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At least 343 records · Page 19Linked to original sources
PubMed2002

Cellular mechanisms of neurogenic inflammation.

Since the initial observations that stimulation of sensory neurons produces vasodilation, plasma extravasation, and hypersensitivity, much progress has been made in understanding the etiology of neurogenic inflammation. Studies have focused largely on the role of the neuropeptides, substance P and calcitonin gene-related peptide, which are released in the periphery by activation of small diameter sensory neurons. Recent work, however, has begun to emphasize the cellular mechanisms involved in regulating the release of proinflammatory substances from sensory neurons. In this perspective, discussion centers on a number of inflammatory mediators that activate various signal transduction pathways to augment excitability of and transmitter release from sensory neurons. Emphasis is placed on those pathways where multiple lines of evidence support their importance in initiating neurogenic inflammation. Recent studies, however, support the notion that there are novel compounds released during injury that can stimulate or sensitize sensory neurons. Furthermore, only now are intracellular signaling pathways that have been identified in other cell systems being studied in sensory neurons to establish their role in neurogenic inflammation. The challenge remains to ascertain the critical transduction pathways that regulate transmitter release from sensory neurons since this phenomenon triggers neurogenic inflammation. In addition, the cellular mechanisms involved in alterations in neuronal excitability during injury and the cellular pathways that maintain the inflammatory response over time need to be determined. With these advances, we will be able to develop therapeutic interventions to minimize deleterious consequences of neurogenic inflammation.

Animals↗
PubMed1999

Cellular and molecular mechanisms of inflammation and thrombosis.

In the last 20 years, the cellular and molecular mechanisms of inflammation and thrombosis have been characterised. These are essentially cell adhesion processes which are regulated by vascular endothelium. Many of the cell adhesion molecules and leucocyte chemoattractants expressed and generated at sites of inflammation have been sequenced and cloned. These inflammatory molecules work together in concert to mediate the adhesion between leucocytes, platelets and vascular endothelium which occurs during the occlusive, thromboembolic, reperfusion and septic complications of atherosclerotic and diabetic vascular diseases. This review aims to summarise our current understanding of the molecular basis of these disorders and the therapeutic implications.

Animals↗
PubMed1998

In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation.

Progression to end-stage renal failure is the final common pathway of many forms of glomerular disease, independent of the type of initial insult. Progressive glomerulopathies have in common persistently high levels of urinary protein excretion and tubulointerstitial lesions at biopsy. Among the cellular mechanisms that may determine progression regardless of etiology, the traffic of excess proteins filtered from glomerulus in renal tubule may have functional importance by initiating interstitial inflammation in the early phase of parenchymal injury. This study analyzes the time course and sites of protein accumulation and interstitial cellular infiltration in two different models of proteinuric nephropathies. In remnant kidneys after 5/6 renal mass ablation, albumin and IgG accumulation by proximal tubular cells was visualized in the early stage, preceding interstitial infiltration of MHC-II-positive cells and macrophages. By double-staining, infiltrates developed at or near tubules containing intracellular IgG or luminal casts. This relationship persisted thereafter despite more irregular distribution of infiltrate. Similar patterns were found in an immune model (passive Heymann nephritis), indicating that the interstitial inflammatory reaction develops at the sites of protein overload, regardless of the type of glomerular injury. Osteopontin was detectable in cells of proximal tubules congested with protein in both models at sites of interstitial infiltration, and by virtue of its chemoattractive action this is likely mediator of a proximal tubule-dependent inflammatory pathway in response to protein load. Protein overload of tubules is a key candidate process translating glomerular protein leakage into cellular signals of interstitial inflammation. Mechanisms underlying the proinflammatory response of tubular cells to protein challenge in diseased kidney should be explored, as well as ways of limiting protein reabsorption/deposition to prevent consequent inflammation and progressive disease.

Albumins↗
PubMedDate not supplied

[Cellular and molecular mechanisms of allergic respiratory tract inflammation].

Knowledge of the cellular and molecular aspects of allergic airway inflammation has increased greatly. It is now clear that the type of specific immune response is determined by the preferential activation of CD4+ T cell subsets which secrete defined patterns of cytokines, and it has been suggested that Th2-like cells, able to produce IL-4 and IL-5, but not IFN-gamma, play an important role in the induction and maintenance of allergic airway inflammation. It has been demonstrated, moreover, that mast cells can secrete cytokines which are analogous to those produced by Th2-like cells. It is thus possible that both mast cells and Th2-like cells are involved in the induction and maintenance of allergic airway inflammation. We review here the genetic and environmental factors predisposing to allergic respiratory diseases, especially those potentially favoring the development of Th2-like cells. Particular attention is paid to the possible role of the antigen presenting cells, HLA class II molecules, T cell repertoire, and microenvironmental cytokines. We also discuss the crucial role that IL-4 plays in the development of Th2-like cells from their precursors as well as hypotheses concerning the possible molecular alterations responsible for the overexpression of the IL-4 gene in atopic subjects. This new information certainly facilitates the planning of preventive and treatment tactics for bronchial asthma.

