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Biomedical subjects

B Hinz

Publications and source records attributed to B Hinz.

At least 19 recordsLinked to original sources
PubMed2001

Marching at the front and dragging behind: differential alphaVbeta3-integrin turnover regulates focal adhesion behavior.

Integrins are cell-substrate adhesion molecules that provide the essential link between the actin cytoskeleton and the extracellular matrix during cell migration. We have analyzed alphaVbeta3-integrin dynamics in migrating cells using a green fluorescent protein-tagged beta3-integrin chain. At the cell front, adhesion sites containing alphaVbeta3-integrin remain stationary, whereas at the rear of the cell they slide inward. The integrin fluorescence intensity within these different focal adhesions, and hence the relative integrin density, is directly related to their mobility. Integrin density is as much as threefold higher in sliding compared with stationary focal adhesions. High intracellular tension under the control of RhoA induced the formation of high-density contacts. Low-density adhesion sites were induced by Rac1 and low intracellular tension. Photobleaching experiments demonstrated a slow turnover of beta3-integrins in low-density contacts, which may account for their stationary nature. In contrast, the fast beta3-integrin turnover observed in high-density contacts suggests that their apparent sliding may be caused by a polarized renewal of focal contacts. Therefore, differential acto-myosin-dependent integrin turnover and focal adhesion densities may explain the mechanical and behavioral differences between cell adhesion sites formed at the front, and those that move in the retracting rear of migrating cells.

Cells, Cultured↗
PubMed2001

R(+)-methanandamide induces cyclooxygenase-2 expression in human neuroglioma cells via a non-cannabinoid receptor-mediated mechanism.

Cannabinoids affect prostaglandin (PG) formation in the central nervous system through as yet unidentified mechanisms. Using H4 human neuroglioma cells, the present study investigates the effect of R(+)-methanandamide (metabolically stable analogue of the endocannabinoid anandamide) on the expression of the cyclooxygenase-2 (COX-2) enzyme. Incubation of cells with R(+)-methanandamide was accompanied by concentration-dependent increases in COX-2 mRNA, COX-2 protein, and COX-2-dependent PGE(2) synthesis. Moreover, treatment of cells with R(+)-methanandamide in the presence of interleukin-1beta led to an overadditive induction of COX-2 expression. The stimulatory effect of R(+)-methanandamide on COX-2 expression was mimicked by the structurally unrelated cannabinoid Delta(9)-tetrahydrocannabinol. Stimulation of both COX-2 mRNA expression and subsequent PGE(2) synthesis by R(+)-methanandamide was not affected by the selective CB(1) receptor antagonist AM-251 or the G(i/o) protein inactivator pertussis toxin. Enhancement of COX-2 expression by R(+)-methanandamide was paralleled by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK. Consistent with the activation of both kinases, R(+)-methanandamide-induced COX-2 mRNA expression and PGE(2) formation were abrogated in the presence of specific inhibitors of p38 MAPK (SB203580) and p42/44 MAPK activation (PD98059). Together, our results demonstrate that R(+)-methanandamide induces COX-2 expression in human neuroglioma cells via a cannabinoid receptor-independent mechanism involving activation of the MAPK pathway. In conclusion, induction of COX-2 expression may represent a novel mechanism by which cannabinoids mediate PG-dependent effects within the central nervous system.

Analgesics, Non-Narcotic↗
PubMed2001

Identification, by homozygosity mapping, of a novel locus for autosomal recessive congenital ichthyosis on chromosome 17p, and evidence for further genetic heterogeneity.

Autosomal recessive congenital ichthyosis (ARCI) comprises a group of severe disorders of keratinization, characterized by variable erythema and skin scaling. It is known for its high degree of genetic and clinical heterogeneity. Mutations in the gene for keratinocyte transglutaminase (TGM1) on chromosome 14q11 were shown in patients with ARCI, and a second locus was described, on chromosome 2q, in families from northern Africa. Three other loci for ARCI, on chromosomes 3p and 19p, were identified recently. We have embarked on a whole-genome scan for further loci for ARCI in four families from Germany, Turkey, and the United Arab Emirates. A novel ARCI locus was identified on chromosome 17p, between the markers at D17S938 and D17S1856, with a maximum LOD score of 3.38, at maximum recombination fraction 0.00, at D17S945, under heterogeneity. This locus is linked to the disease in the Turkish family and in the German family. Extensive genealogical studies revealed that the parents of the German patients with ARCI were eighth cousins. By homozygosity mapping, the localization of the gene could then be refined to the 8.4-cM interval between D17S938 and D17S1879. It could be shown, however, that ARCI in the two Arab families is linked neither to the new locus on chromosome 17p nor to one of the five loci known previously. Our findings give evidence of further genetic heterogeneity that is not linked to distinctive phenotypes.

