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At least 1,171 records · Page 65Linked to original sources
PubMed1995

Methylmercury-injury effect on tube formation by cultured human vascular endothelial cells.

The effect of methylmercury chloride (MeHg) on growth and tube formation by cultured human umbilical vein endothelial cells (HUVECs) was investigated. HUVECs were collected by enzymatic digestion with collagenase. Precultivation of HUVECs with MeHg at concentrations of 1.0-50.0 mumol/L exerted negligible effects on the viable cell number, while the viable cell number was slightly reduced at 100 mumol/L and fell to zero at concentrations exceeding 500.0 mumol/L MeHg. The viable cell number was depressed in a concentration-dependent manner. Tube formation was studied by culturing the cells on gelled basement membrane matrix (Matrigel). Treatment of HUVECs with 0.1-5.0 mumol/L MeHg for 24 h inhibited tube formation dose-dependently. Fetal bovine serum (FBS) increased tube formation in a dose-dependent manner, with half-maximum stimulation of tube formation at approximately 3.4% FBS. The length of tube formation decreased time-dependently at concentrations of 0.1 and 1.0 mumol/L MeHg. Pretreatment of Matrigel with 1 mumol/L MeHg before the cell seeding reduced the tube formation by HUVECs. These results suggest that the growth and tube formation by HUVECs is susceptible to MeHg cytotoxicity, and that MeHg could be injurious to endothelial cell function.

Cell Count↗
PubMed2006

Dexamethasone inhibits the formation of multinucleated osteoclasts via down-regulation of beta3 integrin expression.

Although glucocorticoids are known to affect osteoclast differentiation and function, there have been conflicting reports about the effect of glucocorticoids on osteoclast formation, leading to the assumption that microenvironment and cell type influence their action. We explored the effect of the synthetic glucocorticoid analog dexamethasone on the formation of osteoclasts. Dexamethasone inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts without affecting the formation of TRAP-positive mononuclear cells in a coculture of mouse osteoblasts and bone marrow cells. Dexamethasone did not inhibit mRNA expression levels of the receptor activator of nuclear factor-kappaB ligand and osteoprotegerin, the essential regulators of osteoclastogenesis. Dexamethasone down-regulated the expression of beta3 integrin mRNA and protein but did not alter expression of other osteoclast differentiation marker genes. Both dexamethasone and echistatin, a beta3 integrin function blocker, inhibited TRAP-positive multinucleated osteoclast formation but not TRAP-positive mononuclear cell formation. These results suggest that dexamethasone inhibits the formation of multinucleated osteoclasts, at least in part, through the down-regulation of beta3 integrin, which plays an important role in the formation of multinucleated osteoclasts.

Animals↗
PubMed2000

[Heterotopic and orthotopic bone formation with a vascularized periosteal flap, a matrix and rh-BMP-2 (bone morphogenetic protein) in the rat model].

The purpose of this study was to construct a vascularized bone graft using the osteoinductive bone morphogenetic protein (rh-BMP-2), a polylactic acid matrix (OPLA/HY), and a vascularized periosteal flap containing osteoprogenitor cells ectopically in the groin or orthotopically in a femoral defect. In the Lewis rat, periosteal flaps were harvested from the medial surface of the tibia vascularized by the saphenous artery and vein and were transferred to the groin on its vascularized pedicle. Alternatively, the periosteal flap along its pedicle was transferred between the thigh muscles to be wrapped around a femoral defect of 1 cm. The animals were divided into 10 groups (82 animals). In group 1, the periosteal flap was left empty in the groin. Groups 2 and 3 consisted of the periosteal flap and 20 micrograms rh-BMP-2, but in group 3 the vascular pedicle was ligated proximally. In group 4 the flap was harvested without the periosteal layer and turned "inside out". Groups 5 and 6 consisted of the periosteal flap and the matrix OPLA/HY +/- 20 micrograms rh-BMP-2. In the femoral defect model, bone formation was studied using the matrix OPLA/HY alone (group 7) or combined with the vascularized periosteal flap (group 8), or in combination with OPLA/HY + BMP (group 9) or OPLA/HY + BMP + the periosteal flap (group 10). The presence and density of new bone formation in the groin and femoral defect were evaluated radiologically and histologically at 4 and 8 weeks. Good bone formation in the groin chamber (ectopic) was demonstrated in the periosteal flap + OPLA/HY + BMP group. In the femoral defects, good bone formation (orthotopic) was seen in the OPLA/HY + BMP + the periosteal flap groups. However, with the presence of a vascularized periosteal flap, more bone formation along the rim of the defect was observed. This study of ectopic bone formation in the groin and orthotopic bone formation in the femoral defect demonstrates that optimal bone formation requires four factors: BMP, a biodegradable matrix, osteoprogenitor cells, and blood supply. Potentially in the future, this technique could be used to reconstruct a bony defect or a nonunion by covering the involved area with a vascularized periosteal flap and a suitable matrix combined with BMP. Alternatively, a vascularized bone graft could be prefabricated at a distant site and then transferred microsurgically into a defect.