Antigen-Presenting Cells↗
PubMedDate not supplied

Total parenteral nutrition alters molecular and cellular indices of intestinal inflammation in neonatal piglets.

BACKGROUND: The adverse effects of TPN on systemic immunity are well-documented; however, the impact of IV feeding on neonatal intestinal immunity is unknown. METHODS: A piglet TPN model was used to compare immune cell composition within the intestinal epithelium and lamina propria of parenterally and orally fed piglets. RESULTS: Small intestinal weight of piglets maintained intravenously was reduced 50% after 7 days. Intestinal atrophy in piglets fed parenterally was evidenced by decreased width of intestinal villi and colon cuffs and reduced intestinal crypt depth. The numbers of CD4+ and CD8+ T lymphocytes were threefold greater within the lamina propria of jejunal and ileal villi of piglets supported intravenously. Inverse correlations were observed between villus height or width and T-lymphocyte numbers (r = -.80; p < .05). Major histocompatibility complex class II mRNA expression, an indicator of localized inflammation, was increased in the ileum and colon of piglets receiving parenteral nutrition. Goblet cell numbers were two-fold greater in jejunal and ileal villi, and mast cells were more abundant in the colon of piglets fed parenterally. Furthermore, jejunal T-lymphocyte numbers were correlated with goblet cell numbers (r = .80; p = .01). CONCLUSIONS: These data identify molecular and cellular indices of intestinal inflammation that are responsive to IV feeding in neonates and provide a novel framework to investigate mechanisms underlying gut atrophy during TPN.

Animals↗
PubMed2004

Immunohistochemical analysis of heme oxygenase-1 in preneoplastic and neoplastic lesions during chemical hepatocarcinogenesis.

Heme oxygenase (HO) breaks down the pro-oxidant heme into carbon monoxide, iron and the antioxidant biliverdin. The isoform HO-1 plays an effective role to counteract oxidative damage and to control inflammation. Prolonged cellular damage due to chronic inflammation is one of the reasons leading to the development of tumours. The aim of this work was to investigate HO-1 expression and localization along the different stages of chemically induced hepatocarcinogenesis (HCC) and the occurring morphological changes. To provoke sustained oxidative stress and chronic inflammation, CF1 mice received dietary p-dimethylaminoazobenzene (DAB, 0.5%, w/w) during a whole period of 14 months. HO-1 expression increased along the experimental trial in morphologically normal hepatocytes in DAB-treated animals. HO-1 expression diminished in altered hepatic foci (AHF) and oval cells and early preneoplastic lesions. Otherwise, marked HO-1 overexpression was detected in Kupffer cells and macrophages surrounding necrotic and nodular areas. Adenomas showed decreased HO-1 immunostaining. In hepatocellular carcinomas, an inverse relationship was found between the immunohistochemical expression of HO-1 and the degree of tumour differentiation, being negative in poorly differentiated tumours. In our experimental model, down modulation of HO-1 expression correlated with malignancy progression. Thus, our data point to activation of HO-1 as a potential therapeutic tool.

Adenoma↗
PubMed2002

Nitric oxide-induced cellular stress and p53 activation in chronic inflammation.

Free radical-induced cellular stress contributes to cancer during chronic inflammation. Here, we investigated mechanisms of p53 activation by the free radical, NO. NO from donor drugs induced both ataxia-telangiectasia mutated (ATM)- and ataxia-telangiectasia mutated and Rad3-related-dependent p53 posttranslational modifications, leading to an increase in p53 transcriptional targets and a G(2)M cell cycle checkpoint. Such modifications were also identified in cells cocultured with NO-releasing macrophages. In noncancerous colon tissues from patients with ulcerative colitis (a cancer-prone chronic inflammatory disease), inducible NO synthase protein levels were positively correlated with p53 serine 15 phosphorylation levels. Immunostaining of HDM-2 and p21(WAF1) was consistent with transcriptionally active p53. Our study highlights a pivotal role of NO in the induction of cellular stress and the activation of a p53 response pathway during chronic inflammation.

