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Biomedical subjects

S B Abramson

Publications and source records attributed to S B Abramson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Differential anti-inflammatory effects of immunosuppressive drugs: cyclosporin, rapamycin and FK-506 on inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and PGE2 production.

OBJECTIVE AND DESIGN: Cyclosporin, FK-506 and rapamycin have similar but distinct modes of interaction with cyclophilins, calcineurins and transcription factors. These immunosuppressive drugs have also been shown to inhibit cytotoxic and inflammatory responses in macrophage. Therefore, we evaluated the mechanism of action of these drugs on iNOS and COX-2 expression by macrophages, the products of which (NO and PGE2) have cytotoxic and proinflammatory activities. MATERIALS AND METHODS: The murine macrophage cell line RAW 264.7 was grown as monolayer cultures. The effects of pharmacologically relevant concentrations of cyclosporin, rapamycin and FK-506 were evaluated in the presence and absence of lipopolysaccharide (LPS) which is a known inducer of iNOS and COX-2. Subsequently the expression of iNOS and COX-2 were analyzed by Western and Northern analysis. The production of NO and PGE2 were assayed by Greiss and RIA respectively. RESULTS: Cyclosporin (1-5 microg/ml) and rapamycin (1.0-10 nM) but not FK-506 (5-10 nM) inhibited both iNOS and COX-2 expression at mRNA level which led to significant inhibition of NO and PGE2 production. CONCLUSION: These studies characterize differential mechanistic capacity of the immunophilin-binding immunosuppressive drugs (comparable to hydrocortisone) to inhibit both iNOS and COX-2 expression. Inhibition of iNOS and COX-2 mRNA accumulation by cyclosporin and rapamycin seem to be distinct. These studies also highlight potential anti-inflammatory properties of these drugs in addition to their known immunosuppressive activity.

Animals↗
PubMed2000

COX-2, NO, and cartilage damage and repair.

The production of nitric oxide (NO) and prostaglandin E2 (PGE(2)) is increased in human osteoarthritis-affected cartilage. These and other inflammatory mediators are spontaneously released by OA cartilage explants ex vivo. The excessive production of nitric oxide inhibits matrix synthesis, and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, nitric oxide promotes cellular injury, and renders the chondrocyte susceptible to cytokine-induced apoptosis. PGE(2) exerts both anabolic and catabolic effects on chondrocytes, depending on the microenvironment and physiological condition. Thus, NO and PGE(2), produced by activated chondrocytes in diseased cartilage, may modulate disease rogression in osteoarthritis, and should therefore be considered potential targets for therapeutic intervention

Cartilage, Articular↗
PubMed1999

The pleiotropic functions of aspirin: mechanisms of action.

Recent studies have suggested that aspirin and aspirin-like compounds have a variety of actions in addition to their well-studied ability to inhibit cyclooxygenases. These actions include inhibition of the uncoupling of oxidative phosphorylation, decreases in adenosine triphosphate stores. increases in extracellular adenosine, downregulation of the expression and activity of inducible nitric oxide synthetase, inhibition and/or stimulation of various mitogen-activated protein kinase activities and inhibition of nuclear factor binding kappaB site (NF-kappaB) activation. Moreover, aspirin-like compounds have recently been shown to have previously unappreciated clinical and biological effects, some apparently independent of cyclooxygenase. In this review we discuss the various mechanisms of action of aspirin-like compounds and their relevance to clinical disease and therapy.

Animals↗
PubMed1999

A novel mechanism of action of chemically modified tetracyclines: inhibition of COX-2-mediated prostaglandin E2 production.