Adolescent↗
PubMed2001

Efficiency and toxicity of liposome-mediated gene transfer to corneal endothelial cells.

Gene transfer to corneal endothelial cells could be an important advance to modulate functions of these critical cells and is a field of current investigations. The development of gene transfer methods is a prerequisite for gene therapy to realize its full potential. We attempted to investigate and optimize the efficacy and safety of cationic liposome mediated gene transfer into corneal endothelial cells using different lipid formulations. Mono- and polycationic lipids and the neutral helper lipid dioleolphosphotidyl-ethanolamine (DOPE) were used for preparation of cationic liposomes. Six liposomal formulations containing DAC/DOPE 30/70 (DAC 30), DOSGA/DOPE 30/70 (DOSGA 30), DOSGA 100, DMRIE/DOPE 50/50 (DMRIE 50) and SP/DOPE 20/80 (SP 20) were complexed with the pUT 651-plasmid, encoding the E. coli beta-galactosidase gene. Subconfluent primary and passaged bovine corneal endothelial cells (BCEC) were transfected with different amounts of liposomes and DNA or uncomplexed free DNA as control. Quantitative expression of beta-galactosidase was measured using a colorimetric assay. In order to assess the effects on cell viability and growth, a modified acidic phosphatase assay was employed. Differences were detected using these various liposome preparations. Transfection experiments demonstrated the highest gene expression using SP 20> DMRIE 50 ranging at approximately 3 mU per beta-gal per well. Low expression of beta-galactosidase was achieved using DAC 30, DOSGA 30 and DOSGA 100. No beta-galactosidase expression was found in control dishes. There was no difference seen following transfection of primary or subsequent passages of BCEC. As indicated by the acid phosphatase assay, no significant toxicity was detected for the most efficient lipids used. Of the preparations studied, SP 20 appeared as the optimal vehicle for plasmid-mediated transfection of BCEC. The ability to deliver genes to BCEC via liposomes could be valuable, since the use of other vectors for transfection may be limited by undesired effects.

Animals↗
PubMed2001

Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation.

We have examined the role of mechanical tension in myofibroblast differentiation using two in vivo rat models. In the first model, granulation tissue was subjected to an increase in mechanical tension by splinting a full-thickness wound with a plastic frame. Myofibroblast features, such as stress fiber formation, expression of ED-A fibronectin and alpha-smooth muscle actin (alpha-SMA) appeared earlier in splinted than in unsplinted wounds. Myofibroblast marker expression decreased in control wounds starting at 10 days after wounding as expected, but persisted in splinted wounds. In the second model, granuloma pouches were induced by subcutaneous croton oil injection; pouches were either left intact or released from tension by evacuation of the exudate at 14 days. The expression of myofibroblast markers was reduced after tension release in the following sequence: F-actin (2 days), alpha-SMA (3 days), and ED-A fibronectin (5 days); cell density was not affected. In both models, isometric contraction of tissue strips was measured after stimulation with smooth muscle agonists. Contractility correlated always with the level of alpha-SMA expression, being high when granulation tissue had been subjected to tension and low when it had been relaxed. Our results support the assumption that mechanical tension is crucial for myofibroblast modulation and for the maintenance of their contractile activity.

Actins↗
PubMed2001

Examination of the myoelectric activity of back muscles during random vibration--methodical approach and first results.

OBJECTIVE: To elaborate methods for an elimination of artefacts and the analysis of the relationship between random whole-body vibration and electromyographic responses of back muscles. DESIGN: A procedure involving wavelets and digital filtering has been used for the removal of artefacts from the electromyogram during whole-body vibration. BACKGROUND: Back muscle forces contribute essentially to the whole-body vibration-induced spinal load. The electromyogram can help to estimate these forces during whole-body vibration. METHODS: 38 subjects were exposed to identical random low-frequency whole-body vibration. Artefacts caused by the electrocardiogram in the electromyogram were identified by appropriate wavelets and eliminated in the time-domain. After averaging the individual high-pass filtered and rectified undistorted electromyograms across subjects, the transfer function from seat acceleration to the average electromyogram was determined and used for the prediction of the electromyogram. RESULTS: A sufficient procedure involving wavelets and digital filtering has been elaborated for the removal of artefacts from the electromyogram of back muscles during whole-body vibration. A systematic relationship between random vibration and back muscle-response was obtained and described. The transfer function suggests two different reflex-mechanisms - one elicited below, the other above 4 Hz. CONCLUSIONS: The approach of analysing and predicting the muscle-response to random vibration by using the transfer function seems to be promising and could be a valuable tool for the future calculation of muscle forces as an input to active models. RELEVANCE: The knowledge of the extent and timing of the back muscle-response to random whole-body vibration is relevant for an improved evaluation of whole-body vibration with respect to health.

