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Biomedical subjects

J L Wallace

Publications and source records attributed to J L Wallace.

At least 55 records · Page 3Linked to original sources
PubMed2000

Bacterial colonization and healing of gastric ulcers: the effects of epidermal growth factor.

Experimental gastric ulcers are rapidly colonized by various bacteria, resulting in significantly impaired healing. Epidermal growth factor (EGF) is capable of preventing bacterial colonization of the healthy intestinal mucosa. In this study, we examined the possibility that EGF accelerates gastric ulcer healing by reducing bacterial colonization of the ulcer. Gastric ulcers were induced by serosal application of acetic acid. The effect of daily administration of EGF on ulcer healing and bacterial colonization was assessed and compared with the effect of daily treatment with broad-spectrum antibiotics. EGF administration reduced colonization levels and accelerated ulcer healing as effectively as the antibiotic treatment. EGF was without effect on acid secretion or neutrophil infiltration into the ulcer. Bacterial growth was not inhibited in the presence of EGF in vitro. These results demonstrate that EGF reduces bacterial colonization during an established infection of a compromised mucosal surface. This effect may contribute to the ability of EGF to accelerate gastric ulcer healing. This effect is acid independent and not due to an anti-inflammatory effect or to direct bactericidal actions.

Administration, Oral↗
PubMed2000

Cyclooxygenase-2-derived prostaglandin D(2) is an early anti-inflammatory signal in experimental colitis.

The ability of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors to exacerbate inflammatory bowel disease suggests that prostaglandins are important anti-inflammatory mediators in this context. Prostaglandin D(2) has been suggested to exert anti-inflammatory effects. We investigated the possibility that prostaglandin D(2) derived from cyclooxygenase-2 plays an important role in downregulating colonic inflammation in rats. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid. At various times thereafter (from 1 h to 7 days), colonic prostaglandin synthesis and myeloperoxidase activity (index of granulocyte infiltration) were measured. Prostaglandin D(2) synthesis was elevated >4-fold above controls within 1-3 h of induction of colitis, preceding significant granulocyte infiltration. Treatment with a selective cyclooxygenase-2 inhibitor abolished the increase in prostaglandin D(2) synthesis and caused a doubling of granulocyte infiltration. Colonic granulocyte infiltration was significantly reduced by administration of prostaglandin D(2) or a DP receptor agonist (BW-245C). These results demonstrate that induction of colitis results in a rapid increase in prostaglandin D(2) synthesis via cyclooxygenase-2. Prostaglandin D(2) downregulates granulocyte infiltration into the colonic mucosa, probably through the DP receptor.

Animals↗
PubMed2000

Spontaneously developing chronic colitis in IL-10/iNOS double-deficient mice.

Mice deficient in both inducible nitric oxide synthase (iNOS) and interleukin (IL)-10 (iNOS(-/-)/IL-10(-/-)) were created to examine the role of iNOS in spontaneously developing intestinal inflammation. IL-10(-/-)/iNOS(-/-) mice were compared with IL-10(-/-) (iNOS(+/+)) littermates over 6 mo. RT-PCR, Western blot analysis, and immunohistochemistry were performed to measure iNOS message and protein levels. Plasma nitrate/nitrite (NO(x)) levels were assessed by HPLC. Damage scores (macroscopic and microscopic) and granulocyte infiltration were assessed. At 3-4 wk, IL-10(-/-) and IL-10(-/-)/iNOS(-/-) mice had no signs of colonic inflammation or granulocyte infiltration. Plasma NO(x) levels were not different from controls. By 3-4 mo, IL-10(-/-) mice had increased damage scores and granulocyte infiltration concurrent with increased mRNA and protein synthesis (restricted to the epithelium) for iNOS in intestinal tissues but not other tissues. Plasma NO(x) levels increased fivefold. Interestingly, in the absence of iNOS induction or increased plasma NO(x), iNOS(-/-)/IL-10(-/-) mice had damage and granulocyte infiltration equivalent to those observed in IL-10(-/-) littermates. These data suggest that iNOS does not impact on the development or severity of spontaneous chronic inflammation in IL-10-deficient mice.

Age Factors↗
PubMed2000

Endothelial nitric oxide synthase modulates gastric ulcer healing in rats.

