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PubMed1994

Diarrhea associated with intestinal inflammation increases the potency of mu and delta opioids on the inhibition of gastrointestinal transit in mice.

The aim of the study was to determine the effects of intestinal inflammation induced by croton oil on the antitransit action of systemically administered receptor-specific opioids. Our hypothesis was that inflammation would "sensitize" opioid receptors in peripheral and/or central terminals of myenteric and submucous plexus neurons and enhance the effects of exogenously administered opioids. Diarrhea was induced by p.o. administration of croton oil and was demonstrated by weight loss and increased gastrointestinal transit. Histologically, an increased number of clear vesicles in the cytoplasm of jejunal epithelial cells and enlarged spaces filled with fine granular material in the extravascular compartment were observed. Subcutaneous morphine and fentanyl produced dose-related inhibitions of gastrointestinal transit in saline-treated controls with ED50 values of 1.24 +/- 0.06 and 0.036 +/- 0.010 mg/kg, respectively. In animals with diarrhea, dose-response curves were parallel and shifted to the left with a significant decrease in ED50 values of 2.95 times for morphine and 1.89 for fentanyl. The effects of the delta agonist Tyr-D-Pen-Gly-Phe-D-Pen, but those of U50,488H [trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolydynil)cyclohexyl) benzeneazetamine] also were increased significantly during diarrhea associated with inflammation. Naloxone (0.1 mg/kg), MR-2266 [(-)-a-5,9-diethyl-2'-hydroxy-2-(3-furylmethyl)-6,7-benzomorphan] (3 mg/kg) and naltrindole (1 mg/kg) antagonized the effects of the receptor-specific opioid agonists used in the study. Our results show that the potency of s.c. mu and delta opioids is increased during inflammation of the gut and that the effect is mediated by the same type of opioid receptors present in the noninflamed tissue. These results support the view that a sensitization of opioid receptors occurs during acute inflammation of the gut.

Amino Acid Sequence↗
PubMed1996

Distribution of inflammation and atrophy in the stomach of Helicobacter pylori-positive and -negative patients with chronic gastritis.

OBJECTIVES: To investigate the extent of inflammation and atrophy in the stomach of Helicobacter pylori-positive and -negative patients with chronic gastritis. METHODS: Endoscopy with biopsies from the lesser curvatures of the antrum, angulus, middle body, and the greater curvature of the middle body of the stomach was performed in 59 patients with histologically confirmed chronic gastritis. The extent of atrophic gastritis was assessed endoscopically as well histologically. H. pylori status was assessed by histology as well as enzyme-linked immunosorbent assay. The histological severity of chronic and acute inflammation, glandular atrophy, and intestinal metaplasia was assessed according to the Sydney system. RESULTS: In H. pylori-positive patients, H. pylori was evenly distributed throughout the stomach when the extent of atrophic gastritis was limited to the antrum and the lesser curvature of the body, but disappeared from the antrum of patients with more extensive atrophic gastritis. The severity of acute and chronic inflammation at the greater curvature of the body increased with the extension of atrophic gastritis. In H. pylori-negative patients, the severity of chronic inflammation at the greater curvature of the body was significantly higher in patients with extensive atrophic gastritis than in those with a lesser extent of atrophic gastritis. CONCLUSION: At the greater curvature of the body, the development of atrophy is closely associated with the increase in the severity of inflammation, which is more marked in H. pylori-positive patients.

Adolescent↗
PubMed1996

Pig farmers have signs of bronchial inflammation and increased numbers of lymphocytes and neutrophils in BAL fluid.