Animals↗
PubMed1994

Formation and removal of DNA adducts in Fischer-344 rats exposed to 2,4-diaminotoluene.

32P-Postlabeling was used to examine DNA adduct formation and removal in Fischer-344 rats exposed to the animal carcinogen 2,4-diaminotoluene (DAT). Adduct formation and persistence were compared between target (liver and mammary gland) and non-target organs (kidney and lung) to determine if possible differences could explain the observed organ specificity of DAT induced carcinogenesis. The effects of different exposure conditions on DNA adduct formation and removal were also examined by varying the concentration and frequency of compound administration. DAT produced three distinct DNA adducts. Among the organs examined, DNA binding was highest in the liver, with levels approximately 10 times greater than that of the mammary gland and up to 50 times greater than of the two nontarget sites. Despite the large differences in the initial extent of adduct formation, the persistence of adducts among sites was not significantly different. In the liver, there were dose-dependent differences in DNA adduct formation, but adduct removal following different dosages did not vary significantly. The effects of multiple administration on DNA adduct formation and removal were examined by treating rats with 5 mg/kg DAT daily for 10 consecutive days. Adduct yields from multiple treatment were greater than from a single 50 mg/kg exposure. The persistence of adducts following multiple treatment was also greater than after an equivalent single exposure. The results demonstrated organ-specific and dose-dependent differences in initial extent of DNA adduct formation, but no differences in adduct persistence. However, the results did suggest that adduct formation and persistence may change with repeated administration of DAT.

Analysis of Variance↗
PubMed2005

Escin: inhibiting inflammation and promoting gastrointestinal transit to attenuate formation of postoperative adhesions.

Postoperative peritoneal adhesions are common, serious complications of general abdominal and gynecologic surgery that can lead to chronic abdominal pain, intestinal obstruction, and infertility. As yet, there are no ideal drugs that may be prescribed for patients to prevent adhesion formation effectively. In this study the effects of escin, a natural drug, on the various steps of adhesion formation were investigated. The effects of escin on increased vascular permeability induced by acetic acid in a mouse model of acute inflammation, granuloma formation in a subchronic inflammatory rat model, gastrointestinal transit in rats with intestinal paralysis, intestinal motility in postoperative patients, and postoperative adhesion formation in a rat model were observed. It was shown that escin could inhibit acute inflammation and granuloma formation, cause acceleration of gastrointestinal transit, help recover intestinal motility, and attenuate the formation of postoperative adhesions. The findings suggest that escin attenuates the formation of postoperative adhesions by inhibiting inflammation and promoting gastrointestinal transit. Thus it may be concluded that both inhibition of inflammation and increased gastrointestinal motility during the early postoperative period have a positive effect on decreasing the formation of adhesions.

Adult↗
PubMed2004

Meconium staining of amniotic fluid correlates with intestinal peel formation in gastroschisis.