Tetracyclines (doxycycline and minocycline) inhibit inducible NO synthase expression and augment cyclooxygenase (COX)-2 expression and PGE2 production. In contrast, chemically modified tetracyclines (CMTs), such as CMT-3 and -8 (but not CMT-1, -2, and -5), that lack antimicrobial activity, inhibit both NO and PGE2 production in LPS-stimulated murine macrophages, bovine chondrocytes, and human osteoarthritis-affected cartilage, which spontaneously produces NO and PGE2 in ex vivo conditions. Furthermore, CMT-3 augments COX-2 protein expression but inhibits net PGE2 accumulation. This coincides with the ability of CMT-3 and -8 to inhibit COX-2 enzyme activity in vitro. The action of CMTs is distinct from that observed with tetracyclines because 1) CMT-3-mediated inhibition of PGE2 production coincides with modification of COX-2 protein, which is distinct from the nonglycosylated COX-2 protein generated in the presence of tunicamycin, as observed by Western blot analysis and 2) CMT-3 and -8 have no significant effect on COX-2 mRNA accumulation. In contrast, CMT-3 and -8 do not inhibit COX-1 expression in A549 human epithelial cells at the level of protein and mRNA accumulation or modification of COX-1 protein. CMT-3 and -8 inhibit the sp. act. of COX-2 (but not COX-1) in cell-free extracts. These results demonstrate differential action of CMT-3 (Metastat) on COX-1 and -2 expression, which is distinct from other tetracyclines.

Animals↗
PubMed1999

Regulation of cytosolic COX-2 and prostaglandin E2 production by nitric oxide in activated murine macrophages.

Murine macrophages (RAW 264.7) when stimulated with LPS show 90% distribution of cyclooxygenase-2 (COX-2) in the nuclear fraction and approximately 10% in the cytosolic fraction. Further analysis of this cytosolic fraction at 100,000 x g indicates that the COX-2 is distributed both in the 100,000 x g soluble fraction and membrane fraction. Stimulation of RAW 264.7 cells with LPS in the presence of inducible nitric oxide synthase inhibitor L-NMMA at concentrations that inhibit nitrite accumulation by </=80% is inadequate to augment PGE2 production. However, inhibition of nitrite accumulation by >/=85% with higher concentrations of L-NMMA shows 1) up-regulation of PGE2 production, 2) accumulation of COX-2 protein in the 100,000 x g soluble and membrane fractions of the cytosolic fraction, and 3) with no significant effects on the accumulation of COX-2 mRNA. These experiments suggest that low concentrations of nitric oxide (10-15% of the total) attenuate PGE2 production in response to LPS in RAW 264.7 cells. This inhibition is, in part, due to decreased expression of cytosolic COX-2 protein.

3T3 Cells↗
PubMed1999

Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide.

Tetracyclines (doxycycline and minocycline) augmented (one- to twofold) the PGE2 production in human osteoarthritis-affected cartilage (in the presence or absence of cytokines and endotoxin) in ex vivo conditions. Similarly, bovine chondrocytes stimulated with LPS showed (one- to fivefold) an increase in PGE2 accumulation in the presence of doxycycline. This effect was observed at drug concentrations that did not affect nitric oxide (NO) production. In murine macrophages (RAW 264.7) stimulated with LPS, tetracyclines inhibited NO release and increased PGE2 production. Tetracycline(s) and L-N-monomethylarginine (L-NMMA) (NO synthase inhibitor) showed an additive effect on inhibition of NO and PGE2 accumulation, thereby uncoupling the effects of tetracyclines on NO and PGE2 production. The enhancement of PGE2 production in RAW 264.7 cells by tetracyclines was accompanied by the accumulation of both cyclooxygenase (COX)-2 mRNA and cytosolic COX-2 protein. In contrast to tetracyclines, L-NMMA at low concentrations (< or = 100 microM) inhibited the spontaneous release of No in osteoarthritis-affected explants and LPS-stimulated macrophages but had no significant effect on the PGE2 production. At higher concentrations, L-NMMA (500 microM) inhibited NO release but augmented PGE2 production. This study indicates a novel mechanism of action of tetracyclines to augment the expression of COX-2 and PGE2 production, an effect that is independent of endogenous concentration of NO.

Animals↗
PubMed1999

Regulation of nitric oxide and prostaglandin E2 production by CSAIDS (SB203580) in murine macrophages and bovine chondrocytes stimulated with LPS.

