of the underlying disease mechanisms is acquired, more care should be taken when testing new and potentially efficacious drugs in stroke patients.

Animals↗
PubMed2002

The involvement of nervous and some inflammatory response mechanisms in the acute snuff-induced gingival hyperaemia in humans.

BACKGROUND AND AIM: Tobacco users and especially cigarette smokers are at higher risk than non-smokers for periodontal disease. The pathogenic mechanism has been proposed to be the vasoconstrictive properties of nicotine, with reduced gingival blood flow (GBF) as a contributing factor in the development of periodontal disease. However, in a previous study in humans, we found GBF to increase in response to acute exposure to snuff. The present study was designed to investigate whether the tobacco-induced acute GBF increase is dependent on intact nervous conduction. We further investigated the effect of piroxicam (NSAID) and dexchlorpheniramin (DCPA) (antihistamine) on the snuff-induced responses in the gingiva, to see if chemical mediators of inflammation also influenced the response. MATERIAL AND METHODS: Laser Doppler flowmetry (LDF) was used to measure gingival blood flow bilaterally in the buccal maxillary gingiva, in the forehead skin and in the thumb. Also arterial blood pressure (BP) and heart rate (HR) were monitored. Infraorbital nerve block anaesthesia (INB), superficial mucosal anaesthesia, 20 mg piroxicam or 2 mg DCPA were used in combination with snuff to study the vascular responses to 500 mg snuff (1% nicotine). RESULTS: Snuff induced a rapid increase in GBF that was higher than the increase in BP, indicating an active vasodilatation. The snuff-induced vasodilatation was partly blocked by INB and more so by superficial mucosal anaesthesia. Piroxicam and DCPA exerted diverse effects on vascular homeostasis but had no effect on the snuff-induced vasodilatation in the gingiva. CONCLUSIONS: The results of this study confirm that snuff induces local gingival vasodilatation, and imply that this vasodilatation most likely is a summation of responses due to both autonomic and antidromic reflex mechanisms. We further discuss the possible involvement of the nervously mediated effects of tobacco and nicotine on vascular homeostasis and in tobacco-associated periodontitis.

Adolescent↗
PubMed2001

Inflammatory and mechanical factors of allergen-induced bronchoconstriction in mild asthma and rhinitis.

We studied whether different bronchial responses to allergen in asthma and rhinitis are associated with different bronchial inflammation and remodeling or airway mechanics. Nine subjects with mild asthma and eight with rhinitis alone underwent methacholine and allergen inhalation challenges. The latter was preceded and followed by bronchoalveolar lavage and bronchial biopsy. The response to methacholine was positive in all asthmatic but in only two rhinitic subjects. The response to allergen was positive in all asthmatic and most, i.e., five, rhinitic subjects. No significant differences between groups were found in airway inflammatory cells or basement membrane thickness either at baseline or after allergen. The ability of deep inhalation to dilate methacholine-constricted airways was greater in rhinitis than in asthma, but it was progressively reduced in rhinitis during allergen challenge. We conclude that 1) rhinitic subjects may develop similar airway inflammation and remodeling as the asthmatic subjects do and 2) the difference in bronchial response to allergen between asthma and rhinitis is associated with different airway mechanics.

Adult↗
PubMed2002

Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease.

Inflammatory bowel disease refers to ulcerative colitis and Crohn's disease, two gut diseases with unknown causes. The dramatic increase in the last half century and the big difference in incidence for people with the same ethnic background but living in different areas strongly suggested that environmental factors played the dominant role for these diseases. The similarity in many aspects for these two diseases suggested a common causative factor. Here I suggest the impaired inactivation of digestive proteases by deconjugated bilirubin, as the result of the inhibition of bilirubin deconjugation enzyme, beta-glucuronidase, originated from the luminal bacteria and mucosa of the gut, to be a possible mechanism for both ulcerative colitis and Crohn's diseases. I also provide evidence to suggest that saccharin could be the causative or one of the most important risk factors for inflammatory bowel disease as for its inhibition on beta-glucuronidase in the intestine.

Bilirubin↗
PubMed2005

Sodium channels contribute to microglia/macrophage activation and function in EAE and MS.