Several studies in animal models demonstrate that peel formation in gastroschisis is due to the accumulation and activation of intestinal waste products (IWP) in the amniotic fluid. We reviewed our recent experience with gastroschisis and asked the following questions: First, does staining of the bowel and amniotic fluid with IWP correlate with intestinal peel formation? Second, what prenatal ultrasound findings indicate that peel formation is occurring in utero? Over two years, 16 neonates were treated for gastroschisis; twelve had been diagnosed by prenatal ultrasound and followed closely. Patients were grouped based on the presence of IWP in the amniotic fluid at the time of delivery (staining or no staining), and outcomes were reviewed. All neonates in the staining group (n=7) had a fibrinous peel present at the time of birth whereas a peel was absent in all neonates in the no-staining group (n=9). Matting of the bowel was seen by prenatal ultrasound in four patients in the staining group (0/8 in the no-staining group) and correlated with peel formation (Fisher's exact test p =0.007). Primary closure was done in 14 of the infants, and two required silo closure. In neonates with gastroschisis, staining of the amniotic fluid and bowel serosa with IWP correlated with intestinal peel formation. The ultrasound findings of matting correlated with both peel formation and staining with IWP. These results suggest that spillage of IWP into the amniotic fluid is one of the factors in peel formation in gastroschisis. Identification of matting of the bowel by prenatal ultrasound indicates formation of a peel.

Amniotic Fluid↗
PubMed2000

Tyrosine phosphorylation: a critical component in the formation of hemidesmosomes.

Our goal was to evaluate the role of tyrosine phosphorylation in the complete formation of hemidesmosomes that occurs during development or during remodeling after injury. A corneal organ culture system was used to study hemidesmosome formation as it would occur in an intact tissue. Phosphorylation of the integrin subunit beta 4 and bullous pemphigoid antigen-1 (BPAG-1) was examined, as these proteins are known to play a role in linking the electron-dense plaques along the basal surface with the intermediate filaments to complete the formation of hemidesmosomes. Corneal epithelial sheets were placed on substrata that contained an intact basal lamina or basal laminae that had been either modified or removed. These constructs were incubated for up to 18 h, and hemidesmosome formation was evaluated by using transmission electron microscopy. When epithelial sheets were placed on intact basal laminae and incubated in the presence of the tyrosine kinase inhibitor genistein (200 microM), hemidesmosome formation was impaired. The formation of electron-dense regions was delayed, and no association of intermediate filaments was detected. Results were confirmed by biochemical studies. When the epithelium and underlying proteins were extracted and immunoprecipitated with beta 4 or BPAG-1, tyrosine phosphorylation decreased in the presence of genistein. In addition, the phosphorylation of beta 4 decreased when epithelial sheets were incubated on substrata from which the basal lamina had been removed or altered. Thus, a reduction in phosphorylation of tyrosine residues impairs the formation of mature hemidesmosomes, and substrata that fail to support hemidesmosome formation also demonstrate decreased phosphorylation of tyrosine residues.

Alkalies↗
PubMed2001

The influence of intraoperative complications on adhesion formation during laparoscopic and conventional cholecystectomy in an animal model.

BACKGROUND: The aim of this study was to evaluate the extent of postoperative adhesion formation after laparoscopic and open cholecystectomy. MATERIALS AND METHODS: Qualified surgeons performed 60 experimental laparoscopic cholecystectomies (LC) in dogs with the aim to acquire the laparoscopic technique. To assess the relation between the complications during the operation (bleeding, laceration of the liver bed, or gallbladder perforation) and the formation of adhesions, surviving animals were divided into four groups according to the type of complication occurred. Assessment of the results was made by second-look laparoscopy 4 weeks after LC using the adhesion index (AI; score range, 0-4). The animals then were killed so the extent of adhesion formation could be measured. As a control, open cholecystectomy was performed in 15 dogs without intraoperative complications. The Mann-Whitney rank-sum test and Dunn's method were used for statistical analysis. RESULTS: No adhesion formation or intraoperative complications were registered in the laparoscopic group I. In all the cases wherein bleeding or laceration of the liver bed occurred and was managed with electrocoagulation, adhesions formed. Adhesion formation in these groups was significantly higher than in "ideal LC" or cases of gallbladder perforation alone (p < 0.01). All the animals in the control group developed significantly more adhesions than those in the experimental group (p < 0.05). CONCLUSIONS: It seems that LC has a lower rate of adhesion formation than the conventional open technique. Complications such as bleeding or laceration of the liver bed during LC can enhance adhesion formation. No adhesion formation can be mentioned in relation to gallbladder perforation during LC.

Animals↗
PubMed2006

Crucial role of lysosomal iron in the formation of dinitrosyl iron complexes in vivo.