Animals↗
PubMed2002

Diverse cellular and apoptotic responses to variant shapes of UHMWPE particles in a murine model of inflammation.

The wear of orthopaedic prostheses results in the release of a markedly heterogeneous assortment of particulate debris, with respect to both size and shape. Although particle size has been extensively examined, the role of particle shape in adverse inflammatory reactions to debris remains unclear. Using an in vivo murine model of inflammation, we assessed tissue responses to globular and to elongated ultra-high molecular weight polyethylene (UHMWPE) particles with a similar surface area, and investigated whether inflammation and cellular apoptosis varied with particle shape in the debris-tissue interaction. Histological changes of UHMWPE-stimulated pouch membrane were assessed using a computerized image analysis system. Quantitative real time PCR and ELISA were performed to assess mRNA expression and protein level of the cytokines, and TUNEL assays were conducted to quantify apoptotic cells. The data revealed that elongated particles generated more active inflammatory air pouches, stimulated more severe membrane proliferation and the inflammatory cellular infiltration compared to globular particles. Increased levels of IL-1beta and TNFalpha were detected in the lavage and homogenate of pouches stimulated with elongated particles in comparison to pouches with globular particles, and the apoptotic assay indicated more severe apoptotic changes within the inflammatory membrane provoked with elongated particles. Our results suggest that cellular responses to UHMWPE wear debris are dependent on the shape of the particles.

Animals↗
PubMedDate not supplied

Alzheimer's disease and inflammation: a review of cellular and therapeutic mechanisms.

1. Of the neurodegenerative diseases that cause dementia, Alzheimer's disease (AD) is the most common. Three major pathologies characterize the disease: senile plaques, neurofibrillary tangles and inflammation. We review the literature on events contributing to the inflammation and the treatments thought to target this pathology. 2. The senile plaques of AD consist primarily of complexes of the beta-amyloid protein. This protein is central to the pathogenesis of the disease. 3. Inflammatory microglia are consistently associated with senile plaques in AD, although the classic inflammatory response (immunoglobulin and leucocyte infiltration) is absent. beta-Amyloid fragments appear to mediate such inflammatory mechanisms by activating the complement pathway in a similar fashion to immunoglobulin. 4. Epidemiological studies have identified a reduced risk of AD in patients with arthritis and in leprosy patients treated with anti-inflammatory drugs. Longitudinal studies have shown that the consumption of anti-inflammatory medications reduces the risk of AD only in younger patients (< 75 years). 5. There is a considerable body of in vitro evidence indicating that the inflammatory response of microglial cells is reduced by non-steroidal anti-inflammatory drugs (NSAID). However, no published data are available concerning the effects of these medications on brain pathology in AD. 6. Cyclo-oxygenase 2 enzyme is constitutively expressed in neurons and is up-regulated in degenerative brain regions in AD. Non-steroidal anti-inflammatory drugs may reduce this expression. 7. Platelets are a source of beta-amyloid and increased platelet activation and increased circulating beta-amyloid have been identified in AD. Anti-platelet medication (including NSAID) would prevent such activation and its potentially harmful consequences. 8. Increased levels of luminal beta-amyloid permeabilizes the blood-brain barrier (BBB) and increases vasoconstriction of arterial vessels, paralleling the alterations observed with infection and inflammation. Cerebral amyloidosis is highly prevalent in AD, compromising the BBB and vasoactivity. Anti-inflammatory medications may alleviate these problems.

Aged↗
PubMed1985

Antileukocyte activity I. Systemic inhibition of cellular emigration following local inflammation.

Inflammation in progress at one site decreases edema formation at a second and separate inflammatory focus. This clinically important phenomenon is known as counter-irritation. Since its effect on leukocyte responses has not been defined, we investigated in rats the systemic anti-inflammatory effect of local irritant injection on cellular emigration, particularly monocytes. Macrophage accumulation at a subcutaneous inflammatory site was severely depressed by prior intraperitoneal irritant injection despite continued macrophage accumulation in the peritoneal cavity and normal circulating monocyte levels. The phenomenon also existed in the peritoneal cavity to subcutaneously administered irritants and involved PMNs as readily as macrophages. Anti-inflammation occurred only when the counter-irritant was injected before or simultaneously with the measured inflammatory response while the degree and duration of inhibition depended upon the nature and amount of counter-irritant injected. These studies demonstrate that local inflammation inhibits leukocyte reactivity. Transplantation of syngeneic tumor but not normal cells also produced a depression in macrophage inflammatory responses. This inhibition differed from counter-irritation by not affecting granulocytes and by being transient despite tumor persistence.