The purpose of this study was to investigate whether pig farmers had inflammation of the bronchial mucosa and activation of bronchoalveolar lavage (BAL) cells. Pig farmers are exposed to high dust levels and have a prevalence of work-related respiratory symptoms. Bronchoscopy and BAL were performed in 27 young large-scale pig farmers, who had never smoked. Fifty three lifetime nonsmoking healthy students participated as controls. All farmers and controls had normal lung function (forced expiratory volume in one second (FEV1) 109 and 105% predicted respectively. Estimation of macroscopic signs of inflammation in the bronchi (erythema, oedema, secretion and friability) showed that pig farmers had significantly increased signs of inflammation. The median score was 3 (range 0-6) compared to a median score of 0 (range 0-3) in controls. More pig farmers than controls (41 versus 25%) had a positive histamine challenge (provocative dose producing a 20% fall in FEV1 (PC20) < or = 32 mg.mL-1) but the difference was not significant. The cell concentration in BAL fluid was identical in the two groups. Pig farmers had a significantly increased percentage of lymphocytes (median 7, range 1-27 versus median 2, range 0-7) and neutrophils (median 2, range 0-30 versus median 1, range 0-4) compared to controls. Spontaneous migration (19.8 versus 5.5 microns) and chemotaxis (62.6 versus 11.2 microns) was significantly increased in pig farmers compared to controls. After stimulation with zymosan and phorbol myristrate acetate (PMA), the reactive oxygen radical generation of purified alveolar macrophages was also significantly increased in pig farmers. Lifetime nonsmoking pig farmers with normal lung function have macroscopic signs of bronchial inflammation and an increased number of neutrophils in bronchoalveolar lavage. Their alveolar macrophages showed biological signs of activation. The inflammation of pig farmers bronchi may be early signs of bronchitis.

Adult↗
PubMed1996

[The repopulation and regranulation of tissue basophils at the site of acute inflammation].

Regularities of rat mast cells (MC) repopulation and regranulation in late reparative stage of inflammation compared to that in conditions approximating to MC natural renewal (after their osmiophilic elimination) and MC restoration after the inflammation caused during their absence were established on the model of E.coli induced acute infectious peritonitis. MC number in peritoneal fluid and mesenterium restores by 90th day in typical development of the inflammation, with peritoneal MC regranulation yielding to that in mesenterium and remaining unfinished by 120th day. MC repopulation in peritoneal fluid and mesenterium forestalls the one observed after the osmotic MC elimination. Inflammation, induced during MC absence retards peritoneal MC regranulation and promotes that of mesenterial ones. MC repopulation and regranulation on the site of inflammation combines their degranulation and high content of free histamine in peritoneal fluid and mesenterium.

Acute Disease↗
PubMed1996

[Thy-1 induction and its tissue-specific regulation in the rat--studies on acute rejection and granulomatous inflammation].

Thy-1 is a surface molecule known to be involved in cellular adhesion and signal transduction, and it has been found that Thy-1 induced on endothelial cells regulates vascular permeability both in vitro and in vivo at sites of inflammation. To further investigate regulation of Thy-1 expression at inflammatory sites, we made two in vivo models using LEJ/Hkm, rat strain. One is allogenic transplantation model and another is granulomatous inflammation model induced by Freund's complete adjuvant. Thy-1 mRNA was detected in the normal brain, thymus, heart, lung, liver, kidney, skin and lymph node but not in peripheral blood mononuclear cells by reverse transcription and polymerase chain reaction method. In the skin transplantation and dermal inflammation, Thy-1 expression was up-regulated on endothelial cells. On the other hand, Thy-1 was induced on rat renal tubular epithelial cells in acute cellular rejection. No obvious Thy-1 upregulation was observed in the granulomatous inflammation in the kidney. Moreover, no induction of Thy-1 expression was seen in either acute cellular rejection or granulomatous inflammation in the lung. These observations suggested that there is a tissue-specific regulation on Thy-1 expression and that Thy-1 induction appears to be one of important factors that modulates acute cellular rejection of skin allografts through its function on vascular permeability regulation.

Acute Disease↗
PubMed1996

Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration.