Nitric oxide has been shown to be beneficial for gastric ulcer healing. We determined the relative effects of endothelial and inducible nitric oxide synthases on gastric ulcer healing in rats. Ulcers were induced by serosal application of acetic acid. Ulcer severity, angiogenesis, and nitric oxide synthase expression were assessed 3-10 days later. The effects of inhibitors of nitric oxide synthase were also examined. Inducible nitric oxide synthase mRNA was only detected in ulcerated tissue (maximal at day 3), whereas the endothelial isoform mRNA was detected in normal tissue and increased during ulcer healing. Inducible nitric oxide synthase was expressed in inflammatory cells in the ulcer bed, whereas endothelial nitric oxide synthase was found in the vascular endothelium and in some mucosal cells in both normal and ulcerated tissues. Angiogenesis changed in parallel with endothelial nitric oxide synthase expression. N(6)-(iminoethyl)-L-lysine did not affect angiogenesis or ulcer healing, while N(G)-nitro-L-arginine methyl ester significantly reduced both. In conclusion, endothelial nitric oxide synthase, but not the inducible isoform, plays a significant role in gastric ulcer healing.

Animals↗
PubMed2000

Role of cyclooxygenase-2 in modulating gastric acid secretion in the normal and inflamed rat stomach.

Nonsteroidal anti-inflammatory drugs elevate gastric acid secretion, possibly contributing to their ability to interfere with gastric ulcer healing. Inhibitors of cyclooxygenase-2 have been shown to delay experimental gastric ulcer healing. In the present study, we tested the hypothesis that cyclooxygenase-2-derived prostaglandins modulate gastric acid secretion. Studies were performed in normal rats and in rats with iodoacetamide-induced gastritis. Inflammation in the latter group was confirmed histologically and by a threefold increase in tissue levels of the granulocyte marker myeloperoxidase and was also associated with overexpression of cyclooxygenase-2 in the stomach. Basal acid secretion in both groups of rats was not affected by pretreatment with DuP-697, a selective inhibitor of cyclooxygenase-2. A nonselective cyclooxygenase inhibitor, indomethacin, had no effect on acid secretion in normal rats but caused a doubling of acid secretion in the rats with gastritis. DuP-697 had no effect on pentagastrin-induced secretion in either group of rats. Gastritis itself was associated with significantly increased pentagastrin-induced acid secretion, and this was further increased in rats pretreated with indomethacin. These results suggest that in a setting of gastric inflammation, prostaglandins derived from cyclooxygenase-1, not cyclooxygenase-2, exert inhibitory effects on acid secretion.

Animals↗
PubMed2000

Antihypertensive properties of a nitric oxide-releasing naproxen derivative in two-kidney, one-clip rats.

Nonsteroidal anti-inflammatory drugs have been reported to exacerbate hypertension. In this study, we tested the hypothesis that a nitric oxide-releasing derivative of naproxen would ameliorate hypertension in the rat. Hypertension was induced by partially occluding one renal artery (the "2K,1C" model), and 2 wk later the rats started receiving naproxen, the nitric oxide-releasing derivative HCT-3012, or vehicle each day for 2 wk. Naproxen significantly exacerbated the hypertension. HCT-3012 significantly reduced blood pressure relative to both the naproxen- and vehicle-treated groups. Both naproxen and HCT-3012 markedly suppressed whole blood thromboxane B(2) synthesis. In studies of anesthetized rats, naproxen significantly enhanced the late hypertensive response to endothelin-1 and significantly blunted the early hypotensive response. In contrast, HCT-3102 did not affect either response to endothelin-1. In vitro, HCT-3012 significantly reduced the responsiveness of aortic rings to the contractile effects of phenylephrine. These studies suggest that HCT-3012 reduces blood pressure in hypertensive rats, not simply through the vasodilatory actions of the nitric oxide it releases, but through alterations in the responsiveness of the vasculature to endogenous pressor agents.

Animals↗
PubMed2000

Anti-inflammatory activities of a new series of selective phosphodiesterase 4 inhibitors derived from 9-benzyladenine.