Adult↗
PubMed2001

Intradiscal pressure together with anthropometric data--a data set for the validation of models.

OBJECTIVE: To provide a database of intradiscal pressure measurements together with anthropometric data as basis for the validation of models that predict spinal loads. DESIGN: Intradiscal pressure was measured in a non-degenerated L4-5 disc of a volunteer. The anthropometric characteristics of this subject were extensively determined. BACKGROUND: Since it is usually impossible to quantify the load in the spine directly, it is predicted by various biomechanical models. However, they often cannot be validated because of the few in vivo data and missing anthropometric characteristics pertaining to them. METHODS: A pressure transducer (diameter 1.5 mm) was implanted in the nucleus pulposus of a non-degenerated L4-5 disc of a volunteer. Pressure was determined during exercises while standing, lifting activities, sitting unsupported on a stool or an ergonomic sitting ball, sitting in different postures and others. The anthropometric characteristics were determined using different tools. RESULTS: Pressure values: relaxed standing 0.5 MPa; standing flexed forward 1.1 MPa; standing extended backward 0.6 MPa; sitting unsupported 0.46 MPa; maximum values during lateral bending 0.6 MPa, during axial rotation 0.7 MPa, lifting a 20 kg weight with a round flexed back 2.3 MPa, with flexed knees 1.7 MPa, close to the body 1.1 MPa; sitting unsupported relaxed 0.45 MPa, actively straightening the back 0.55 MPa, with flexion 0.9 MPa; non-chalant sitting 0.3 MPa and others. Anthropometric characteristics with emphasis on data for the trunk are provided in tables.Conclusions. Intradiscal pressure depends on the kind of preceding activity, posture, external loads and muscle activity. RELEVANCE: The data set can be used to verify a biomechanical model adjusted to the individual characteristics by a comparison of measured and predicted intradiscal pressures.

Anthropometry↗
PubMed2001

Application of finite-element models to predict forces acting on the lumbar spine during whole-body vibration.

OBJECTIVE: To predict forces acting on the spine during whole-body vibration for a variety of boundary conditions - body mass, height and posture.Design. Representative anthropometric data and models for an upright, relaxed and bent forward sitting posture were used to derive model families with 30 variants of a finite-element model. BACKGROUND: A given exposure to whole-body vibration can cause a variable health risk depending on the concomitant conditions. The latter could contribute to the considerable uncertainty of the current evaluation of whole-body vibration. METHODS: Plane symmetric linear finite-element models were used for the prediction of static and dynamic compression and shear forces acting on the lumbar discs during whole-body vibration. Transfer functions from seat acceleration to forces were determined. RESULTS: A bent forward posture augments essentially the compressive and shear stress, predicted for erect and relaxed sitting postures. The normal variation of body mass and height causes a considerable variation of static internal shear stress, but a minor variation of compressive pressure. The dynamic internal stress varies nearly proportionally to the body mass. The transfer functions from seat acceleration to compressive force depend significantly on the posture. CONCLUSIONS: The variability of the spinal loads for a given whole-body vibration and associated with a normal range of several biological factors suggests a ratio between the minimum and maximum internal loads of about 1:2. RELEVANCE: Finite-element models can be used to compare the health risk arising from different whole-body vibration exposures and individual conditions. These results help to prevent work-related disorders of the lumbar spine.

Adult↗
PubMed2001

Transfer functions as a basis for the verification of models--variability and restraints.

