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Biomedical subjects

John L Wallace

Publications and source records attributed to John L Wallace.

At least 19 recordsLinked to original sources
PubMed2006

Role of cyclooxygenases in oedema-forming activity of bothropic venoms.

The venoms of Bothrops asper (BaV) and Bothrops jararaca (BjV), two of the most medically important poisonous snakes of Latin America, cause pronounced oedema in the victims through poorly understood mechanisms. In the present study, we examined the possible role of cyclooxygenases (COX) in the genesis of mouse paw oedema caused by BaV and BjV injections. BaV at 2.5 microg/paw and BjV at 0.75 microg/paw induced significant oedema that persisted for up to 6h following subplantar injection. Treatment with indomethacin (2 mg/kg), rofecoxib, (10 mg/kg), or dexamethasone (2 mg/kg) significantly reduced the BaV- and BjV-induced oedema formation. Treatment with SC-560 (30 mg/kg) significantly reduced the oedema formation induced by BjV but had no effect on that induced by BaV. Both venoms induced significant increases in the levels of prostaglandin E(2) (PGE(2)) and the expression of COX-1 and COX-2 in paw tissue. The peak of oedema formation and PGE(2) release correlated with marked expression of COX-2 in the paw tissue. These results demonstrate that injection of BaV and BjV results in a rapid increase in oedema formation that is, at least partially, mediated by arachidonic acid metabolites formed by COX-2. In the case of BjV, COX-1-derived prostanoids also appear to contribute significantly to the inflammatory changes.

Analysis of Variance↗
PubMed2006

Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation.

Hydrogen sulfide (H2S) is increasingly recognized as an important signaling molecule in the cardiovascular and nervous systems. Recently, H2S donors were reported to induce neutrophil apoptosis and to suppress expression of some leukocyte and endothelial adhesion molecules. Using rats, we examined the possibility that H2S is an endogenous regulator of key inflammatory events at the leukocyte-endothelial interface. Via intravital microscopy, we observed that H2S donors (NaHS and Na2S) inhibited aspirin-induced leukocyte adherence in mesenteric venules (ED50 of 5.0 micromol/kg for Na2S), likely via activation of ATP-sensitive K+ (K(ATP)) channels. Inhibition of endogenous H2S synthesis elicited leukocyte adherence. Leukocyte infiltration in an air pouch model was also suppressed by H2S donors (NaHS, Lawesson's reagent, and N-acetylcysteine; ED50 of 42.7, 1.3, and 29.9 micromol/kg, respectively) and exacerbated by inhibition of endogenous H2S synthesis. Carrageenan-induced paw edema was suppressed by H2S donors (NaHS and Na2S; ED50s of 35 and 28 micromol/kg, respectively) to the same extent as by diclofenac and enhanced by an inhibitor of H2S synthesis. Suppression of edema formation by H2S donors was mimicked by a K(ATP) channel agonist and reversed by an antagonist of this channel. These results suggest that endogenous H2S is an important mediator of acute inflammation, acting at the leukocyte-endothelium interface. These findings have important implications for anti-inflammatory drug development.

Animals↗
PubMed2006

5-Amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester (ATB-429), a hydrogen sulfide-releasing derivative of mesalamine, exerts antinociceptive effects in a model of postinflammatory hypersensitivity.