We evaluated entorhinal cortex and superior frontal gyrus for hallmarks of Alzheimer's disease (AD) pathology, including inflammation, in three patient sets: AD patients, nondemented elderly patients with few or no neurofibrillary tangles (NFTs) and amyloid beta peptide (A beta) deposits, i.e. normal controls (NC), and nondemented elderly patients with profuse entorhinal cortex NFTs and neocortical A beta deposits, i.e. high pathology controls (HPC). Membrane attack complex (C5b-9) immunoreactivity and immune activation of microglia (MHCII expression) were used as general markers for inflammation. Compared to NC patients, AD patients exhibited significant cortical synapse loss, A beta deposition, NFT formation, and inflammation. HPC patients also had significantly elevated A beta deposition and NFT formation, but there was no evidence of synapse loss and little or no evidence of inflammation. Across patients and brain regions the measures of inflammation each accounted for significant percentages of the variance in synaptophysin immunoreactivity and each was more highly correlated with synapse estimates than NFT formation or A beta deposition.

Aged↗
PubMed1996

Platelet-activating factor (PAF) stimulates giant migrating contractions during ileal inflammation.

The role of platelet-activating factor (PAF) and substance P in stimulating abnormal motor activity during ileal inflammation was investigated in conscious dogs. All test substances were infused close-i.a. in short segments of the ileum. Ileal inflammation was induced by mucosal exposure to a series of ethanol and acetic acid infusions. In the normal state, PAF stimulated phasic contractions and some giant migrating contractions (GMCs), whereas substance P stimulated only phasic contractions. During inflammation, PAF stimulated a significantly greater number of GMCs, but there was no significant difference in the area under phasic contractions between the normal and inflamed states. Atropine, tetrodotoxin, hexamethonium, verapamil, diltiazem, and dantrolene significantly inhibited the response to PAF in both the normal and the inflamed state. By contrast, inhibition of nitric oxide by N omega-nitro-L-arginine methyl ester enhanced the contractile response to PAF. N-(6-ammohexyl)-5-chloro-1-naphtalenesulfonamide hydrochloride, a calmodulin antagonist, did not affect the response to PAF. Methacholine, neostigmine and motilin stimulated only phasic contractions during the normal state, but they stimulated both phasic contractions and GMCs during the inflamed state. We conclude that PAF is one of the inflammatory response mediators that may stimulate GMCs during ileal inflammation. The inflammatory response may modulate the enteric neuronal and cellular control of contractions such that the cholinergic mechanisms of stimulation of GMCs are sensitized during inflammation.

Animals↗
PubMed1997

Patchy cecal inflammation associated with distal ulcerative colitis: a prospective endoscopic study.

OBJECTIVES: It is generally believed that the mucosal inflammation in ulcerative colitis is characterized by a diffuse, continuous involvement starting from the rectum without "skip areas." It was the aim of this study to examine 20 patients with established "left-sided ulcerative colitis" prospectively by ileocolonoscopy with biopsies to determine the extent and the continuity of the mucosal inflammation and the incidence of skip lesions in ulcerative colitis. METHODS: Twenty patients with left-sided ulcerative colitis underwent a complete ileocolonoscopy with biopsies of the terminal ileum and all colonic segments. The patients remained in clinical follow-up for at least 8 yr after the initial examination. RESULTS: The upper margin of inflammation was sharply demarcated in 6 patients and gradual in 14. Segmental inflammation, separated from the distal inflamed segment by apparently uninvolved mucosa, was found in 15 patients (75%) and always included the area around the appendiceal orifice. The correlation between endoscopic abnormalities and histological changes was excellent. CONCLUSION: In so-called "left-sided" ulcerative colitis distal involvement may be accompanied by more proximal areas of inflammation, particularly in the periappendiceal area of the cecum.

Adolescent↗
PubMed1998

Comparison of technetium-99m-MDP, technetium-99m-WBC and technetium-99m-HIG in musculoskeletal inflammation.

