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At least 145 records · Page 8Linked to original sources
PubMed2005

TNF regulates leukocyte-endothelial cell interactions and microvascular dysfunction during immune complex-mediated inflammation.

1. The aim of this study was to assess directly the role of TNF in immune complex-induced leukocyte-endothelial cell interactions and microvascular dysfunction. 2. Intravital microscopy was used to examine immune complex-induced leukocyte rolling, adhesion and emigration and microvascular permeability in cremasteric postcapillary venules in wild-type and TNF(-/-) mice. The reverse passive Arthus (RPA) reaction was used to localize immune complex formation to the cremaster muscle. 3. In wild-type mice, immune complex deposition induced a reduction in leukocyte rolling velocity and increases in leukocyte adhesion and emigration. In TNF(-/-) mice, the immune complex-induced reduction in leukocyte rolling velocity was significantly attenuated, and leukocyte adhesion and emigration were also significantly reduced relative to responses in wild-type mice. 4. The alterations in TNF(-/-) mice were associated with decreased expression of endothelial P-selectin and VCAM-1, and an absence of E-selectin-dependent rolling normally seen in wild-type mice at the peak of the response. In addition, the level of immune complex-induced microvascular permeability was attenuated in TNF(-/-) mice. 5. These findings demonstrate that in immune complex-induced inflammation, TNF promotes leukocyte rolling and adhesive interactions, and entry of leukocytes into sites of immune complex deposition, in part via the increased expression and/or function of endothelial P-selectin, E-selectin and VCAM-1. In addition, this increase in leukocyte recruitment mediated by TNF correlates directly with an increase in microvascular injury.

Animals↗
PubMed1979

Immune-mediated inflammation in the lumen of the bovine mammary gland.

Two groups of cows were sensitized to ovalbumin (OA) during lactation by a subcutaneous injection of OA either in Freund's complete or incomplet adjuvant; two groups of animals injected with the respective adjuvants only served as controls. Intraluminal infusion of microgram quantities of OA in uninflamed mammary glands elicited inflammation, i.e., release of leukocytes into the milk, only in the animals previously sensitized to OA. This indicates that an antigen-specific inflammatory pathway can be established in the mammary gland by parenteral sensitization. Immune-mediated release of leukocytes into the milk could not be reproduced by infusing complement fixing. OA-anti-OA complexes into the lumen of uninflamed glands of unsensitized cows.

Animals↗
PubMed2003

Inflammation-mediated retinal edema in the rabbit is inhibited by topical nepafenac.

The purpose of this study was to evaluate the ability of the nonsteroidal anti-inflammatory drug nepafenac to prevent development of mitogen-induced pan-retinal edema following topical ocular application in the rabbit. Anesthetized Dutch Belted rabbits were injected intravitreally (30 microg/20 microL) with the mitogen concanavalin A to induce posterior segment inflammation and thickening (edema) of the retina. The Heidelberg Retina Tomograph was used to generate edema maps using custom software. Blood-retinal barrier breakdown was assessed by determining the protein concentration in vitreous humor, whereas analysis of PGE2 in vitreous humor was performed by radioimmunoassay. Inhibition of concanavalin A-induced retinal edema was assessed 72 h after initiation of topical treatment with nepafenac (0.1-1.0%, w/v), dexamethasone (0.1%), VOLTAREN (0.1%), or ACULAR (0.5%). Concanavalin A elicited marked increases in vitreal protein and PGE2 synthesis at 72 h postinjection. Retinal thickness was also increased by 32%, concomitant with the inflammatory response. Topical application of 0.5% nepafenac produced 65% reduction in retinal edema which was correlated with 62% inhibition of blood-retinal barrier breakdown. In a subsequent study, 0.5% nepafenac significantly inhibited (46%) blood-retinal barrier breakdown concomitant with near total suppression of PGE2 synthesis (96%). Neither Voltaren nor Acular inhibited accumulation of these markers of inflammation in the vitreous when tested in parallel. This study demonstrates that nepafenac exhibits superior pharmacodynamic properties in the posterior segment following topical ocular dosing, suggesting a unique therapeutic potential for a variety of conditions associated with retinal edema.

Administration, Topical↗
PubMed1997

A newly recognized pathway for the negative regulation of mast cell-dependent hypersensitivity and inflammation mediated by an endogenous cell surface receptor of the gp49 family.

Mast cells are constitutively present at the portals between self and nonself, and contain a large and diverse complement of proinflammatory mediators. These characteristics suggest that the activation of mast cells must be carefully regulated in vivo. Regulation of pathologic and physiologic mast cell activation has been traditionally associated simply with the presence or absence of an activating signal. We examine here evidence supporting a new paradigm: mast cell homeostasis may result from inhibition of activation mediated by receptors on the surface of mast cells, typified by a member of the gp49 family.