H(2)S functions as a neuromodulator and exerts anti-inflammatory activities. Recent data indicate that irritable bowel syndrome (IBS) is linked to inflammation of the gastrointestinal tract. In this study, we have investigated the role of a novel H(2)S-releasing derivative of mesalamine (5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester, ATB-429) in modulating nociception to colorectal distension (CRD), a model that mimics some features of IBS, in healthy and postcolitic rats. Four graded (0.4-1.6 ml of water) CRDs were produced in conscious rats, and colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal response and spinal c-Fos expression. In healthy rats, ATB-429 dose dependently (25, 50, or 100 mg/kg) attenuated CRD-induced hypersensitivity and significantly inhibited CRD-induced overexpression of spinal c-FOS mRNA, whereas mesalamine had no effect. ATB-429-induced antinociception was reversed by glibenclamide, a ATP-sensitive K(+) (K(ATP)) channel inhibitor. The antinociceptive effect of ATB-429 was maintained in a rodent model of postinflammatory hypersensitivity (4 weeks after colitis induction). At a dose of 100 mg/kg, ATB-429 reversed the allodynic response caused by CRD in postcolitic rats. Colonic cyclooxygenase-2 and interkeukin-1beta mRNA and spinal c-FOS mRNA expression were significantly down-regulated by ATB-429, but not by mesalamine. ATB-429, but not mesalamine, increased blood concentrations of H(2)S in both healthy and postcolitic rats. Taken together, these data suggest that ATB-429 inhibits hypersensitivity induced by CRD in both healthy and postcolitic, allodynic rats by a K(ATP) channel-mediated mechanism. This study provides evidence that H(2)S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.

Analgesics↗
PubMed2006

COX-2: a pivotal enzyme in mucosal protection and resolution of inflammation.

The discovery of a second form of cyclooxygenase, COX-2, led to a burst of research aimed at the development of nonsteroidal anti-inflammatory drugs that would not damage the gastrointestinal tract. In the years since, this promise has only been partially fulfilled. Selective COX-2 inhibitors cause less gastric damage than conventional, nonselective COX inhibitors, but their use is still associated with significant gastrointestinal injury, and with toxicity in the renal and cardiovascular systems. COX-2 is now recognized as a source of mediators that produce many beneficial and detrimental effects in the digestive system. In this review, the roles of COX-2 in mucosal defense and injury are discussed. Furthermore, contributions of COX-2-derived products to the long-term consequences of intestinal inflammation, including cancer, are reviewed.

Animals↗
PubMed2006

The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver.

Hydrogen sulfide, like nitric oxide, was best known as a toxic pollutant before becoming recognized as a key regulator of several physiologic processes. In recent years, evidence has accumulated to suggest important roles for hydrogen sulfide as a mediator of several aspects of gastrointestinal and liver function. Moreover, alterations in hydrogen sulfide production could contribute to disorders of the gastrointestinal tract and liver. For example, nonsteroidal anti-inflammatory drugs can reduce production of hydrogen sulfide in the stomach, and this has been shown to contribute to the generation of mucosal injury. Hydrogen sulfide has also been shown to play a key role in modulation of visceral hyperalgesia. Inhibitors of hydrogen sulfide synthesis and drugs that can generate safe levels of hydrogen sulfide in vivo have been developed and are permitting interventional studies in experimental models and, in the near future, humans.

Air Pollutants↗
PubMed2006

Platelets accelerate gastric ulcer healing through presentation of vascular endothelial growth factor.

1. Platelets contain an array of growth factors that can modulate healing processes, including both pro- (e.g., vascular endothelial growth factor (VEGF)) and antiangiogenic (e.g., endostatin) factors. Previous studies have shown that circulating platelets contribute significantly to gastric ulcer healing, acting as a delivery system for these growth factors to the site of injury. In this study, we examined the effects of orally administered human platelets on the healing of gastric ulcers in rats, and determined the contribution of VEGF and endostatin to healing in this model. 2. Twice-daily administration of human platelets significantly accelerated ulcer healing, but platelet-poor plasma (PPP), lysed platelets and serum failed to produce this effect. There was no correlation between ulcer healing and the levels of VEGF or endostatin in serum, PPP or platelet-rich plasma (PRP). 3. Accelerated ulcer healing could not be produced by oral administration of the angiogenic factors themselves, at concentrations matching those in PRP. 4. The accelerated healing induced by platelets could be reversed by immuno-neutralization of VEGF. In contrast, immuno-neutralization of endostatin did not affect PRP-induced ulcer healing. 5. These studies indicate that VEGF released from platelets accounts for the accelerated healing of gastric ulcers. However, as intact (rather than lysed) platelets were required for the accelerated healing, the presentation of VEGF by the platelet at the site of injury appears to be crucial for enhancement of the healing process.