Loss of axons is a major contributor to nonremitting deficits in the inflammatory demyelinating disease multiple sclerosis (MS). Based on biophysical studies showing that activity of axonal sodium channels can trigger axonal degeneration, recent studies have tested sodium channel-blocking drugs in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and have demonstrated a protective effect on axons. However, it is possible that, in addition to a direct effect on axons, sodium channel blockers may also interfere with inflammatory mechanisms. We therefore examined the novel hypothesis that sodium channels contribute to activation of microglia and macrophages in EAE and acute MS lesions. In this study, we demonstrate a robust increase of sodium channel Nav1.6 expression in activated microglia and macrophages in EAE and MS. We further demonstrate that treatment with the sodium channel blocker phenytoin ameliorates the inflammatory cell infiltrate in EAE by 75%. Supporting a role for sodium channels in microglial activation, we show that tetrodotoxin, a specific sodium channel blocker, reduces the phagocytic function of activated rat microglia by 40%. To further confirm a role of Nav1.6 in microglial activation, we examined the phagocytic capacity of microglia from med mice, which lack Nav1.6 channels, and show a 65% reduction in phagocytic capacity compared with microglia from wildtype mice. Our findings indicate that sodium channels are important for activation and phagocytosis of microglia and macrophages in EAE and MS and suggest that, in addition to a direct neuroprotective effect on axons, sodium channel blockade may ameliorate neuroinflammatory disorders via anti-inflammatory mechanisms.

Animals↗
PubMed2004

Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia.

Numerous experimental studies provide evidence that proinflammatory cytokines induce or facilitate inflammatory as well as neuropathic pain and hyperalgesia. Direct receptor-mediated actions of cytokines on afferent nerve fibers have been reported as well as cytokine effects involving further mediators. The final outcome of cytokine action greatly depends on whether they act in the central of in the peripheral nervous system. Here we summarize recent findings on the peripheral mechanisms of action of three prototypic proinflammatory cytokines, interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha, with regards to pain and hyperalgesia.

Animals↗
PubMed1998

[Inhibitory effects of shimotsu-to, a traditional Chinese herbal prescription, on ultraviolet radiation-induced cell damage and prostaglandin E2 release in cultured Swiss 3T3 cells].

We have investigated the effects of Shimotsu-to, a traditional Chinese herbal prescription (Kampo medicine), on ultraviolet (UV) radiation-induced cell damage and prostaglandin E2 (PGE2) release in cultured Swiss 3T3 cells to examine the anti-inflammatory mechanism of Shimotsu-to. Short-term UV irradiation significantly induced cell damage and stimulated PGE2 release in Swiss 3T3 cells cultured for 4 h. The UV-radiation-induced cell damage and the stimulation of PGE2 release were significantly suppressed by the treatment with Shimotsu-to. Among the single crude drug components of Shimotsu-to, Rehmanniae Radix showed significant protective effects against UV-radiation-induced cell damage and PGE2 release. Other synthetic anti-inflammatory agents, such as dexamethasone, dipotassium glycyrrhizinate and allantoin also protected against UV-induced cell damage and inhibited PGE2 release in cultured Swiss 3T3 cells. These results suggest that the anti-inflammatory mechanism of Shimotsu-to against UV-irradiated erythema (acute skin inflammation) in guinea pigs in vivo may be mediated by the inhibition of PGE2 release from cutaneous target cells.

3T3 Cells↗
PubMed2005

Endogenous attenuation of allergic lung inflammation by syndecan-1.

The airway plays a vital role in allergic lung diseases by responding to inhaled allergens and initiating allergic inflammation. Various proinflammatory functions of the airway epithelium have been identified, but, equally important, anti-inflammatory mechanisms must also exist. We show in this study that syndecan-1, the major heparan sulfate proteoglycan of epithelial cells, attenuates allergic lung inflammation. Our results show that syndecan-1-null mice instilled with allergens exhibit exaggerated airway hyperresponsiveness, glycoprotein hypersecretion, eosinophilia, and lung IL-4 responses. However, administration of purified syndecan-1 ectodomains, but not ectodomain core proteins devoid of heparan sulfate, significantly inhibits these inflammatory responses. Furthermore, syndecan-1 ectodomains are shed into the airway when wild-type mice are intranasally instilled with several biochemically distinct inducers of allergic lung inflammation. Our results also show that syndecan-1 ectodomains bind to the CC chemokines (CCL7, CCL11, and CCL17) implicated in allergic diseases, inhibit CC chemokine-mediated T cell migration, and suppress allergen-induced accumulation of Th2 cells in the lung through their heparan sulfate chains. Together, these findings uncover an endogenous anti-inflammatory mechanism of the airway epithelium where syndecan-1 ectodomains attenuate allergic lung inflammation via suppression of CC chemokine-mediated Th2 cell recruitment to the lung.

Adjuvants, Immunologic↗
PubMed1997

Cellular immune mechanisms in inflammatory myopathies.