Dinitrosyl non-heme-iron complexes (DNIC) are found in many nitric oxide producing tissues. A prerequisite of DNIC formation is the presence of nitric oxide, iron and thiol/imidazole groups. The aim of this study was to investigate the role of the cellular labile iron pool in the formation of DNIC in erythroid K562 cells. The cells were treated with a nitric oxide donor in the presence of a permeable (salicylaldehyde isonicotinoyl hydrazone) or a nonpermeable (desferrioxamine mesylate) iron chelator and DNIC formation was recorded using electron paramagnetic resonance. Both chelators inhibited DNIC formation up to 50% after 6 h of treatment. To further investigate the role of lysosomal iron in DNIC formation, we prevented lysosomal proteolysis by pretreatment of whole cells with NH4Cl. Pretreatment with NH4Cl inhibited the formation of DNIC in a time-dependent manner that points to the importance of the degradation of iron metalloproteins in DNIC formation in vivo. Fractionation of the cell content after treatment with the nitric oxide donor revealed that DNIC is formed predominantly in the endosomal/lysosomal fraction. Taken together, these data indicate that lysosomal iron plays a crucial role in DNIC formation in vivo. Degradation of iron-containing metalloproteins seems to be important for this process.

Aldehydes↗
PubMed2006

Differential effects of two types of formative assessment in predicting performance of first-year medical students.

Formative assessments are systematically designed instructional interventions to assess and provide feedback on students' strengths and weaknesses in the course of teaching and learning. Despite their known benefits to student attitudes and learning, medical school curricula have been slow to integrate such assessments into the curriculum. This study investigates how performance on two different modes of formative assessment relate to each other and to performance on summative assessments in an integrated, medical-school environment. Two types of formative assessment were administered to 146 first-year medical students each week over 8 weeks: a timed, closed-book component to assess factual recall and image recognition, and an un-timed, open-book component to assess higher order reasoning including the ability to identify and access appropriate resources and to integrate and apply knowledge. Analogous summative assessments were administered in the ninth week. Models relating formative and summative assessment performance were tested using Structural Equation Modeling. Two latent variables underlying achievement on formative and summative assessments could be identified; a "formative-assessment factor" and a "summative-assessment factor," with the former predicting the latter. A latent variable underlying achievement on open-book formative assessments was highly predictive of achievement on both open- and closed-book summative assessments, whereas a latent variable underlying closed-book assessments only predicted performance on the closed-book summative assessment. Formative assessments can be used as effective predictive tools of summative performance in medical school. Open-book, un-timed assessments of higher order processes appeared to be better predictors of overall summative performance than closed-book, timed assessments of factual recall and image recognition.

Curriculum↗
PubMed1991

Increase in fidelity of rat liver Ile-tRNA formation by both spermine and the aminoacyl-tRNA synthetase complex.

To examine the polyamine effects on the fidelity at the aminoacylation level and the physiological significance of the existence of the aminoacyl-tRNA synthetase complex (ARSC) in animal cells, a single-chain Ile-tRNA synthetase (IRSS) was isolated from the complex by treatment with trypsin. Ile-tRNA formation by IRSS was strongly stimulated by spermine, similar to the results with ARSC. Two misacylations (Val-tRNAIle and Ile-tRNAiMet formation) by IRSS were measured. The error frequency was higher in Ile-tRNAiMet formation (tRNA misacylation) than in Val-tRNAIle formation (amino acid misacylation). Spermine did not influence significantly Ile-tRNAiMet formation, but it stimulated Val-tRNAIle formation by IRSS. Accordingly, spermine decreased the error frequency of tRNA misacylation, but not amino acid misacylation. These results suggest that the conformational changes of individual tRNA by spermine differ from each other, meaning that spermine influences the interaction between individual tRNA and aminoacyl-tRNA synthetase variously. When the aminoacylations of tRNAIle from rat liver, yeast, and Escherichia coli were compared with ARSC and IRSS, the relative speed of Ile-tRNA formation with tRNAIle from other species was faster with IRSS than with ARSC. This indicates that ARSC can recognize tRNAIle from the same species more specifically than IRSS. These results show that both spermine and ARSC are involved in the increase of fidelity of rat liver Ile-tRNA formation.