Amino Acid Sequence↗
PubMed2005

Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation.

Thalidomide was developed in the 1950s as a sedative drug and withdrawn in 1961 because of its teratogenic effects, but has been rediscovered as an immuno-modifying drug. It has been administered successfully for the treatment of erythema nodosum leprosum, aphthous ulceration in HIV disease, inflammatory bowel diseases, and multiple myeloma. So far, investigations into the mode of action of thalidomide have focused on lymphocytes and vascular endothelial cells and have shown that this agent inhibits the production of tumor necrosis factor (TNF)-alpha and is an inhibitor of tumor angiogenesis. Recently, other immunological effects of this drug have been gaining attention, including attenuation of neutrophil activation and inhibition of myelo-proliferative responses. In autoimmune diseases, inflammation is characterized by an influx of granulocytes, and the association of granulocytes with gastrointestinal ulcer formation or rheumatic arthritis has been well documented. The suppressive effect of thalidomide on the activation of the nuclear transcription factor NF-(kappa)B may explain these effects of thalidomide. NF-(kappa)B is retained in the cytoplasm with I(kappa)B(alpha), and is activated by a wide variety of inflammatory stimuli including TNF, IL-1 and endotoxin followed by its translocation to the nucleus. Constitutive activation of NF-(kappa)B has been detected in various inflammatory diseases, while angiogenesis and organogenesis also require NF-(kappa)B activation. Thalidomide, on the other hand, has been shown to selectively suppress NF-(kappa)B activation induced by inflammatory mediators. NF-(kappa)B is known to be located downstream of proliferative and/or survival signaling induced by growth factors, which regulate anti-apoptotic genes. Myeloid cells in vitro, however, have been found to proceed to apoptosis as the result of the treatment with thalidomide and subsequent inactivation of NF-(kappa)B. These findings are consistent with clinical symptoms that showed the recovery from leukocytosis and/or neutrophilia after the administration of thalidomide. These findings shed new light on the anti-inflammatory properties of thalidomide and suggested that they may inhibit granulocyte-mediated tissue injury.

Animals↗
PubMed2006

The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology.

Disturbance to early brain development is implicated in several neuropsychiatric disorders including autism, schizophrenia, and mental retardation. Epidemiological studies have indicated that the risk of developing these disorders is enhanced by prenatal maternal infection, presumably as a result of neurodevelopmental defects triggered by cytokine-related inflammatory events. Here, we demonstrate that the effects of maternal immune challenge between middle and late gestation periods in mice are dissociable in terms of fetal brain cytokine responses to maternal inflammation and the pathological consequences in brain and behavior. Specifically, the relative expression of pro- and anti-inflammatory cytokines in the fetal brains in response to maternal immune challenge may be an important determinant among other developmental factors for the precise pathological profile emerging in later life. Thus, the middle and late gestation periods correspond to two windows with differing vulnerability to adult behavioral dysfunction, brain neuropathology in early adolescence, and of the acute cytokine responses in the fetal brain.

Analysis of Variance↗
PubMed2003

VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization.

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte-mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.

Animals↗
PubMed1992

Hyperosmolality impairs ammonia-mediated inflammation: implications for the renal medulla.

Although ammonia modifies the third component of complement (C3) and activates the alternative pathway, inflammation is not seen in the renal medulla where ammonia concentrations are normally elevated. We examined the effect of the unique hyperosmolar milieu of the renal medulla on the interaction of ammonia with C3 and the capacity of ammonia-modified C3 (NH3.C3) to induce cytolytic injury and stimulate neutrophils (PMN). Incubation of purified human C3 with ammonia in concentrations found in urine results in significant disruption of the C3 thiolester bond compared with ammonia-free controls. Coincubation with urinary osmolytes and hyperosmolar NaCl and urea does not impair thiolester disruption over a range of ammonia concentrations. However, hyperosmolar NaCl and urea virtually abolish cytolytic injury mediated by the alternative pathway. Coincubation with the organic osmolytes betaine, sorbitol, and inositol fails to reverse this inhibitory effect of hyperosmolar NaCl and urea. Hyperosmolar NaCl and urea also suppress lytic injury mediated by ammonia and complement in MDCK, a cell line derived from canine distal tubular epithelium. Both PMN degranulation and respiratory burst responses to NH3.C3 are significantly blunted in the presence of hyperosmolar NaCl and urea. Hyperosmolality also impairs PMN responses to the formyl peptide N-formyl-Met-Leu-Phe and phorbol 12-myristate 13-acetate (PMA). Therefore, in an in vitro setting of hyperosmolar NaCl and urea, amidation of C3 occurs, but subsequent membrane-directed and receptor-mediated functions of NH3.C3 are markedly impaired.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonia↗
PubMed1991

Calpain and kininogen mediated inflammation.