OBJECTIVE: The seat-to-head transfer function of the human body reflects the biodynamic response. Based on measured data, biodynamic models have been proposed to reflect this response. They must satisfy usually the international published mean values of the seat-to-head transfer function. The question arises to what extent mean values reflect individual pattern of biodynamics. METHODS: An experimental study was performed with 39 male subjects sitting on a hard seat without back rest and with supported feet. They were exposed to random whole-body vibration at three intensities with a relaxed and an erect posture. The accelerations in the z-direction were measured at the seat and head. The seat-to-head transfer functions with the associated coherence functions were calculated. RESULTS: The biodynamic response characterised by the maximum of the seat-to-head transmissibility and the frequency of its occurrence is influenced by the posture of the subjects in a dominant way and shows an individual variability of considerable extent. The mean responses suggest a missing effect of vibration intensity, but individually different effects of the intensity were found. Repeated measurements confirmed this result. CONCLUSIONS: The application of a model validated by the comparison with mean values of the transmissibility could cause misleading conclusions, if it is used for the prediction of individual spinal loads. Models prepared for the calculation of individual loads should be validated by a mean individual transmissibility derived from repeated measurements. RELEVANCE: The results illustrate the loss of information by averaging individual transfer functions and the consequence of a limited validity and applicability in occupational health, ergonomics, and design.

Acceleration↗
PubMed2001

Flurbiprofen enantiomers inhibit inducible nitric oxide synthase expression in RAW 264.7 macrophages.

PURPOSE: Using RAW 264.7 macrophages, the present study investigates the influence of optically pure enantiomers of the nonsteroidal anti-inflammatory drug flurbiprofen on lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression. METHODS: iNOS and cyclooxygenase-2 (COX-2) mRNA levels were measured by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR). Concentrations of nitrite (index of cellular NO production) and prostaglandin E2 (index of COX-2 activity) in cell culture supernatants were determined by Griess assay and enzyme immunoassay, respectively. RESULTS: R(-)- and S(+)-flurbiprofen decreased LPS-induced iNOS mRNA and nitrite levels in an equipotent and concentration-dependent manner. Suppression of iNOS mRNA expression by R(-)- and S(+)-flurbiprofen was gene-specific in that both substances failed to inhibit LPS-induced COX-2 mRNA expression. By contrast, flurbiprofen enantiomers suppressed LPS-induced prostaglandin E2 formation enantioselectively with S(+)-flurbiprofen being considerably more potent than its R(-)-antipode. CONCLUSIONS: Our results show that R(-)- and S(+)-flurbiprofen, albeit differing in their potency as inhibitors of COX-2 activity, equipotently suppress iNOS expression. Because sustained high NO levels are associated with pain and tissue injury under various pathological conditions, a suppression of the inducible NO pathway may contribute to the pharmacological action of both R(-)- and S(+)-flurbiprofen.

Animals↗
PubMed2001

Activity-dependent changes of the presynaptic synaptophysin-synaptobrevin complex in adult rat brain.

The vesicular protein synaptobrevin contributes to two mutually exclusive complexes in mature synapses. Synaptobrevin tightly interacts with the plasma membrane proteins syntaxin and SNAP 25 forming the SNARE complex as a prerequisite for exocytotic membrane fusion. Alternatively, synaptobrevin binds to the vesicular protein synaptophysin. It is unclear whether SNARE complex formation is diminished or facilitated when synaptobrevin is bound to synaptophysin. Here we show that the synaptophysin-synaptobrevin complex is increased in adult rat brain after repeated synaptic hyperactivity in the kindling model of epilepsy. Two days after the last kindling-induced stage V seizure the relative amount of synaptophysin-synaptobrevin complex obtained by co-immunoprecipitation from cortical and hippocampal membranes was increased twofold compared to controls. By contrast the relative amounts of various synaptic proteins as well as that of the SNARE complex did not change in membrane preparations from kindled rats compared to controls. The increased amount of synaptophysin-synaptobrevin complex in kindled rats supports the idea that this complex represents a reserve pool for synaptobrevin enabling synaptic vesicles to adjust to an increased demand for synaptic efficiency. We conclude that the synaptophysin-synaptobrevin interaction is involved in activity-dependent plastic changes in adult rat brain.

Age Factors↗
PubMed2001

Alpha-smooth muscle actin expression upregulates fibroblast contractile activity.