Acylation↗
PubMed1994

Modulation of pulmonary leukotriene formation and perfusion pressure by bestatin, an inhibitor of leukotriene A4 hydrolase.

We investigated the effects of bestatin, a prototype leukotriene A4 (LTA4) hydrolase inhibitor, on leukotriene (LT) formation and pulmonary artery perfusion pressure (Ppa) in isolated, perfused rat lungs. In lung parenchymal strips stimulated with a 10 microM concentration of the Ca2+ ionophore A23187, bestatin inhibited LTB4 formation with an IC50 = 10.4 +/- 30 microM (mean +/- SD, N = 4). It did not alter cysteinyl LT formation, confirming that it inhibited LTA4 hydrolase selectively, without inhibiting phospholipase, 5-lipoxygenase, or LTC4 synthase. In isolated, perfused lungs stimulated with 10 microM A23187, 300 microM bestatin inhibited LTB4 release by 72.2 +/- 10.6% (mean +/- SEM, N = 6, P < 0.01) but had no significant effect on LTE4 formation (P > 0.5). In these perfused lungs, bestatin did not alter the change in Ppa following stimulation with A23187. This effect is consistent with the insubstantial re-direction of LTA4 toward formation of vasospastic cysteinyl LTs. Separate experiments used lungs from rats treated with lipopolysaccharide endotoxin in vivo, prior to isolation, perfusion, and stimulation with 5 microM formyl-methionyl-leucyl-phenylalanine, in vitro. In these inflamed lungs, 750 microM bestatin inhibited LTB4 formation (P < 0.05) and increased LTE4 formation (P < 0.05), compatible with selective inhibited LTB4 hydrolase. The re-direction of LTA4 metabolism toward formation of cysteinyl LTs by inflamed, perfused lungs did not cause an increase in P(pa).

Animals↗
PubMed1994

Differences in in vivo and in vitro sequence-specific sites of cisplatin-DNA adduct formation and detection of a dose-response relationship.

The cytotoxic and mutagenic properties of the anticancer drug cis-diammine-dichloroplatinum(II) (cisplatin) are mediated by bifunctional adducts between purines. Experiments performed in this study employed a new repetitive thermal-cycling technique to detect cisplatin adduct formation following exposure of cells in culture (in vivo) or following treatment of purified DNA (in vitro exposure). The initial goal of this study was to determine if cisplatin-DNA adduct formation could be measured accurately using phosphor-imaging over a broad concentration range. If this proved possible, it would then be feasible to determine if adduct formation differed within chromatin compared with purified DNA. There were no significant differences in the cisplatin-DNA adduct pattern induced in closed circular or linear double-stranded plasmids in vitro, suggesting that this type of tertiary structural change does not affect the formation of adduct sites. Sequence-specific DNA adduct formation within a human repetitive DNA target sequence, alphoid DNA, following cisplatin treatment of prostate cancer cells in culture (in vivo) and treatment of purified DNA in vitro revealed consistent increases in adduct formation over a broad concentration range, validating the experimental technique. Comparing preferences for cisplatin adduct site formation under these different conditions of exposure demonstrated statistically significant differences. Similar differences were detected for cisplatin repair-deficient Xeroderma pigmentosum cells treated in cell culture, indicating that in vivo/in vitro preferences for adduct site formation are not the result of DNA repair in vivo.

Base Sequence↗
PubMed1988

The human villous cytotrophoblast: interactions with extracellular matrix proteins, endocrine function, and cytoplasmic differentiation in the absence of syncytium formation.