Animals↗
PubMed1992

Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation.

Interaction of T and B lymphocytes, platelets, granulocytes, macrophages and mast cells with the subendothelial extracellular matrix (ECM) is associated with degradation of heparan sulfate (HS) by a specific endoglycosidase (heparanase) activity. The enzyme is released from intracellular compartments (i.e., lysosomes, specific granules) in response to various activation signals (i.e., thrombin, calcium ionophore, immune complexes, antigens, mitogens), suggesting its regulated involvement in inflammation and cellular immunity. In contrast, various tumor cells appear to express and secrete heparanase in a constitutive manner, in correlation with their metastatic potential. Heparanase enzymes produced by different cell types may exhibit different molecular properties and substrate cleavage specificities. The platelet enzyme appears also in a latent form. It can be activated by tumor cells and thereby facilitate their extravasation in the process of metastasis. Degradation of ECM-HS by all cell types was facilitated by a proteolytic activity residing in the ECM and/or expressed by the invading cells. This proteolytic activity produced a more accessible substrate for the heparanase enzymes. Heparanase-inhibiting, nonanticoagulant species of heparin markedly reduced the incidence of lung metastasis in experimental animals. These species of heparin also significantly impaired the traffic of T lymphocytes and suppressed cellular immune reactivity and experimental autoimmune diseases. Heparanase activity expressed by intact cells (i.e., platelets, mast cells, neutrophils, lymphoma cells) was found to release active HS-bound basic fibroblast growth factor from ECM and basement membranes. Heparanase may thus elicit an indirect neovascular response in processes such as wound repair, inflammation and tumor development. The significant anticancerous effect of heparanase-inhibiting molecules may therefore be attributed to their potential inhibition of both tumor invasion and angiogenesis. Both normal leukocytic cells and metastatic tumor cells can enter the bloodstream, travel to distant sites and extravasate to the parenchyma at these sites. We suggest that heparanase is utilized for this purpose by both types of cells. Other functions (i.e., enzyme activities, adhesive interactions, chemotactic and proliferative responses) of metastatic tumor cells seem to mimic the equivalent functions of leukocytes as they migrate across blood vessels to gain access to sites of inflammation.

Animals↗
PubMed2002

Cellular network in airways inflammation and remodelling.

Chronic inflammation and airway remodelling are two key steps in asthma pathophysiology. The development of chronic airway inflammation depends upon the continuous recruitment of inflammatory cells from the bloodstream towards the bronchial mucosa and by their subsequent functional activation. The release of inflammatory mediators by activated cells contributes to the generation of a complex network which involves mobile inflammatory cells and structural cells such as epithelial cells, fibroblasts and myofibroblasts. This network is responsible for the amplification and persistence of the inflammatory process as well as for the development of a peculiar microenvironment which can directly modulate the survival of inflammatory cells in the inflamed airways. Increased cellular recruitment and activation, enhanced cell survival and cell:cell interactions are therefore the key steps in the development of chronic airway inflammation in asthma and represent the major causes for tissue damage, repair and remodelling.

Adolescent↗
PubMed1978

Cellular aspects of conjunctival inflammation induced by the synergistic action of histamine and prostaglandins.

Histamine or prostaglandin (PG) E1 or E2 administered to rabbits topically alone in high doses produced conjunctival vasodilation associated with little or no edema while their mixture at lower concentrations produced conjunctival vasodilation associated with profound edema. Sections of tissues treated with the mixture of histamine and PGE1 or PGE2 showed widespread epithelial and subepithelial inflammatory cellular infiltration. Conjunctival smears from eyes treated with the histamine/PG mixture contained small lymphocytes and polymorphonuclear leukocytes, including eosinophilic and occasionally basophilic cells. Differential staining of the polymorphs demonstrated both eosinophils and pseudoeosinophils. Histological examination of the conjunctival smears and sections of the lids obtained from eyes treated with either histamine or PGE1 or PGE2 alone did not show any detectable increase of inflammatory cells when compared to normal controls. The clinical and histological results indicate that the synergistic effect of histamine with PGs of the E-type in the conjunctiva produces an inflammatory response similar to that seen in various clinical forms of human allergic conjunctivitis. Such a response could not be produced by histamine or PGE1 or PGE2 alone even at much higher doses than in the mixture. The data indicate that an interplay of several different mediators may be crucial in the conjunctival response in allergy.

Alprostadil↗