Showing papers by "Matthew B. Grisham published in 1991"
TL;DR: It was found that the addition of TNBS (1 mmol/L) to the 10,000 x g supernatant of rat colon homogenates increased the rate of superoxide production from normally undetectable levels to 2.6 +/- 0.23 nmol, suggesting that TNBS was required for the enhanced oxidative metabolism.
136 citations
TL;DR: There is a growing body of experimental data to suggest that the chronically inflamed intestine and/or colon may be subjected to considerable oxidative stress and one such drug is the sulfasalazine metabolite 5-ASA, a potent antioxidant that possesses multiple mechanisms of action including nitrogen, carbon and oxygen-centered free radical scavenging properties as well as the ability to decompose HOCl and scavenge hemoprotein-associated oxidants.
Abstract: There is a growing body of experimental data to suggest that the chronically inflamed intestine and/or colon may be subjected to considerable oxidative stress. The most probable sources of these oxidants are the phagocytic leukocytes since these cells are known to be present in large numbers in the inflamed mucosa and are known to produce significant amounts of reactive oxygen species in response to certain inflammatory stimuli. Because the colonic mucosa contains relatively small amounts of antioxidant enzymes (e.g. SOD, catalase, GSH peroxidase) it is possible that the gut mucosa may be overwhelmed during times of active inflammation which could result in intestinal injury. If reactive oxygen species play an important role in mediating mucosal injury in IBD then it should be possible to attenuate this injury by the use of antioxidants. One such drug is the sulfasalazine metabolite 5-ASA. It may not be coincidence that this potent antiinflammatory metabolite is a potent antioxidant that possesses multiple mechanisms of action including nitrogen, carbon and oxygen-centered free radical scavenging properties as well as the ability to decompose HOCl and scavenge hemoprotein-associated oxidants. In addition 5-ASA has the additional property of being able to chelate iron and render it poorly redox active. The reason that 5-ASA is so effective in vivo may be due to this multitude of antioxidant properties. This would also suggest that other, more potent antioxidants may prove beneficial in the treatment of IBD.
114 citations
TL;DR: The results of in vivo experiments indicate that H2O2 and NH2Cl, but not HOCl, promote leukocyte adhesion to venular endothelium, and both oxidants promoteLeukocyte adherence via activation of CD11/CD18.
108 citations
TL;DR: The data derived from in vivo and in vitro studies indicate that leukocyte adhesion per se does not necessarily lead to increased vascular protein leakage and leukocytes emigration, and adhesion-dependent PMN functions such as emigration and superoxide production may play an important role in producing the alterations in vascular integrity observed in inflamed microvessels.
Abstract: The overall objective of this study was to determine whether leukocyte adherence and/or emigration is a prerequisite for the increased vascular protein leakage associated with acute inflammation. A...
100 citations
TL;DR: The findings of the present study suggest that the intestinal epithelium is injured and restitutes during the normal course of digestion and absorption of a meal.
Abstract: The effects of hydrolytic products of carbohydrate, protein, and lipid digestion on jejunal mucosal injury and restitution were assessed in anesthetized rats. Mucosal epithelial integrity was conti...
94 citations
TL;DR: Results and data in the literature indicate that many of the agents that are commonly used to either scavenge or inhibit the production of oxygen radicals in postischemic tissues exert a significant inhibitory influence on leukocyte adhesion to microvascular endothelium in vivo.
Abstract: The objective of this study was to determine whether agents that either scavenge or inhibit the production of oxygen radicals can alter the adhesive interactions between leukocytes and venular endothelium elicited by ischemia-reperfusion. Cat mesenteric and intestinal blood flows were reduced to 20% of baseline for 1 hr, followed by 1 hr of reperfusion. Sixty minutes after reperfusion, red blood cell velocity (Vr), leukocyte rolling velocity (Vw), and the number of adherent leukocytes were measured in mesenteric venules. Then, either manganese-superoxide dismutase (Mn-SOD), catalase, desferrioxamine, or oxypurinol was administered intravascularly. Ten minutes later, repeat measurements were obtained and compared with pretreatment values. Catalase, Mn-SOD, and oxypurinol significantly attenuated neutrophil adherence while neither inactivated-catalase nor desferrioxamine altered the reperfusion-induced leukocyte adhesion. The ratio of Vw to erythrocyte velocity, an index of the fracture stress between rolling leukocytes and venular endothelium, was not altered by any of the agents studied. These results and data in the literature indicate that many of the agents that are commonly used to either scavenge or inhibit the production of oxygen radicals in postischemic tissues exert a significant inhibitory influence on leukocyte adhesion to microvascular endothelium in vivo. Our results are also consistent with the view that xanthine oxidase-derived oxidants contribute to the leukocyte-endothelial cell adhesive interactions associated with reperfusion of ischemic tissues.
88 citations
TL;DR: The mechanism by which 5-ASA inhibited lipid peroxidation appeared to be due to its ability to donate electrons to and thus scavenge the radical and nonradical forms of HB(IV).
69 citations
Journal Article•
TL;DR: At concentrations found in inflamed tissue, both NH2Cl and H2O2 increase Isc probably by stimulating release of arachidonate metabolites and neurotransmitter(s).NH2Cl also may act directly on the epithelial cell to stimulate Isc and evoke Cl- secretion.