Adenine derivatives substituted in position 9 have been demonstrated to have potent phosphodiesterase (PDE) inhibition properties with high selectivity toward PDE4. We compared the effects of various compounds derived from 9-benzyladenine with those of the selective PDE4 inhibitor RP 73401 on the inhibition of PDE4 isolated from bovine aorta, arachidonic acid, and tumor necrosis factor-alpha release by mononuclear cells from healthy subjects. The rank order of potency of the various compounds for in vitro activities on arachidonic acid release is RP 73401 > NCS 613 > NCS 630 > NCS 632 > BWA 78U = NCS 631. The most effective compounds in vitro (RP 73401 and NCS 613) were further investigated in vivo. Both PDE inhibitors dose dependently (1, 10, and 30 mg/kg per os) inhibited the recruitment of neutrophils in the bronchoalveolar lavage fluid of mice exposed to endotoxin via aerosol. Significant differences were observed with 10 and 30 mg/kg RP 73401 and 30 mg/kg NCS 613. In rats, RP 73401, but not NCS 613, significantly increased basal acid secretion at 30 mg/kg i.v. and pentagastrin-stimulated acid secretion at 0.3, 1, and 10 mg/kg. These results demonstrate that the compounds derived from 9-benzyladenine, namely NCS 613, elicit anti-inflammatory activities. It is also suggested that their activities have been mediated through the inhibition of PDE4 isoenzyme. The fact that NCS 613 did not stimulate the gastric acid secretion suggests that this compound may produce fewer gastrointestinal side effects than second-generation PDE4 inhibitors, such as RP 73401.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

Distribution and expression of cyclooxygenase (COX) isoenzymes, their physiological roles, and the categorization of nonsteroidal anti-inflammatory drugs (NSAIDs).

The molecular identification of a second isoform of cyclooxygenase-2 (COX-2) led to a major investment by several pharmaceutical companies in the development of selective inhibitors. The central tenets of the rationale for developing selective COX-2 inhibitors are that prostaglandins that contribute to inflammation are derived from COX-2, whereas prostaglandins that are involved in normal physiological processes are derived from the constitutively expressed isoform COX-1. There is now considerable evidence that COX-2 is actually expressed constitutively in many tissues and performs important physiological functions. Thus, suppression of COX-2 with selective inhibitors should not be expected to be without some adverse consequences. Moreover, there is strong evidence that COX-1 contributes to inflammation and pain, so selective inhibition of COX-2 will not necessarily produce the same degree of efficacy that is seen with mixed inhibitors of COX-1 and COX-2.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Synthesis and analgesic activity of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic acid methyl esters, acetic acids, and acetamides.

A group of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic acid methyl esters (7), weak acetic acids (8), and acetamides (9) were designed for evaluation as less acidic non-ulcerogenic non-steroidal antiinflammatory drugs (NSAIDs). In this respect, the model compound 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)]acetic acid (8a), unlike traditional arylacetic acid NSAIDs, was shown to be a weak acid with a pKa of 9.17. In contrast to arylacetic acid NSAIDs, the alpha-methylacetic acid sodium salt of 8a, or the methyl alpha-methylacetate ester (7a) did not inhibit cyclooxygenase-1 (COX-1) or -2 (COX-2). In vitro stability studies showed that the methyl alpha-methylacetate ester (7a) acts as a prodrug to the alpha-methylacetic acid derivative (8a), undergoing rapid (< 10 minutes) and quantitative conversion upon incubation with rat plasma, or incubation with rat liver homogenate (t1/2 = 25 min). In contrast, the alpha-methylacetamide (9a) underwent negligible (< 2%) conversion to the alpha-methylacetic acid derivative (8a) upon incubation with either rat plasma, or rat liver homogenate, for incubation times up to 24 h. The effect of a C-3 para-substituted-benzoyl substituent (R1 = H, Cl, Me), a C-4 substituent (R2 = aryl, benzyl, cyclohexyl, alkyl), and the nature of the N1-acetic acid moiety [methyl ester (R3 = OMe), acetic acid (R3 = OH), acetamide (R3 = NH2)] on analgesic activity was determined using the 4% NaCl-induced abdominal constriction (writhing) assay. Compounds 7-9 inhibited writhing 27-95% relative to the reference drug aspirin (58% inhibition). The analgesic potency with respect to the para-benzoyl substituent was H > Cl or Me. Although the effect of the C-4 R2-substituent on analgesic activity was variable within the ester, acid and amide sub-groups of compounds, compounds having a R2-cyclohexyl substituent generally provided superior analgesic activity relative to those having a lipophilic alkyl substituent. The nature of the R3-substituent (OMe, OH, NH2) was a determinant of analgesic activity where the potency order was acetic acid methyl ester > acetic acid or acetamide, except when the C-4 R2-substituent was cyclohexyl or benzyl where the potency order was acetamide > acetic acid methyl ester or acetic acid. Reduction of the 5,6-olefinic bond of the 1,4-dihydropyridyl compound (9a, 94% inhibition) to the corresponding 1,2,3,4-tetrahydropyidyl derivative (10, 69% inhibition) reduced analgesic activity.