OBJECTIVE AND DESIGN: To compare two anti-inflammatory drugs: CSAIDS (SB203580) and hydrocortisone on iNOS and COX-2 expression. MATERIAL OR SUBJECTS: Murine macrophages and bovine chondrocytes stimulated with LPS and human OA-affected cartilage were used in this study. TREATMENT: The macrophages and chondrocytes were preincubated (30 min) with 0.1-1.0 microM CSAIDS or 10 microM of hydrocortisone before stimulating them with 1-100 microg/ml LPS. METHODS: The end products of iNOS and COX-2: nitric oxide (NO) and PGE2 were estimated by Greiss method and RIA, respectively. RESULTS: CSAIDS (1 microM) inhibited the production of NO and PGE2 (p< or =0.01) in bovine chondrocytes, but not in murine macrophages (RAW 264.7) (p< or =0.1). In fact, CSAIDS (in murine macrophages) marginally augmented nitrite accumulation (approximately 20%) at 14-24 h of LPS stimulation. Western blot analysis of COX-2 in bovine chondrocytes show decrease in COX-2 expression by hydrocortisone but not CSAIDS, although hydrocortisone and CSAIDS inhibit PGE2 accumulation. Hydrocortisone inhibited both PGE2 and NO production significantly (p< or =0.01) in murine macrophages. Furthermore, hydrocortisone significantly inhibited (p< or =0.01) PGE2 but marginally (p< or =0.05) NO in bovine chondrocytes. CONCLUSION: These experiments demonstrate differential action of CSAIDS and hydrocortisone on NO and PGE2 production in bovine chondrocytes and RAW 264.7 cells.

Animals↗
PubMed1999

Selective cyclooxygenase-2 inhibitors.

The identification of COX-2 less than a decade ago has been followed by an unprecedented period of discovery and drug development. An awareness of the existence of two COX isoforms has led to potential novel insights into disease pathogenesis (arthritis, Alzheimer's disease, cancer) and the regulation of normal physiology (brain, kidney). The preliminary in vivo experience with COX-2-selective inhibitors has provided evidence for proof of concept for the COX-1 and COX-2 hypothesis, namely that the selective inhibition of COX-2-derived prostaglandins is sufficient to inhibit inflammation and is nonulcerogenic. It may be that we have moved closer to the "better aspirin" envisioned by Sir John Vane for the treatment of degenerative and inflammatory arthritides; however, caution is still warranted. Some toxicities of current NSAIDs may result from COX-2 inhibition, as in the kidney and brain; such side effects may be shared by the selective compounds. In addition, unexpected toxicities may arise simply because new chemical compounds will be widely prescribed. Finally, since the efficacy of traditional NSAIDs derives largely from their capacity to inhibit COX-2, it may be that the COX-2 selective drugs will not prove to be therapeutically superior to available agents. Given the well-recognized toxicity of NSAIDs, however, the availability of COX-2-selective agents promises to provide significant advantage to patients with chronic diseases, such as RA and OA.

Animals↗
PubMed1999

The role of COX-2 produced by cartilage in arthritis.

The development of selective COX-2 inhibitors has renewed interest in the treatment of osteoarthritis with prostaglandin synthesis inhibitors. The therapeutic effects of COX inhibitors in OA may be due to their analgesic properties. However, it is now apparent that stable prostaglandins are produced by chondrocytes in OA cartilage where they may act to alter matrix synthesis and degradation. In vitro, PGEs activate metalloproteinases, but also enhance proteoglycan and type II collagen synthesis. Their net effect on matrix homeostasis in vivo remains to be determined.

Cartilage↗
PubMed1999

Nitric oxide synthase and cyclooxygenases: distribution, regulation, and intervention in arthritis.