To evaluate whether alpha-smooth muscle actin (alpha-SMA) plays a role in fibroblast contractility, we first compared the contractile activity of rat subcutaneous fibroblasts (SCFs), expressing low levels of alpha-SMA, with that of lung fibroblasts (LFs), expressing high levels of alpha-SMA, with the use of silicone substrates of different stiffness degrees. On medium stiffness substrates the percentage of cells producing wrinkles was similar to that of alpha-SMA-positive cells in each fibroblast population. On high stiffness substrates, wrinkle production was limited to a subpopulation of LFs very positive for alpha-SMA. In a second approach, we measured the isotonic contraction of SCF- and LF-populated attached collagen lattices. SCFs exhibited 41% diameter reduction compared with 63% by LFs. TGFbeta1 increased alpha-SMA expression and lattice contraction by SCFs to the levels of LFs; TGFbeta-antagonizing agents reduced alpha-SMA expression and lattice contraction by LFs to the level of SCFs. Finally, 3T3 fibroblasts transiently or permanently transfected with alpha-SMA cDNA exhibited a significantly higher lattice contraction compared with wild-type 3T3 fibroblasts or to fibroblasts transfected with alpha-cardiac and beta- or gamma-cytoplasmic actin. This took place in the absence of any change in smooth muscle or nonmuscle myosin heavy-chain expression. Our results indicate that an increased alpha-SMA expression is sufficient to enhance fibroblast contractile activity.

3T3 Cells↗
PubMed2000

Cyclooxygenase-2 expression in lipopolysaccharide-stimulated human monocytes is modulated by cyclic AMP, prostaglandin E(2), and nonsteroidal anti-inflammatory drugs.

Using human blood monocytes (for determination of cyclooxygenase-2 (COX-2) mRNA by RT-PCR) and human whole blood (for prostanoid determination), the present study investigates the influence of the second messenger cAMP on lipopolysaccharide (LPS)-induced COX-2 expression with particular emphasis on the role of prostaglandin E(2) (PGE(2)) in this process. Elevation of intracellular cAMP with a cell-permeable cAMP analogue (dibutyryl cAMP), an adenylyl cyclase activator (cholera toxin), or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) substantially enhanced LPS-induced PGE(2) formation and COX-2 mRNA expression, but did not modify COX-2 enzyme activity. Moreover, up-regulation of LPS-induced COX-2 expression was caused by PGE(2), butaprost (selective agonist of the adenylyl cyclase-coupled EP(2) receptor) and 11-deoxy PGE(1) (EP(2)/EP(4) agonist), whereas sulprostone (EP(3)/EP(1) agonist) left COX-2 expression unaltered. Abrogation of LPS-induced PGE(2) synthesis with the selective COX-2 inhibitor NS-398 caused a decrease in COX-2 mRNA levels that was restored by exogenous PGE(2) and mimicked by S(+)-flurbiprofen and ketoprofen. Overall, these results indicate a modulatory role of cAMP in the regulation of COX-2 expression. PGE(2), a cAMP-elevating final product of the COX-2 pathway, may autoregulate COX-2 expression in human monocytes via a positive feedback mechanism.

1-Methyl-3-isobutylxanthine↗
PubMed2000

Salicylate metabolites inhibit cyclooxygenase-2-dependent prostaglandin E(2) synthesis in murine macrophages.

The poor cyclooxygenase (COX) inhibitor and major aspirin metabolite salicylic acid is known to exert analgesic and anti-inflammatory effects by still unidentified mechanisms. In RAW 264.7 macrophages, lipopolysaccharide (LPS)-induced COX-2-dependent synthesis of prostaglandin E(2) (PGE(2)) was suppressed by aspirin (IC(50) of 5. 35 microM), whereas no significant inhibition was observed in the presence of sodium salicylate and the salicylate metabolite salicyluric acid at concentrations up to 100 microM. However, the salicylate metabolite gentisic acid (2,5-dihydroxybenzoic acid; 10-100 microM) and salicyl-coenzyme A (100 microM), the intermediate product in the formation of salicyluric acid from salicylic acid, significantly suppressed LPS-induced PGE(2) production. In contrast, gamma-resorcylic acid (2,6-dihydroxybenzoic acid) as well as unconjugated coenzyme A failed to affect prostanoid synthesis, implying that the para-substitution of hydroxy groups and the activated coenzyme A thioester are important for COX-2 inhibition. Using real-time RT-PCR, none of the salicylate derivatives tested were found to interfere with COX-2 expression. Overall, our results suggest that certain metabolites of salicylic acid may contribute to the pharmacological action of its parent compound by inhibiting COX-2-dependent PGE(2) formation at sites of inflammation.

Acyl Coenzyme A↗
PubMed2000

Prostaglandin E(2) upregulates cyclooxygenase-2 expression in lipopolysaccharide-stimulated RAW 264.7 macrophages.