UNLABELLED: This study compared three radionuclide techniques in distinguishing musculoskeletal infection from noninfectious inflammation. METHODS: Thirty-five orthopedic patients with suspected musculoskeletal infection were examined using three radionuclide techniques in sequence: triphasic bone scintigraphy, 99mTc radioleukocytes (99mTc-WBC) scintigraphy and 99mTc human immunoglobulin (99mTc-Hig) scintigraphy. Two "early" and "late" acquisitions were performed, at 4-6 hr and 20-24 hr postinjection, respectively. Patients who were diagnosed as suffering from noninflammatory lesions became the controls. We calcu"late"d for all studies one index of inflammation (Infl) as the ratio between counts in the uptake area and counts in an equal area of normal tissue. RESULTS: The "early" radiolabeled leukocytes and "late" Hig scintigraphy allowed the greatest ability to distinguish between infections and noninfectious inflammations (p < 0.011 and p < 0.016) with a sensitivity of 96.6% and 96.5% and specificity of 71% and 100%, respectively. Hig and radioleukocytes allowed distinguishing infections from noninflammatory diseases at both examinations. CONCLUSION: The "early" radioleukocyte scintigraphy allowed us to separate infections from noninfectious inflammations. In contrast, the same result can be obtained only with the "late" scan in the Hig study, but Hig mapped the spread of the inflammation into soft tissues better. Hig might be an alternative to radioleukocytes because of its simple preparation, similar accuracy and safety.

Adult↗
PubMed1998

Oral administration of L-arginine potentiates allergen-induced airway inflammation and expression of interleukin-5 in mice.

The role of nitric oxide in the airway hyperresponsiveness and inflammation of bronchial asthma has not yet been established. However, L-arginine, the substrate for nitric oxide synthases, reportedly alleviates airway hyperresponsiveness caused by parainfluenza virus and reduces granulocytic inflammation induced by ischemia-reperfusion. We investigated the effects of L-arginine on a murine model of allergic asthma that included airway hyperresponsiveness, eosinophilic inflammation and expression of interleukin (IL)-5 in the lung. The mice received drinking water with or without L-arginine for 9 weeks. Histologic evaluation and cellular profiles in bronchoalveolar lavage fluid showed that p.o. administration of L-arginine (72 micromol/kg/day) significantly enhanced eosinophilic airway inflammation and goblet cell proliferation that were associated with intratracheal instillation of ovalbumin. L-Arginine also increased protein levels of IL-5 and IL-2 in supernatants from the lung exposed to ovalbumin. The number of eosinophils in bronchoalveolar lavage fluid correlated significantly with the expression of IL-5. L-Arginine did not reverse ovalbumin-associated airway hyperresponsiveness to inhaled ACh. These results suggest that p.o. administration of L-arginine aggravates allergen-induced eosinophilic airway inflammation via expression of IL-5, and in this model it does not show therapeutic efficacy against airway hyperresponsiveness associated with allergen exposure. Oral administration of L-arginine, the precursor of nitric oxide, may not be an effective intervention in allergic asthma.

Animals↗
PubMed1999

Selective requirements for leukocyte adhesion molecules in models of acute and chronic cutaneous inflammation: participation of E- and P- but not L-selectin.

Adhesion molecules borne by both endothelial cells and circulating leukocytes are in large measure responsible for guiding the process of extravasation. The selectin family has been primarily associated with the early stages of adhesion involving initial contact and rolling. A significant body of evidence has accumulated indicating a fundamental role for the endothelial members of this family, E- and P-selectin, in a variety of inflammatory states and models. Although originally identified as the lymph node-specific lymphocyte homing receptor, L-selectin has also been suggested to play an important role in leukocyte recruitment to sites of inflammation. We have recently demonstrated, using L-selectin-deficient mice, that defects in contact hypersensitivity (CHS) responses are in essence due to the inability of T cells to home to and be sensitized within peripheral lymph nodes, whereas nonspecific effector cells are fully capable of entry into sites of cutaneous inflammation (Catalina et al, J Exp Med 184:2341, 1996). In the present study, we perform an analysis of adhesion molecule usage in two models of skin inflammation and show in both L-selectin-deficient as well as wild-type mice that a combination of P- and E-selectin is crucial for the development of both acute (croton oil) and chronic (contact hypersensitivity) inflammation at sites of the skin, whereas L-selectin does not appear to play a significant role. Moreover, alpha4 integrins are shown to be integral to a CHS but not an acute irritant response, whereas CD44 does not significantly contribute to either. These results provide a systematic examination in one study of major adhesion molecules that are critical in acute and chronic skin inflammation. They reinforce the essential role of the collaboration of E- and P-selectin in both specific and nonspecific skin inflammatory responses and the importance of alpha4 in the specific response only. In addition, they substantiate only a limited role, if any, for L-selectin in these cutaneous effector mechanisms and demonstrate the essential equivalence in this analysis of L-selectin-deficient mice compared with normal mice treated with blocking antibodies.