Acetamides↗
PubMed1999

Enhanced anti-inflammatory effects of a nitric oxide-releasing derivative of mesalamine in rats.

BACKGROUND & AIMS: Nitric oxide (NO)-releasing derivatives of cyclooxygenase inhibitors exhibit enhanced anti-inflammatory activity and greatly reduced gastrointestinal toxicity. We evaluated whether a similar derivatization of mesalamine (5-aminosalicylic acid) would improve its anti-inflammatory activity. METHODS: Effects of an NO-releasing derivative of mesalamine (NCX-456; NO-mesalamine) were compared with those of mesalamine itself and 2 other NO donors in a rat model of colitis. These drugs were compared for their ability to inhibit leukocyte adherence to the vascular endothelium in vivo, interleukin (IL)-1beta and interferon (IFN)-gamma release in vitro (splenocytes and colon), and messenger RNA expression in the inflamed colon. RESULTS: NO-mesalamine was significantly more effective than mesalamine in reducing the severity of colitis (damage and granulocyte infiltration). Unlike mesalamine, NO-mesalamine significantly suppressed leukocyte adherence to the vascular endothelium in vivo. NO-mesalamine inhibited IL-1beta and IFN-gamma release and caspase 1 activity in splenocytes; such effects were not found in the inflamed colon. CONCLUSIONS: These studies show that an NO-releasing derivative of mesalamine has significantly enhanced anti-inflammatory activity, including improved efficacy in a rat model of colitis. The improved efficacy of this derivative is most likely caused by its enhanced ability to suppress leukocyte infiltration and possibly to scavenge peroxynitrite.

Aminosalicylic Acids↗
PubMed1999

Pro- and anti-inflammatory actions of thrombin: a distinct role for proteinase-activated receptor-1 (PAR1).

1. Thrombin has well characterized pro-inflammatory actions that have recently been suggested to occur via activation of its receptor, proteinase-activated receptor-1 (PAR1). 2. In the present study, we have compared the effects of thrombin to those of two peptides that selectively activate the PAR1 receptor, in a rat hindpaw oedema model. We have also examined whether or not thrombin can exert anti-inflammatory activity in this model. 3. Both thrombin and the two PAR1 activating peptides induced significant oedema in the rat hindpaw following subplantar injection. 4. The oedema induced by thrombin was abolished by pre-incubation with hirudin, and was markedly reduced in rats in which mast cells were depleted through treatment with compound 48/80 and in rats pretreated with indomethacin. In contrast, administration of the PAR1 activating peptides produced an oedema response that was not reduced by indomethacin and was only slightly reduced in rats pretreated with compound 48/80. 5. Co-administration of thrombin together with a PAR1 activating receptor resulted in a significantly smaller oedema response than that seen with the PAR1 activating peptide alone. This anti-inflammatory effect of thrombin was abolished by pre-incubation with hirudin. 6. These results demonstrate that the pro-inflammatory effects of thrombin occur through a mast-cell dependent mechanism that is, at least in part, independent of activation of the PAR1 receptor. Moreover, thrombin is able to exert anti-inflammatory effects that are also unrelated to the activation of PAR1.

Animals↗
PubMed1999

Limited anti-inflammatory efficacy of cyclo-oxygenase-2 inhibition in carrageenan-airpouch inflammation.