Nitric oxide (NO) and prostaglandin E2 (PGE2) are two pleiotropic inflammatory mediators overproduced in arthritis-affected joints. The inducible isoform of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) are found both in the synovial tissue and in the cartilage. Their expression is regulated by catabolic cytokines, such as interleukin-1beta and tumor necrosis factor-alpha. These inflammatory mediators play a profound role in the pathogenic processes that arise in the pannus of rheumatoid arthritis and also interfere with cartilage homeostasis in osteoarthritis. Several drugs, including nonsteroidal anti-inflammatory drugs, immunosuppressive agents, and tetracyclines, attenuate the activity of NO and PGE2. These pleiotropic mediators are targets for pharmacologic intervention and gene therapy.

Arthritis, Rheumatoid↗
PubMed1998

TNF-alpha convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-alpha.

A snake venom-like protease isolated by a differential display screen between normal and osteoarthritis (OA)-affected cartilage (designated as cSVP) has a cDNA sequence identical to TNF-alpha convertase enzyme (TACE). TACE shows the presence of an unknown prodomain, a cysteine switch, a catalytic domain, a zinc binding region, a disintegrin region, an EGF-like domain, a transmembrane domain, and a unique cytoplasmic region. A TACE construct harboring the signal + prodomain + catalytic region (TACE-SPCdeltaDETCy), expressed in baculovirus could cleave preferentially (approximately 12-fold) the TNF-specific peptide over the matrix metalloproteases peptide in vitro. This recombinant protein also cleaved the natural substrate GST-ProTNF-alpha to TNF-alpha (17 kDa) in vitro. The mRNA for TACE, which is broadly distributed and differentially expressed in a variety of human tissues, is up-regulated in arthritis-affected cartilage, but not normal cartilage. OA-affected cartilage also expressed TNF-alpha mRNA that was not detected in normal cartilage. The OA-affected cartilage (in explant assays) spontaneously released TNF-alpha and IL-8 in ex vivo conditions. Addition of TNF-alphaR fused to IgG Fc fragment (TNF-alphaR:Fc) in the presence or absence of soluble IL-1R (with which it acted additively) significantly attenuated the spontaneous/autocrine release of articular IL-8 in this assay. These experiments demonstrate a functional paracrine/autocrine role of TNF-alpha in OA-affected cartilage that may depend, in part, on up-regulated levels of chondrocyte-derived TACE.

ADAM Proteins↗
PubMed1998

SLE: mechanisms of vascular injury.

The chronic elevation of complement split products seen in many patients with systemic lupus erythematosus should be regarded as equivalent to silent hypertension, or hyperglycemia in a patient with incipient diabetes mellitus. Although the consequences may not be immediately evident, such patients should be monitored and perhaps even treated.

Adult↗
PubMed1998

Up-regulation of inducible nitric oxide synthase and production of nitric oxide by the Swarm rat and human chondrosarcoma.

Production of nitric oxide by solid tumors may have important ramifications regarding tumor growth and potential metastasis. This study demonstrated that the chondrosarcoma of the Swarm rat has upregulated mRNA for inducible nitric oxide synthase and produces nitric oxide. These results were confirmed by (a) the presence of a 4.4-kb band of mRNA detected by Northern blot using a probe for inducible nitric oxide synthase, (b) a 133-kDa band of protein that was detected with either a polyclonal or monoclonal antibody to the inducible nitric oxide synthase of the murine macrophage, and (c) the detection of nitrites from the culture medium of freshly cultured, isolated chondrosarcoma cells. This study showed that the expression of inducible nitric oxide synthase and the production of nitric oxide by the tumor can be increased by stimulation with endotoxin lipopolysaccharide and can be inhibited by inducible nitric oxide synthase inhibitors (L-N(g)-monomethyl arginine and aminoguanidine). Immunostaining confirmed the presence of inducible nitric oxide synthase within the tumor cells and appeared to localize the enzyme to the cytoplasm of the cells. A human chondrosarcoma was also shown to have an upregulated inducible nitric oxide synthase by both the detection of mRNA for inducible nitric oxide synthase and the presence of nitrites from the culture medium of the tumor in organ culture. Because the chondrosarcoma of the Swarm rat is a well differentiated solid tumor that rarely metastasizes, nitric oxide may be produced by the tumor to promote local growth by effects on vascular supply.

Animals↗