The inflammatory myopathies include dermatomyositis, polymyositis, and inclusion body myositis. In dermatomyositis, muscle fiber injury is secondary to an antibody- or immune-complex-mediated immune response against a vascular-endothelial component. In polymyositis and inclusion body myositis, CD8+ T cells and macrophages invade and eventually destroy initially nonnecrotic muscle fibers. The autoaggressive T cells have the phenotype of activated (HLA-DR+) memory (CD45RO+) cells. T-cell receptor analyses indicate that the autoaggressive T cells are oligoclonal. In inflammatory lesions, muscle fibers express various cytoplasmic and surface molecules that are not detectable in normal fibers. These molecules, which include HLA class I antigens, heat-shock proteins, adhesion molecules, and Fas, are probably induced by locally secreted cytokines. The autoaggressive CD8+ T cells harbor granules containing perforin that aggregate near the contact zone with the target muscle fiber. This is consistent with a perforin- and secretion-dependent mechanism of muscle fiber injury. Many invaded muscle fibers also express the Fas "death receptor," but signs of apoptosis are absent.

Cell Adhesion Molecules↗
PubMedDate not supplied

Interleukin-6-associated inflammatory processes in Alzheimer's disease: new therapeutic options.

The cytokine interleukin-6 is consistently detected in the brains of Alzheimer's disease patients but not in the brains of nondemented elderly persons. Until recently it was unclear whether an interleukin-6-associated inflammatory mechanism is an early or late event in the pathological cascade of Alzheimer's disease. We investigated whether interleukin-6 could be detected in plaques of Alzheimer's disease patients prior to the onset of neuritic degeneration. We found interleukin-6 mostly in plaques where neuritic pathology has not yet developed. This indicates that the appearance of interleukin-6 may precede neuritic changes and is not just a consequence of neuritic degeneration. Therefore, one may hypothesize that activation of inflammatory mechanisms may cause neuritic degeneration in plaques. A suppression of interleukin-6 synthesis could, therefore, be of therapeutic value. Upon screening a number of substances, we found that a small number of nonsteroidal antiinflammatory drugs, including tenidap, were able to inhibit interleukin-6 synthesis in cultured human astrocytoma cells. These substances may be therapeutically useful in Alzheimer's disease and should be evaluated in clinical studies.

Aged↗
PubMed2001

Immunological aspects of alzheimer's disease: therapeutic implications.

Alzheimer's disease (AD) is a chronic neurodegenerative disease causing progressive impairment of memory and cognitive function. The amyloid cascade hypothesis suggests that mismetabolism of the beta-amyloid (A beta) precursor protein (APP) followed by subsequent formation of non-fibrillar and fibrillar A beta deposits leads to glial activation and eventually to neurotoxicity, causing cognitive impairment. Several lines of evidence indicate that an inflammatory process contributes to the pathology of AD. First, inflammatory proteins have been identified as being associated with neuritic plaques and in glial cells surrounding these plaques. Second, certain polymorphisms of acute-phase proteins and cytokines associated with AD plaques increase the risk or predispose for earlier onset of developing AD. Third, epidemiological studies indicate that anti-inflammatory drugs can retard the development of AD. Several steps in the pathological cascade of AD have been identified as possible targets for actions of nonsteroidal anti-inflammatory drugs. For instance, microglia are considered a target because this cell type is closely involved in AD pathology through secretion of neurotoxic substances and by modulating a positive feedback loop of the inflammatory mechanism that may be involved in the pathological cascade in AD. On the basis of studies in APP transgenic mice, immunisation with A beta was recently suggested as a novel immunological approach for the treatment of AD. Immunisation elicits A beta-specific antibodies that could affect several early steps of the amyloid-driven cascade. Antibodies could prevent A beta from aggregating into fibrils and accelerate clearance of A beta by stimulating its removal by microglial cells. This review outlines the pathological and genetic evidence that an inflammatory mechanism is involved in AD and the therapeutic approaches based on inhibition or mediation of inflammation.

Alzheimer Disease↗
PubMed2001

Age-related differences in pulmonary inflammatory responses to JP-8 jet fuel aerosol inhalation.