Animals↗
PubMed2006

Gastrointestinal inflammation: a central component of mucosal defense and repair.

The mucosal layer of the gastrointestinal (GI) tract is able to resist digestion by the endogenous substances that we secrete to digest foodstuffs. So-called "mucosal defense" is multi-factorial and can be modulated by a wide range of substances, many of which are classically regarded as inflammatory mediators. Damage to the GI mucosa, and its subsequent repair, are also modulated by various inflammatory mediators. In this article, we provide a review of some of the key inflammatory mediators that modulate GI mucosal defense, injury, and repair. Among the mediators discussed are nitric oxide, polyamines, the eicosanoids (prostaglandins and lipoxins), protease-activated receptors, and cytokines. Many of these endogenous factors, or the enzymes involved in their synthesis, are considered potential therapeutic targets for the treatment of diseases of the digestive tract that are characterized by inflammation and ulceration.

Animals↗
PubMed2006

COX-inhibiting nitric oxide donors (CINODs): potential benefits on cardiovascular and renal function.

The COX-inhibiting nitric oxide donors (CINODs) are a new class of agents designed for the treatment of pain and inflammation. CINODs have a multi-pathway mechanism of action that involves COX inhibition and nitric oxide donation. The anti-inflammatory and analgesic effects of COX inhibition are reinforced through inhibition of caspase-1 regulated cytokine production, while nitric oxide donation provides multiorgan protection. Whereas both conventional nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2-selective NSAIDs are associated with a variety of adverse effects on the renal system, such as hypertension and edema, CINODs may offer an improved renal safety profile. These agents are devoid of hypertensive effects in animal models and their mechanism of action suggests that they may not cause edema. CINODs also have other renal-sparing effects, being better tolerated than NSAIDs in models of kidney failure. CINODs have been shown to prevent platelet activation in vitro and exhibit anti-thrombotic activity in vivo. In animal models of ischemia/reperfusion, CINODs treatment results in improved recovery of heart contractility and reduced left ventricular end-diastolic pressure, in contrast to the effects of aspirin. The combination of improved analgesia, reduced gastrointestinal toxicity and cardiorenal protection has been established in animal models, and early clinical results suggest a favourable gastrointestinal safety profile in humans. The potential for CINODs to provide cardiorenal protection in humans is currently being investigated.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Nitric oxide, aspirin-triggered lipoxins and NO-aspirin in gastric protection.

The use of nonsteroidal anti-inflammatory drugs is associated with an incidence of severe gastrointestinal adverse events of 2-4%, the most common of which is bleeding. These events are largely attributable to the ability of these drugs to suppress prostaglandin and thromboxane synthesis. Prostaglandins perform a number of important functions in the gastrointestinal tract, particularly with respect to resistance of the mucosa to injury. Nitric oxide also appears to be a key mediator of gastrointestinal mucosal defence, and this has been exploited in the development of a novel class of anti-inflammatory drugs, called "NO-NSAIDs", which exhibit little if any gastrointestinal toxicity. NO-NSAIDs are more effective than traditional NSAIDs in reducing pain and inflammation. Another class of inflammatory mediators that contribute to gastrointestinal mucosal defence are the lipoxins. These products of arachidonic acid metabolism can increase the resistance of the stomach to the damaging effects of aspirin. Indeed, aspirin can trigger the formation of a lipoxin by the stomach which acts to diminish the damaging effects of this drug. Lipoxins and nitric oxide are important mediators of mucosal defence in the stomach (and elsewhere in the gastrointestinal tract) and represent attractive therapeutic targets for reducing the incidence of gastric ulceration.