On the basis of previous findings that N-acetyl nonapeptide from the human calpain I large subunit has chemotactic activity for neutrophils, more than 30N-acetyl and unmodified peptides which have N-terminal amino acid sequences of the large and small subunits of calpains I and II were synthesized and their chemotactic activity was estimated. In addition to the above N-acetyl nonapeptide from the calpain I large subunit, an unmodified nonapeptide from the calpain II large subunit and several N-acetyl peptides of different lengths from the small subunit showed chemotactic activity. Furthermore, when calpain was incubated with either high molecular weight or low molecular weight kininogen, kinin liberation occurred with simultaneous inhibition of calpain by kininogen. These data suggest that chemical mediators generated from the calpain-kininogen system may participate in migration and accumulation of neutrophils to the inflammatory locus.

Amino Acid Sequence↗
PubMed1998

Mechanisms of cell signaling in immune-mediated inflammation.

Deposition of immune complexes in tissues is the pathogenic mechanism underlying tissue injury in a number of diverse clinical conditions affecting the skin, joints, blood vessels and renal glomeruli. Initial approaches to the understanding of these conditions have stressed the roles of both the activation of the complement system and the accumulation of polymorphonuclear leukocytes as the main molecular and cellular mechanisms explaining the sequence of events leading to tissue damage. Recent findings on (i) the molecular biology of the leukocyte chemoattractants, (ii) the chemical structure and function of receptors for the Fc portion of the antibody molecule and (iii) the signaling events coupled to the engagement of these receptors have led to an understanding of the biochemical events involved in immune-complex injury and have provided a promising avenue for the development of therapeutic approaches. This review will focus on our current understanding of signal transduction events in the effector phase of immune-complex-mediated tissue injury.

Anaphylatoxins↗
PubMed2004

(-)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial activation and protects against inflammation-mediated dopaminergic neuronal injury.

Microglial activation is believed to play a pivotal role in the selective neuronal injury associated with several neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease. We provide evidence that (-)-epigallocatechin gallate (EGCG), a major monomer of green tea polyphenols, potently inhibits lipopolysaccharide (LPS)-activated microglial secretion of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) through the down-regulation of inducible NO synthase and TNF-alpha expression. In addition, EGCG exerted significant protection against microglial activation-induced neuronal injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. Our study demonstrates that EGCG is a potent inhibitor of microglial activation and thus is a useful candidate for a therapeutic approach to alleviating microglia-mediated dopaminergic neuronal injury in PD.

Analysis of Variance↗
PubMed2006

Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation.

Nedd4 family interacting protein-1 (Ndfip1) is a protein whose only known function is that it binds Nedd4, a HECT-type E3 ubiquitin ligase. Here we show that mice lacking Ndfip1 developed severe inflammation of the skin and lung and died prematurely. This condition was due to a defect in Ndfip1(-/-) T cells. Ndfip1(-/-) T cells were activated, and they proliferated and adopted a T helper 2 (Th2) phenotype more readily than did their Ndfip1(+/+) counterparts. This phenotype resembled that of Itchy mutant mice, suggesting that Ndfip1 might affect the function of Itch, an E3 ubiquitin ligase. We show that T cell activation promoted both Ndfip1 expression and its association with Itch. In the absence of Ndfip1, JunB half-life was prolonged after T cell activation. Thus, in the absence of Ndfip1, Itch is inactive and JunB accumulates. As a result, T cells produce Th2 cytokines and promote Th2-mediated inflammatory disease.

Animals↗
PubMed2004

Protective effect of the SOD/catalase mimetic MnTMPyP on inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuronal-glial cultures.

Reactive oxygen species (ROS) produced by activated microglia are deleterious to neurons. In this study, we studied the effect of Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), a superoxide dismutase/catalase mimetic, on the lipopolysaccharide (LPS)-induced degeneration of dopaminergic neurons in rat mesencephalic neuroglia cultures. MnTMPyP exhibited a significantly protective effect against LPS (5 ng/ml)-induced neurotoxicity as determined by [3H]dopamine uptake and immunocytochemical analysis. MnTMPyP significantly attenuated LPS-induced production of superoxide free radical and prostaglandin E(2) (PGE(2)) in microglia. These results indicate that MnTMPyP may potentially be used for the treatment of inflammation-related degenerative neurological disorders.