Our previous studies have demonstrated that JP-8 jet fuel aerosol inhalation induced lung injury and dysfunction. To further examine JP-8 jet fuel-induced inflammatory mechanisms, a total of 40 male C57BL/6 mice (young, 3.5 months; adult, 12 months; half in each age group) were randomly assigned to the exposure or control groups. Mice were nose-only exposed to room air or atmospheres of 1000 mg/m3 JP-8 jet fuel for 1 h/day for 7 days. Lung injury was assessed by pulmonary mechanics, respiratory permeability, lavaged cell profile, and chemical mediators in bronchoalveolar lavage fluid (BALF). The young and adult mice exposed to JP-8 jet fuel had similar values with regards to increased lung dynamic compliance, lung permeability, BALF cell count, and decreased PGE2. However, there were several different responses between the young-versus-adult mice with respect to BALF cell differential, TNF-alpha, and 8-iso-PGF2,, levels after exposure to JP-8 jet fuel. These data suggest that JP-8 jet fuel may have different inflammatory mechanisms leading to lung injury and dysfunction in the younger-versus-adult mice.

Administration, Inhalation↗
PubMed1991

[Renal complications due to non-steroidal anti-inflammatory drugs: mechanism and clinical implications].

1. Despite the fact that the incidence of renal complications due to non-steroidal antiinflammatory drugs (NSAID) is low when compared to their massive utilisation, signs of deteriorating renal function due to the use of NSAID seem to have increased in recent years. 2. Most renal complications are reversed when NSAID are withdrawn. 3. Clinicians should always search for signs of risk situations (decreased effective plasma volume, preexisting renal failure, age, etc.). In these situations, the hydration state should be checked before, and blood creatinine after, the start of therapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Pain due to tissue acidosis: a mechanism for inflammatory and ischemic myalgia?

To study the role of protons in ischemic muscle pain we employed the "submaximal effort tourniquet technique' and, in a second attempt, an intramuscular pressure infusion of acid phosphate buffer. The pH measured in the forearm skin covering the muscles at work during the tourniquet test continuously dropped to a mean value of pH 7.00 +/- 0.26, starting 1 min after the contractions, while the pain increased in direct correlation with the hydrogen ion concentration (r = 0.96). After restoring the blood supply, the intradermal proton concentration decreased more slowly than the muscular pain. The same subjective quality of deep muscular pain was achieved with pressure infusion of acid phosphate buffer (pH 5.2) into the forearm muscles. Constant flow rates evoked constant, apparently non-adapting magnitudes of pain with a log-linear stimulus-response relationship (r = 0.93). Changes in flow rate were followed by changes in pain ratings with a certain phase lag. We conclude that muscular pain induced by infusion of acidic phosphate buffer and pain from ischemic contractions are generated through the same mechanisms based on the algogenic action of protons.

Acidosis↗
PubMed1990

Immune effector mechanisms in inflammatory myopathies.

PM, IBM, and DM represent the commonly occurring inflammatory myopathies. In DM, the effector response appears to be predominantly humoral and directed against intramuscular blood vessels; a local humoral response may occur in muscle itself. Capillary lysis precedes other pathologic changes, suggesting that the capillary endothelium is an early and possibly primary target of the immune response. Questions remain about the role of immune complexes versus circulating antibodies, whether the muscle fiber injury can be explained by ischemia alone, and the possible role of endomysial CD8+ T cells. In PM and IBM, there is evidence for T-cell mediated cytotoxicity against the muscle fibers; however, muscle fiber destruction also could result from antibody-dependent complement-mediated lysis of the sarcolemma. Questions remain about the identity of the muscle fiber surface antigen(s) recognized by T cells and the molecular mechanisms of T-cell-mediated muscle fiber destruction.

Antigen-Antibody Complex↗
PubMed2003

Inflammation in pulmonary arterial hypertension.

Inflammatory mechanisms appear to play a significant role in some types of pulmonary hypertension (PH), including monocrotaline-induced PH in rats and pulmonary arterial hypertension of various origins in humans, such as connective tissue diseases (scleroderma, systemic lupus erythematosus, mixed connective disease), human immunodeficiency virus infection, or plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal (M) protein and skin changes (POEMS) syndrome. Interestingly, some patients with severe pulmonary arterial hypertension associated with systemic lupus erythematosus have experienced significant improvements with immunosuppressive therapy, emphasising the relevance of inflammation in a subset of patients presenting with PH. Patients with primary PH (PPH) also have some immunological disturbances, suggesting a possible role for inflammation in the pathophysiology of this disease. A subset of PPH patients have been shown to have circulating autoantibodies, including antinuclear antibodies, as well as elevated circulating levels of the pro-infammatory cytokines, interleukins -1 and -6. Lung histology has also revealed inflammatory infiltrates in the range of plexiform lesions in patients displaying severe PPH, as well as an increased expression of the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES) and fractalkine. Further analysis of the role of inflammatory mechanisms is necessary to understand whether this component of the disease is relevant to its pathophysiology.

Animals↗