Animals↗
PubMed1998

Blood brain barrier permeability and acute inflammation in two models of traumatic brain injury in the immature rat: a preliminary report.

We sought to investigate the course and magnitude of blood brain barrier (BBB) permeability following focal and diffuse traumatic brain injury (TBI) in immature rats and examine the time course of markers of acute inflammation (neutrophil accumulation and E-selectin [E-sel] expression) following these two types of injury. We measured BBB permeability using i.v. injection Evans Blue (EB) and the extent of inflammation using immunohistochemical techniques identifying neutrophils (monoclonal antibody RP-3) and the endothelial adhesion molecule, E-selectin. Male Sprague-Dawley immature (17 day-old) rats (30-45 g, n = 80) were subjected to a controlled cortical impact (CCI: 2 mm, 4 m/s), a closed head diffuse injury (DI: 150 g/2m) or a corresponding sham procedure (with or without craniotomy). EB was injected i.v. at 30 min before sacrifice, which occurred at 1 h, 4 h, or 24 h after injury. BBB permeability was observed in both the CCI and DI rats at 1 h after injury which largely resolved by 24 h. In the CCI, EB extravasation was seen within and around the contusion. In DI, diffuse BBB permeability was seen. DI was not associated with acute inflammation since there was neither neutrophil accumulation nor E-selectin expression. The CCI rats though had 5.1 +/- 2.2 neutrophils/hpf and 3.0 +/- 0.4 endothelial cells/hpf expressing E-selectin (mean +/- SEM) (both p < 0.05 vs sham and DI). These data suggest that BBB breakdown occurs in the immature rat after both focal and diffuse TBI. This early BBB permeability was not associated with acute inflammation in DI but was in CCI. These data also suggest that contusion is a key factor in the development of a traditional acute inflammatory response after TBI in the immature rat.

Animals↗
PubMed2005

Global inflammation predicts cardiovascular risk in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study.

BACKGROUND: Measurement of C-reactive protein (CRP), a marker of inflammation, is recommended to improve cardiovascular disease (CVD) risk stratification. However, no studies have collectively evaluated how inflammatory markers cluster empirically and relate to angiographic coronary artery disease and CVD events. METHODS: From the WISE study, 580 women with fasting plasma samples of inflammatory markers (interleukin [IL]-6, IL-18, tumor necrosis factor alpha, transforming growth factor beta, CRP, serum amyloid A [SAA], and intercellular adhesion molecules) were analyzed over a median of 4.7 years follow-up. All women were referred for coronary angiography (1996-2000) to evaluate suspected myocardial ischemia. RESULTS: In factor analysis, a "proinflammation" factor (cluster) loaded on IL-6, CRP, and SAA (r = 0.63-0.87); a "proinflammation and anti-inflammation" cluster loaded on IL-18 and tumor necrosis factor alpha (r = 0.72, 0.77); and an "immunosuppressive" factor loaded singly on transforming growth factor beta (r = 0.96). No cluster was independently associated with angiographic coronary artery disease. However, quartile increases of the "proinflammation" cluster (IL-6, CRP, and SAA) yielded death rates of 2.6%, 7.2%, 13.1%, 26.6%, respectively (P < .0001). Women with > or = 2 of 3 proinflammation markers in the upper quartile had an adjusted relative risk of death of 4.21 (95% CI 1.91-9.25), a higher conferred risk than any single marker alone, all of which were roughly equally predictive. CONCLUSIONS: Although IL-6, CRP, and SAA all predict CVD risk in women, development of global measures of inflammation and simply counting the number of markers with high levels improve CVD risk stratification. In addition, results indicate that the adverse impact of inflammation may be largely through other mechanisms than promotion of atherogenesis (ie, destabilization of vulnerable plaques).