Acetylation↗
PubMed2006

Nitric oxide and inflammation.

There are several pre-clinical studies on the involvement of NO in inflammation. From this large amount of information it is clear that virtually every cell and many immunological parameters are modulated by NO. Thus, the final outcome is that NO cannot be rigidly classified as an anti-inflammatory or pro-inflammatory molecule. This peculiar aspect of the pathophysiology of NO has hampered the development of new drugs based on the concepts developed. Recent therapeutic approach are targeted to increase endogenous NO by activating the gene and some promising early data are available. At the present stage one of the most promising approach in the inflammation field is represented by a new class of NO-releasing compounds namely NO-NSAIDs that have recently enrolled in phase 2 clinical studies.

Acetaminophen↗
PubMed2005

Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels.

Hydrogen sulfide (H(2)S) functions as a neuromodulator, but whether it modulates visceral perception and pain is unknown. Cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) mediate enzymatic generation of H(2)S in mammalian cells. Here we have investigated the role of H(2)S in modulating nociception to colorectal distension, a model that mimics some features of the irritable bowel syndrome. Four graded (0.4-1.6 ml of water) colorectal distensions (CRDs) were produced in conscious rats (healthy and postcolitic), and rectal nociception was assessed by measuring the behavioral response during CRD. Healthy rats were administered with sodium hydrogen sulfide (NaHS) (as a source of H(2)S), L-cysteine, or vehicle. In a second model, we investigated nociception to CRD in rats recovering from a chemically induced acute colitis. We found that CBS and CSE are expressed in the colon and spinal cord. Treating rats with NaHS resulted in a dose-dependent attenuation of CRD-induced nociception with the maximal effect at 60 micromol/kg (p < 0.05). Administration of L-cysteine, a CSE/CBS substrate, reduced rectal sensitivity to CRD (p < 0.05). NaHS-induced antinociception was reversed by glibenclamide, a ATP-sensitive K(+) (K(ATP)) channel inhibitor, and N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric-oxide (NO) synthase inhibitor. The antinociceptive effect of NaHS was maintained during the resolution of colon inflammation induced by intrarectal administration of a chemical irritant. In summary, these data show that H(2)S inhibits nociception induced by CRD in both healthy and postcolitic rats. This effect is mediated by K(ATP) channels and NO. H(2)S-releasing drugs might be beneficial in treating painful intestinal disorders.

ATP-Binding Cassette Transporters↗
PubMed2005

Recent advances in gastric ulcer therapeutics.

In developed countries at least, ulcers related to Helicobacter pylori infection are becoming rarer. However, ulcers associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) remain a major clinical problem, which has not been solved through the introduction of selective inhibitors of cyclooxygenase (COX)-2. Recent studies suggest that NSAID-induced ulcers can be prevented largely through co-administration of a proton pump inhibitor to block acid secretion in the stomach. In patients requiring aspirin therapy to prevent cardiovascular diseases, co-administration of aspirin plus a proton pump inhibitor was found to be safer than using another anti-platelet therapy that does not block gastric prostaglandin production (e.g. clopidogrel). Several recent papers have clarified further the contribution of COX-2 to gastric mucosal defence and to the healing of ulcers. In some circumstances, COX-2 produces a highly potent gastroprotective substance (15-R-lipoxin A(4)), and analogues of this substance could have therapeutic value for preventing gastric ulceration. Nitric oxide-releasing NSAIDs continue to show promise in terms of limiting damage to the gastrointestinal tract, even when given in combination with aspirin. Recent studies support the notion that platelets make a major contribution to ulcer healing, and the release of several key growth factors from platelets appears to be regulated by proteinase-activated receptors.

Annexins↗
PubMed2005

Nitric oxide as a regulator of inflammatory processes.