Analysis of Variance↗
PubMedDate not supplied

The effects of inflammation-mediated osteoporosis (IMO) on the skeletal Ca/P ratio and on the structure of rabbit bone and skin collagen.

The relationships between the skeletal Ca/P ratio (used as an index of bone quality) and structural changes in the bone and skin was studied in inflammatory mediated osteoporosis (IMO). The bone Ca/P ratio in IMO rabbits was significantly lower than in controls. Also, severe alterations were detected at the ultrastructural level in bone and skin collagen fibrils from IMO rabbits.

Absorptiometry, Photon↗
PubMed2002

Role of human heme oxygenase-1 in attenuating TNF-alpha-mediated inflammation injury in endothelial cells.

Heme oxygenase (HO) is the rate-limiting enzyme in the formation of bilirubin, an antioxidant, and carbon monoxide (CO), a cell cycle modulator and a vasodilator. Cyclooxygenase (COX) is a hemeprotein that catalyzes the conversion of arachidonic acid (AA) to various prostanoids, which play an important role in the regulation of vascular endothelial function in normal and disease states. The influence of suppression or overexpression of HO isoforms on COX expression and synthesis of prostanoids is of considerable physiological importance. Consequently, the goal of the present study was to determine whether the heme-HO system regulates COX enzyme expression and activity in vascular endothelial cells in the absence and presence of TNF-alpha (100 ng/ml). Endothelial cells stably transfected with the retrovirus containing the human HO-1 gene exhibited a several-fold increase in HO-1 protein levels, which was accompanied by an increase in HO activity and a marked decrease in PGE(2) and 6-keto PGF(1alpha) levels. We also assessed the effect of retrovirus-mediated HO-1 gene transfer in the sense and antisense orientation on HO-1 expression and cell cycle progression in human endothelial cells. The levels of CO and HO activity were increased in cells transduced with the HO-1 sense and were greatly suppressed in cells transduced with HO-1 antisense as compared to control sham-transduced cells (P < 0.05). The percentage of the G(1)-phase in cells transduced with HO-1 significantly increased (41.4% +/- 9.1) compared with control endothelial cells (34.8% +/- 4.9). We measured COX activity by determining the levels of PGI(2) and PGE(2). The levels of PGI(2) decreased in cells transduced with HO-1 sense and increased in cells transduced with HO-1 in antisense orientation. The expression of p27 was also studied and showed a marked decrease in cells transduced with HO-1 sense and a marked increase in the HO-1 antisense transduced cells. Cell cycle analysis of endothelial cell DNA distributions indicated that the TNF-alpha-induced decrease in the proportion of G(1)-phase cells and increase in apoptotic cells in control cultures could be abrogated by transfection with HO-1 in the sense orientation. Tin mesoporphyrin (SnMP) reversed the protective effect of HO-1. These results demonstrate that overexpressing HO-1 mitigated the TNF-alpha-mediated changes in cell cycle progression and apoptosis, perhaps by a decrease in the levels of COX activity.

6-Ketoprostaglandin F1 alpha↗
PubMed2006

The role of CD69 in acute neutrophil-mediated inflammation.

The leukocyte activation marker CD69 functions as a negative regulator of the immune response, both in NK-dependent tumor rejection and in the inflammation associated with lymphocyte-dependent collagen-induced arthritis. In contrast, it has been reported that CD69-deficient mice are refractory to the neutrophil-dependent acute inflammatory response associated with anti-type II collagen antibody-induced arthritis (CAIA), suggesting a positive regulatory role for CD69 in neutrophil function during arthritis induction. To clarify this discrepancy, the CAIA response was independently analyzed in our CD69-deficient mice. In these experiments, the inflammatory response was unaffected by CD69 deficiency. Additionally, the in vivo down-regulation of CD69 expression by treatment of wild-type mice with the anti-CD69 mAb 2.2, which mimics the CD69-deficient phenotype, did not affect the course of arthritis in this model. Moreover, down-regulation of CD69 expression increased expression in arthritic joints of key inflammatory mediators, including IL-1beta, IL-6 and the chemokine MCP-1. Neutrophil accumulation in zymosan-treated air pouches and in thioglycolate-treated peritoneal cavities was also unaffected in CD69-deficient mice. In addition, CD69 expression was absent in activated neutrophils. Taken together, these results rule out a significant stimulatory role for CD69 in acute inflammatory responses mediated by neutrophils.

Animals↗