Adult↗
PubMed2026

Glial Connexin-43 Is a Pathogenic Mechanism Promoting Gut Inflammation in Postoperative Ileus Induced by Gut Surgical Manipulation With Potential Relevance to Humans.

BACKGROUND & AIMS: Abdominal surgery often precipitates postoperative ileus (POI), a frequent and severe gastrointestinal (GI) motility disorder, through mechanisms that involve intestinal inflammation. Emerging data show that enteric glia acquire a reactive phenotype that aggravates POI, but how glia exert this effect remains unclear. Enteric glia express connexin-43 hemichannels (gCx43), which are implicated in neurological and inflammatory disorders. Thus, we aimed to decipher contributions of glial connexin-43 (Cx43) in the pathophysiology of POI. METHODS: We induced POI in mice using in vivo intestinal manipulation and used glial Cx43cKO (Sox10CreERT2;Cx43fl/fl) or RiboTag (Sox10CreERT2/Rpl22HA/+) mice to evaluate Cx43-dependent signaling. Human enteric glial cultures (hEGC) and muscularis externa obtained during intestinal surgery translated findings to patients. Transcriptome analysis, immunofluorescence co-labeling, Western blots, and Cx43 hemichannel activation were used for quantitative analysis. RESULTS: Cx43 is the highest expressed connexin in enteric glia in mice and humans. Up-regulation of Cx43 occurs in various disease models linked to POI, GI surgical trauma, inflammation, immune cell activation, and enteric gliosis. In the mouse POI model, glial Cx43-deletion reduces glial reactivity, pro-inflammatory signals, upregulates host protection genes, regulates immune cell activation, and prevents enteric neuropathy. In hEGCs, interleukin (IL)-1&#x3b2; induction opens Cx43 and stimulates release of IL-6 and C-C motif ligand 2 (CCL2). The Cx43 peptide inhibitor, 43Gap26, inhibits glial Cx43 activation, reduces IL-6 release, and blocks upregulation of macrophage activation factors and immune cell regulation factors. Surgical intestinal trauma in patients upregulates Cx43 during inflammation and enteric gliosis in mouse POI. CONCLUSIONS: Glial Cx43 signaling promotes enteric gliosis, immune cell activation, inflammation, and enteric neuropathy in mice with potential translatability to humans after intestinal surgical trauma and mechanical stress in POI. Interventions that block glial Cx43 activation may be protective against POI development.

Animals↗
PubMed2024

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts.

Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N&#xa0;= 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.

Humans↗
PubMed2004

Novel endogenous small molecules as the checkpoint controllers in inflammation and resolution: entrée for resoleomics.