Human syncytiotrophoblasts are derived from villous cytotrophoblasts by cell fusion. Coincident with this morphologic transformation, trophoblasts acquire specific endocrine functions, including elaboration of chorionic gonadotropin (hCG). We wondered if syncytia formation was a prerequisite for biochemical differentiation or simply was one part of the differentiation program. By growing purified human cytotrophoblasts under serum-free conditions and manipulating the culture surface, we were able to disassociate morphologic from biochemical differentiation. We have shown previously (Endocrinology 1986, 118:1567) that human cytotrophoblasts grown in the presence of fetal calf serum flatten out, aggregate, and form functional syncytiotrophoblasts in vitro over 24-96 hr. Here we demonstrate that when grown in the absence of serum, the cells do not undergo these morphologic changes, but remain as individual spherical cells. If the culture surface was precoated with fibronectin or a variety of collagens, but not albumin, the cells regained their ability to flatten, aggregate, and form syncytia. Attachment to and syncytia formation on fibronectin was blocked by the addition of the R-G-D-S-containing peptide, Gly-Arg-Gly-Asp-Ser-Pro. Attachment to and syncytia formation on type I collagen was blocked by anti-human fibronectin F(ab')2 fragments, while association with type IV collagen was not affected by this antibody, suggesting that fibronectin mediates trophoblast association with type I collagen, but not type IV. Although syncytia formation did not occur when cytotrophoblasts were cultured under serum-free conditions in the absence of ECM proteins, biochemical differentiation was not affected. These cells secreted hCG at the same rate under serum-free conditions whether they were plated on plastic only--which prevented syncytia formation--or fibronectin, laminin or, type IV collagen--which allowed syncytia formation to occur. Furthermore, cytoplasmic differentiation in the absence of syncytia formation was confirmed by performing transmission electron microscopy on cytotrophoblasts grown under serum-free conditions in the presence of 8-bromo-cAMP. We conclude that syncytia formation is not a prerequisite for biochemical differentiation, but simply part of the trophoblast differentiation program.

Cell Adhesion↗
PubMed1989

The H-L subgroup of guinea-pig cardiac M2 receptors (M2 beta) regulates inositol phosphate formation.

In previous studies, we showed that cardiac muscarinic receptors (M2) are composed of two subgroups, M2 alpha and M2 beta, with different affinities for agonists and that the M2 alpha subgroup is coupled with inhibition of adenylate cyclase. We now studied which subgroup was responsible for the formation of inositol mono- (IP), bis- (IP2), tris- (IP3) and tetrakis- (IP4) phosphates in guinea pig heart. Carbachol (1 mM) significantly stimulated the formation of all four IPs in [3H]myoinositol-preloaded slices of guinea-pig ventricles. Acetylcholine (1 mM) also stimulated the formation of IP2, IP3 and IP4. However, oxotremorine (1 mM) only slightly stimulated the formation of IP2, and pilocarpine did not stimulate the formation of any IP. The pED50 values of carbachol for IP2 and IP3 formation were 3.76 and 4.23, respectively, which coincided with the pKd values of the low-affinity agonist binding site (L site) measured by competition of carbachol with [3H]quinuclidinyl benzilate [( 3H]QNB) binding while the pKd value for inhibition of adenylate cyclase coincided with the pKd value of the high-affinity agonist binding site (H site). Treatment of animals with pertussis toxin decreased the formation of IP2 and IP3 by carbachol to 66 and 54%, respectively, but resulted in complete inhibition of adenylate cyclase. These results suggested that muscarinic stimulation of the formation of IPs was manifested through a different receptor subgroup (M2 beta) and GTP binding protein different from those for inhibition of adenylate cyclase.

Acetylcholine↗
PubMed1983

Biochemical evaluation of postsurgical wound repair: prevention of intraperitoneal adhesion formation with ibuprofen.

Proteins central to normal wound repair, including collagen and proteoglycans, were extracted during postoperative mesothelial regeneration, then the quantitation was correlated to macroscopic observations of normal peritoneal reepithelialization and/or postoperative adhesion formation. Sixty-three New Zealand white female rabbits of reproductive age were prospectively assigned to either Group A, untreated control; Group B, which received intramuscular injections of ibuprofen, 70 mg/kg per injection (immediately and 6 hr after surgery); or Group C, which received 5 intramuscular injections of ibuprofen (4 hr before surgery, and immediately, 6, 12, and 18 hr after surgery). The right uterine horn underwent one of three standardized surgical traumas: (1) abrasion of the peritoneal surface with a scalpel until punctate bleeding developed, (2) ischemia of the uterine horn by removal of the collateral blood supply (devascularization), (3) crushing of the uterine horn by cross clamping for 3 min with a Kelley hemostat. Thereafter, 10 microCi of C-14-labeled glucosamine and 10 microCi of C-14-labeled proline were injected into the marginal ear vein of each rabbit. All rabbits underwent a laparotomy on the fifth postoperative day for evaluation of adhesion formation and tissue biopsy for protein extraction. No reduction in adhesion formation was found using a 2-dose postoperative treatment regimen. However, using a 70 mg/kg X 5-doses regimen in the immediate perioperative interval, a significant reduction in both adhesion formation and severe adhesion formation (both P less than 0.025) were found following standardized surgical injury. The extent of adhesion formation was correlated with the extractable glycosaminoglycan and collagen concentrations. As determined by recovered glucosamine and proline, a positive correlation was apparent between the severity of adhesion grade and formation of new glycosaminoglycans or collagens. Thus, ibuprofen appears to inhibit adhesion formation through suppression of fibroproliferative inflammation.