Nitric oxide (NO) plays an important role in mediating many aspects of inflammatory responses. NO is an effector molecule of cellular injury, and can act as an anti-oxidant. It can modulate the release of various inflammatory mediators from a wide range of cells participating in inflammatory responses (e.g., leukocytes, macrophages, mast cells, endothelial cells, and platelets). It can modulate blood flow, adhesion of leukocytes to the vascular endothelium and the activity of numerous enzymes, all of which can have an impact on inflammatory responses. In recent years, NO-releasing drugs have been developed, usually as derivatives of other drugs, which exhibit very powerful anti-inflammatory effects.

Antioxidants↗
PubMed2005

A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis.

Citrobacter rodentium is a bacterial pathogen that causes a murine infectious colitis equivalent to enterohemorrhagic Escherichia coli infection in humans. Colonic luminal fluid from C. rodentium-infected mice, but not from sham-infected mice, contains active serine proteinases that can activate proteinase-activated receptor-2 (PAR2). We have identified granzyme A and murine trypsins to be present in C. rodentium-infected luminal fluid, as determined by mass spectrometry and Western blot analysis. Inflammatory indices (colonic mucosa macroscopic damage score, increased intestinal wall thickness, granulocyte infiltration, and bacterial translocation from the colonic lumen to peritoneal organs) were all increased in C. rodentium-infected mice, compared with sham-infected mice. Soybean trypsin inhibitor-treated wild-type mice and untreated PAR2-deficient (PAR2-/-) mice (compared with their wild-type littermates) both had substantially reduced levels of C. rodentium-induced inflammation. These data point to an important role for both pathogen-induced host serine proteinases and PAR2 in the setting of infectious colitis.

Animals↗
PubMed2005

Roles of platelets and proteinase-activated receptors in gastric ulcer healing.

Proteinase-activated receptors (PARs) are expressed on the surface of many cells, but those on the platelet have been among the most thoroughly characterized. PARs act as key receptors mediating the proaggregatory and pro-secretory effects of thrombin. In addition to contributing to hemostasis, platelets are increasingly being viewed as important contributors to healing and to tumor growth. This is attributable to the many pro- and anti-angiogenic factors that are stored within platelets, which can be released at the sites of injury and new vessel growth. In this paper, we review the importance of the platelet in gastric ulcer healing, the contribution of platelet-contained angiogenic factors to the healing of gastric ulcers, and the role of PARs in regulating the release of angiogenic factors from platelets. Taken together, our results suggest that PARs, including those expressed on platelets, are a rational therapeutic target for modulating healing processes and tumor growth.

Blood Platelets↗
PubMed2005

Predisposition to colorectal cancer in rats with resolved colitis: role of cyclooxygenase-2-derived prostaglandin d2.

Colitis markedly increases the risk of developing colon cancer, but the underlying mechanisms are not fully understood. In a rat model of colitis, alterations in epithelial secretion, proliferation, and barrier function persist long after healing has occurred. In the present study, we examined whether rats that have recovered from a bout of colitis are more susceptible to preneoplastic lesions and whether this susceptibility is mediated by cyclooxygenase (COX)-2-derived prostaglandin (PG) D2. Colitis was induced by intracolonic administration of trinitrobenzenesulfonic acid. Six weeks later, weekly treatment with the carcinogen azoxymethane was initiated. Postcolitis rats exhibited significantly more aberrant crypt foci after azoxymethane treatment than controls. The postcolitis rats also exhibited markedly increased colonic PGD2 synthesis and elevated COX-2, H-PGD synthase, and beta-catenin expression. Treatment for 1 week with a selective COX-2 inhibitor or with a selective PGD2 receptor (DP1) antagonist significantly reduced susceptibility of postcolitis rats to aberrant crypt foci development, beta-catenin expression, and mucosal thickness. The results from this animal model suggest that prolonged elevation of COX-2-derived PGD2 synthesis after resolution of colitis may contribute significantly to colitis-associated increases in colon cancer incidence. PGD2 may therefore represent a rational target for therapies directed at reducing the incidence of colitis-associated colorectal cancer.

Animals↗