Endogenously-generated small chemical mediators or autacoids play key roles in controlling inflammation and its organized resolution. Among them, lipoxins are the trihydroxy-tetraene-containing eicosanoids that are generated primarily by tight cell-cell interactions by way of transcellular biosynthesis and serve as local endogenous anti-inflammatory mediators. These "stop signals" in inflammation and other related processes may be involved in switching the cellular response from additional PMN recruitment toward monocytes (in a nonphlogistic fashion) that could lead to resolution of the inflammatory response or promotion of repair and healing. ASA impinges on this homeostatic system and evokes the endogenous biosynthesis of the carbon 15 epimers of lipoxins, namely ATLs, that mimic the bioactions of native LX in several biologic systems and, thus, can modulate in part, the beneficial actions of ASA in humans. Moreover, the temporal and spatial components in LX formation and actions are important determinants of their impact during an acute inflammatory reaction. Generation of lipid (ie, ATL) versus protein (ie, ANXA1) mediators during the host inflammatory response display different time courses. The temporal difference suggests that ALX could regulate PMN by interacting with each class of ligands within specific phases of the inflammatory response. ALX is the first cloned lipoxygenase-derived eicosanoid receptor. The signaling pathways and bioactions of ALX are cell type-specific. In agreement with in vitro results, ALX agonists, namely LXA4 and 15-epi-LXA4 and their stable analogs, regulate PMN during acute inflammation. In addition, it seems that LXs also display organ-specific actions, in addition to host defense and immune roles in the eye, kidney, lung, and oral and gastrointestinal tract and within bone marrow progenitors, possibly involving stem cells. The development of these few synthetic stable analogs has provided valuable tools to evaluate the biologic roles, significance, and pharmacologic actions of ALX and provided novel therapies for inflammatory diseases. The relationship between LX generation and current NSAID therapies is more intertwined than currently appreciated. ASA inhibits COX-1 and converts COX-2 into an ASA-triggered lipid mediator-generating system that produces an array of novel endogenous local autacoids from dietary omega-3 PUFA. Some of the local autacoids display potent anti-inflammatory or antineutrophil recruitment activity as well as impinge on the role of these compounds in resolution, and, thus, are termed "resolvins." It is not surprising that investigators recently found a protective action for COX-2 in cardiovascular disease. Together with the lipoxins and 15-epi-lipoxins, the identification of the resolvins gives us new avenues of approach in considering therapies for inflammation, cardiovascular diseases and cancer.

Animals↗
PubMed2000

Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches.

Glutathione (L-gamma-glutamyl-L-cysteinylglycine, GSH), is a vital intra- and extracellular protective antioxidant. Glutathione is synthesized from its constituent amino acids by the sequential action of gamma-glutamylcysteine synthetase (gamma-GCS) and GSH synthetase. The rate-limiting enzyme in GSH synthesis is gamma-GCS. Gamma-GCS expression is modulated by oxidants, phenolic antioxidants, and inflammatory and anti-inflammatory agents in various mammalian cells. The intracellular GSH redox homeostasis is strictly regulated to govern cell metabolism and protect cells against oxidative stress. Growing evidence has suggested that cellular oxidative processes have a fundamental role in inflammation through the activation of stress kinases (JNK, MAPK, p38) and redox-sensitive transcription factors such as NF-kappaB and AP-1, which differentially regulate the genes for proinflammatory mediators and protective antioxidant genes such as gamma-GCS, Mn-SOD, and heme oxygenase-1. The critical balance between the induction of proinflammatory mediators and antioxidant genes and the regulation of the levels of GSH in response to oxidative stress at the site of inflammation is not known. Knowledge of the mechanisms of redox GSH regulation and gene transcription in inflammation could lead to the development of novel therapies based on the pharmacological manipulation of the production of this important antioxidant in inflammation and injury. This FORUM article features the role of GSH levels in the regulation of transcription factors, whose activation and DNA binding leads to proinflammatory and antioxidant gene transcription. The potential role of thiol antioxidants as a therapeutic approach in inflammatory lung diseases is also discussed.

Animals↗
PubMed2006

Inflammation in Alzheimer disease: driving force, bystander or beneficial response?

Alzheimer disease is a progressive dementia with unknown etiology that affects a growing number of the aging population. Increased expression of inflammatory mediators in postmortem brains of people with Alzheimer disease has been reported, and epidemiological studies link the use of anti-inflammatory drugs with reduced risk for the disorder. On the initial basis of this kind of evidence, inflammation has been proposed as a possible cause or driving force of Alzheimer disease. If true, this could have important implications for the development of new treatments. Alternatively, inflammation could simply be a byproduct of the disease process and may not substantially alter its course. Or components of the inflammatory response might even be beneficial and slow the disease. To address these possibilities, we need to determine whether inflammation in Alzheimer disease is an early event, whether it is genetically linked with the disease and whether manipulation of inflammatory pathways changes the course of the pathology. Although there is still little evidence that inflammation triggers or promotes Alzheimer disease, increasing evidence from mouse models suggests that certain inflammatory mediators are potent drivers of the disease. Related factors, on the other hand, elicit beneficial responses and can reduce disease.

Alzheimer Disease↗