Animals↗
PubMed1992

Regulation of phospholipid hydrolysis and second messenger formation by protein kinase C.

The binding of a variety of agonists to their receptors leads to the breakdown of membrane phospholipids and the formation of intracellular second messengers. Hydrolysis of inositol phospholipids by phospholipase C results in the formation of two second messengers, inositol-1,4,5-trisphosphate which mobilizes intracellular calcium and the neutral lipid diacylglycerol (DAG) which binds to and activates protein kinase C (PKC). PKC is actually a family of homologous serine/threonine protein kinases which play a central role in regulation of growth, differentiation and secretion reactions in a variety of cell types. In addition to these feedforward roles of PKC, it is thought to play an important feedback role, regulating early events in signal transduction. To explore these feedback functions we have examined the effect of PKC inhibitors on second messenger formation in thrombin-stimulated human platelets (a rapidly responding system) and the effect of PKC overexpression on second messenger formation and mitogenesis in rat fibroblasts (a system where sustained signaling occurs). Treatment of platelets with inhibitors of PKC potentiates DAG mass formation in response to thrombin while prior activation of PKC with phorbol esters blocks DAG mass formation, consistent with PKC playing a negative feedback role, inhibiting inositol phospholipid breakdown. DAG can also be formed by the sequential hydrolysis of phosphatidylcholine by phospholipase D and phosphatidic acid phosphohydrolase. This is a minor reaction in the rapidly responding platelet system, but may play a role in sustained signaling events. We have found that fibroblasts which overexpress the beta 1 isozyme of PKC display greatly enhanced DAG formation and phospholipase D activation in response to phorbol ester treatment. Upon stimulation of fibroblasts with thrombin, phospholipase D activation is also enhanced by PKC overexpression while formation of inositol phosphates is suppressed. These data suggest that PKC may act as a switch, terminating inositol phospholipid hydrolysis and activating the hydrolysis of phosphatidylcholine. Furthermore, we have observed a strong correlation between activation of phospholipase D and mitogenesis, suggesting an important role for this enzyme in long-term cellular responses to activation.

Blood Platelets↗
PubMed1994

Effect of a neurokinin-1 (NK1) receptor antagonist on oedema formation induced by tachykinins, carrageenin and an allergic response in guinea-pig skin.

The effect of the neurokinin-1 (NK1) receptor antagonist RP67580 in modulating inflammatory oedema formation has been investigated in guinea-pig skin. Oedema formation was measured over 30 min by the extravascular accumulation of intravenously-injected 125I-albumin in the anaesthetised guinea-pig. RP67580 was injected intradermally with the agents under test. Intradermal RP67580 (10 nmol/site) inhibits oedema formation induced by substance P (30 pmol) and neurokinin A (100 pmol), but not that induced by bradykinin (10-1000 pmol) or histamine (10 nmol). Substance P-induced oedema formation is similar in control (saline) and mepyramine (histamine H1 receptor antagonist) pretreated guinea-pigs suggesting a minimal involvement of histamine in substance P induced oedema formation in guinea-pig skin. Oedema formation induced by intradermal carrageenin (0.2%) was not inhibited by RP67580 (1-10 nmol). A significant but partial inhibition of oedema formation induced in a passive cutaneous anaphylaxis (PCA) response was observed. The oedema formation in the PCA was inhibited 50% by mepyramine pretreatment but in the presence of mepyramine no further inhibition of the PCA response by RP67580 was observed.

Animals↗