1. Cyclo-oxygenase-2 (COX-2) is expressed at sites of inflammation and is believed to be the major source of inflammation-associated prostaglandin synthesis. Selective inhibition of COX-2 has been suggested to produce anti-inflammatory effects with reduced toxicity in the gastrointestinal tract. We examined the extent to which suppression of COX-2 led to inhibition of various components of inflammation in the carrageenan-airpouch model in the rat. 2. Indomethacin (> or =0.3 mg kg(-1)), nimesulide (> or =3 mg kg(-1)) and the selective COX-2 inhibitor, SC-58125 (> or =0.3 mg kg(-1)), significantly suppressed the production of prostaglandin E2 at the site of inflammation. At higher doses, indomethacin (> or =1 mg kg(-1)) and nimesulide (30 mg kg(-1)), but not SC-58125 (up to 10 mg kg(-1)), significantly inhibited COX-1 activity (as measured by whole blood thromboxane synthesis). 3. All three test drugs significantly reduced the volume of exudate in the airpouch, but only at doses greater than those required for substantial (>90%) suppression of COX-2 activity. Similarly, reduction of leukocyte infiltration was only observed with the doses of indomethacin and nimesulide that caused significant suppression of COX-1 activity. 4. SC-58125 did not significantly affect leukocyte infiltration into the airpouch at any dose tested (up to 10 mg kg(-1)). A second selective COX-2 inhibitor, Dup-697, was also found to suppress exudate PGE2 levels without significant effects on leukocyte infiltration. 5. These results indicate that selective inhibition of COX-2 results in profound suppression of PGE2 synthesis in the carrageenan-airpouch, but does not affect leukocyte infiltration. Exudate volume was only reduced with the highly selective COX-2 inhibitor when a dose far above that necessary for suppression of COX-2 activity was used. Inhibition of leukocyte infiltration was observed with indomethacin and nimesulide, but only at doses that inhibited both COX-1 and COX-2.

Animals↗
PubMed1999

Characterization of the inflammatory response to proteinase-activated receptor-2 (PAR2)-activating peptides in the rat paw.

In the present study, we have observed the development of an inflammatory reaction in the rat hindpaw, following the injection of specific agonists of PAR2 (two PAR2 activating peptides). This inflammation was characterized by oedema and granulocyte infiltration. Two selective PAR2 activating peptides, SLGRL-NH2 and trans-cinnamoyl-LIGRLO-NH2 induced significant oedema in the rat hindpaw from 1-6 h following subplantar injection. Six hours after the PAR2-activating peptide injection, the paw tissues showed a complete disruption of tissue architecture along with an inflammatory cell infiltrate. In the inflamed paw, PAR2-immunoreactivity was expressed on endothelial cells as well as on the infiltrating inflammatory cells. The oedema induced by the injection of the two PAR2 activating peptides was slightly reduced in rats pre-treated with compound 48/80, but was not modified by pre-treatment of rats with cromolyn, a mast cell stabilizer. Pre-treatment of rats with a cyclo-oxygenase inhibitor (indomethacin) or a nitric oxide synthase inhibitor (L-N(omega)-nitro-L-arginine methyl ester) had no effect on the oedema induced by the PAR2-activating peptides. These results demonstrate that the administration of PAR2-activating peptides into the rat paw induced an acute inflammatory response characterized by a persistent oedema (at least 6 h) and granulocyte infiltration. The PAR2-induced inflammatory response occurred through a mechanism largely independent of mast cell activation, and of the production of prostanoids and nitric oxide.

Animals↗
PubMed1999

N-bisphosphonates cause gastric epithelial injury independent of effects on the microcirculation.

BACKGROUND: Nitrogen-containing bisphosphonates have been shown to be effective for the treatment of osteoporosis and Paget's disease of bone. Unfortunately, these drugs also have the capacity to irritate the upper gastrointestinal mucosa. In this study we investigated the ability of alendronate and pamidronate to directly damage the gastric epithelium and attempted to determine whether these drugs caused injury through gastric microcirculatory alterations. METHODS: An ex vivo gastric chamber model was used. Effects of topically applied alendronate and pamidronate on transmucosal potential difference and epithelial integrity (histology) were determined. Also, the effects of agents capable of preventing microvascular injury in the stomach (PGE2 and two nitric oxide donors) were examined for their ability to prevent gastric injury induced by the two N-bisphosphonates. RESULTS: Alendronate and pamidronate caused a concentration-dependent decrease in transmucosal potential difference, widespread epithelial injury and infiltration of neutrophils into the mucosa. PGE2 and the two nitric oxide donors did not prevent the changes in potential difference or the epithelial injury, but did reduce neutrophil infiltration. Significant release of PGE2 into the lumen was observed following application of the two bisphosphonates, but neither drug altered mucosal blood flow. CONCLUSIONS: These results suggest that these N-bis- phosphonates directly damage the gastric epithelium independent of actions on the microvasculature.

Administration, Topical↗