Prostaglandin E(2) (PGE(2)) has been implicated in the regulation of inflammatory and immunological events. Using RAW 264.7 macrophages, the present study investigates the influence of PGE(2) on the expression of cyclooxygenase-2 (COX-2). Incubation of cells with PGE(2) increased lipopolysaccharide (LPS)-induced COX-2 mRNA levels in a concentration-dependent manner. Upregulation of COX-2 expression by PGE(2) was completely abolished by the specific adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and mimicked by butaprost, a selective agonist of the adenylyl cyclase-coupled PGE(2) receptor subtype 2 (EP(2)), or 11-deoxy PGE(1), an EP(2)/EP(4) receptor agonist. By contrast, the EP(3)/EP(1) receptor agonists 17-phenyl-omega-trinor PGE(2) and sulprostone left LPS-induced COX-2 expression virtually unaltered. Upregulation of LPS-induced COX-2 expression and subsequent PGE(2) synthesis was also observed in the presence of the cell-permeable cAMP analogue dibutyryl cAMP and the adenylyl cyclase activator cholera toxin. Together, our data demonstrate that PGE(2) potentiates COX-2 mRNA expression via an adenylyl cyclase/cAMP-dependent pathway. In conclusion, upregulation of COX-2 expression via an autocrine feed-forward loop may in part contribute to the well-known capacity of PGE(2)/cAMP to modulate inflammatory processes.

Adenylyl Cyclase Inhibitors↗
PubMed2000

Nitric oxide inhibits inducible nitric oxide synthase mRNA expression in RAW 264.7 macrophages.

Using cultured murine RAW 264.7 macrophages, the present study investigates the influence of nitric oxide (NO) on the expression of the inducible NO synthase (iNOS) enzyme at the transcriptional level. Incubation of cells with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) led to a marked increase in iNOS mRNA levels. Inhibition of LPS/IFN-gamma-induced NO synthesis with the L-arginine analogue N(G)-monomethyl-L-arginine (L-NMMA) was accompanied by a significant up-regulation of iNOS mRNA that was reversed in the presence of the NO donor sodium nitroprusside (SNP). Treatment of cells with SNP alone decreased LPS/IFN-gamma-induced iNOS mRNA levels in a concentration-dependent manner. The inhibitory effect of SNP on iNOS mRNA expression was not prevented by 1H-[1,2, 4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of the soluble guanylyl cyclase. In agreement with this finding, incubation of cells with the membrane-permeable cyclic GMP analogue 8-bromo cyclic GMP left LPS/IFN-gamma-induced iNOS mRNA expression virtually unaltered. Together, our results demonstrate that both iNOS-derived and exogenous NO exert an inhibitory effect on the expression of iNOS by a mechanism independent of the soluble guanylyl cyclase/cyclic GMP pathway. In conclusion, NO may control the extent of iNOS mRNA expression by a negative autoregulatory feedback.

Animals↗
PubMed2000

[Specific cyclooxygenase-2 inhibitors. Basis and options of a pharmacotherapeutic concept].

The therapeutic and unwanted side effects of non-steroidal antiinflammatory drugs (NSAIDs) are attributable to inhibition of the cyclooxygenase (COX) enzyme which catalyzes the first step of the synthesis of prostanoids. In the early 1990s, COX was demonstrated to exist as two distinct isoforms. COX-1 is constitutively expressed as a 'housekeeping' enzyme in most tissues. In contrast, COX-2 can be upregulated by various proinflammatory agents, including endotoxin, cytokines and growth factors. Whereas many of the side effects of NSAIDs (e.g. gastrointestinal ulceration and bleeding, platelet dysfunctions) are due to a suppression of COX-1 activity, inhibition of COX-2-derived prostanoids facilitates the anti-inflammatory, analgesic and antipyretic effects of NSAIDs. Thus, the hypothesis that specific inhibition of COX-2 might have therapeutic actions similar to those of NSAIDs, but without causing the unwanted side effects, was the rationale for the development of specific inhibitors of the COX-2 enzyme as a new class of anti-inflammatory and analgesic agents with improved gastrointestinal tolerability. However, the simple concept that COX-2 is an exclusively proinflammatory and inducible enzyme cannot be supported any longer. Recently, COX-2 was shown to be also expressed under basal conditions in organs such as the ovary, uterus, brain, spinal cord, kidney and bone, suggesting that this isoenzyme may play a more complex physiological role than was expected. The present review assesses concept and molecular mechanism underlying specific COX-2 inhibition as well as indications, pharmakokinetics and unwanted side effects of the recently approved specific COX-2 inhibitors celecoxib and rofecoxib. Moreover, recent advances in COX-2 research, with particular emphasis on new insights into physiological functions of this isoenzyme will be discussed.

Animals↗