Abstract: Neutrophil-derived oxidants may be involved in inflammatory bowel disease. Stable oxidants formed by halogenation of primary amines (e.g., monochloramine, NH2Cl) are extremely potent and may be of major importance in the pathophysiological response in inflammatory bowel disease. We tested the effects of NH2Cl relative to other oxidants on muscle-stripped rat colon under short-circuit conditions. Serosal addition of the oxidants evoked a concentration-dependent increase in short-circuit current (Isc). The EC50 values were 3.2 microM for NH2Cl, 6.5 microM for HOCl and 6.5 microM for H2O2. Responses to NH2Cl and H2O2 were abolished by removal of Cl- or Ca++. Unidirectional 36Cl- flux measurements showed that both oxidants (50 microM) evoked significant decreases in net chloride absorption. Tetrodotoxin (0.5 microM) and atropine (0.5 microM) partially inhibited the initial phase of the response to 50 microM NH2Cl; tetrodotoxin completely inhibited and atropine partially inhibited the response to 50 microM H2O2. Piroxicam (5 microM) inhibited the increase in Isc to 50 microM NH2Cl and H2O2 by 20-45% and 90%, respectively. Serosal prostaglandin E2 levels were significantly increased after the addition of 50 microM NH2Cl and H2O2. The morphological response to NH2Cl consisted of changes in mucosal depth and crypt architecture. In conclusion, at concentrations found in inflamed tissue, both NH2Cl and H2O2 increase Isc probably by stimulating release of arachidonate metabolites and neurotransmitter(s). NH2Cl also may act directly on the epithelial cell to stimulate Isc and evoke Cl- secretion.
56 citations
TL;DR: The data demonstrate that infiltrating neutrophils do not mediate the mucosal injury and inflammation observed in acetic acid-induced colitis, and suggested that inflammatory neutrophil may mediate mucosal Injury and inflammation in this model of colitis.
Abstract: Intrarectal administration of 4% acetic acid produces diffuse inflammation that ultimately results in erosions and ulcerations of the rat colon. Although this model of colitis has been used extensively over the past several years, there are no quantitative data available regarding the relationship between neutrophil infiltration and mucosal injury during times of active inflammation. Therefore, the objective of this study was to define the role of extravasated neutrophils as mediators of mucosal injury and inflammation in acetic acid-induced colitis. We found the intrarectal administration of 4% acetic acid produced an 11-fold increase in colonic mucosal permeability, a 9-fold increase in colonic MPO activity, and a 1.6-fold increase in colon weight at 48 h following administration of acetic acid. In addition, we found significant correlations between colonic MPO activity and mucosal permeability and between colonic MPO activity and colon weight (P < 0.01 for both). These data suggested that inflammatory neutrophils may mediate mucosal injury and inflammation in this model of colitis. To assess the role of circulating neutrophils, rats were rendered neutropenic for 48 h by the intraperitoneal administration of antiserum directed toward rat neutrophils (ANS). Although ANS treatment reduced both the number of circulating neutrophils and colonic MPO activity to less than 10% of control values, it did not attenuate the increases in colonic mucosal permeability nor did it attenuate the increases in colon weight produced by acetic acid. Histological inspection confirmed that ANS treatment was not effective in attenuating the injury to the epithelial barrier. These data demonstrate that infiltrating neutrophils do not mediate the mucosal injury and inflammation observed in acetic acid-induced colitis.
56 citations
TL;DR: In this article, the authors examined the ability of 5aminosalicylic acid (5-ASA), a drug used to treat inflammatory bowel disease (IBD), to inhibit oxidation of l -cysteine by NH 2 Cl, HOCl and H 2 O 2.
43 citations
TL;DR: Miso pretreatment significantly attenuated the increases in colonic myeloperoxidase activity, mucosal permeability, and colon weight as well as prevented the loss of body weight.
Abstract: The objectives of this study were 1) to quantify the effects of misoprostol (Miso; prostaglandin E1 analogue) on acetic acid-induced increases in mucosal permeability and inflammation; 2) to determine what effect acetic acid, Miso, or the combination of Miso plus acetic acid has on colonic blood flow; and 3) to assess whether the protective effect of Miso may be attributable to its vasodilatory properties. We found that intrarectal administration of acetic acid produced a 6.4-fold increase in colonic myeloperoxidase activity (an index of granulocyte infiltration), an 8.2-fold increase in mucosal permeability, a 1.6-fold increase in colonic weight, and a 6.8% decrease in body weight 48 h after enema. Miso pretreatment significantly attenuated the increases in colonic myeloperoxidase activity, mucosal permeability, and colon weight as well as prevented the loss of body weight. In a different series of experiments, we found that blood flow in the descending, transverse, and ascending colon increased 2.5- to 3.5-fold immediately after the acetic acid enema; however, it returned to control values at 1 and 4 h after enema. Miso pretreatment, followed by acetic acid, resulted in a further increase (2.5-fold) in blood flow in the descending colon 1 h after enema compared with acetic acid alone. This Miso-induced increase in blood flow at 1 h could not account for its protective effect inasmuch as colonic mucosal permeability (i.e., injury) in Miso-pretreated animals was not significantly different from values obtained in animals pretreated with vehicle and then given the enema.
Journal Article•
TL;DR: Oxidant-induced contraction of guinea pig ileum appears to be via release of prostaglandins and one or more neurotransmitters, and high concentrations of reactive oxygen metabolites may alter receptor function.
Abstract: Large numbers of polymorphonuclear leukocytes which generate reactive oxygen metabolites are found in mucosa and submucosa of the intestinal wall of subjects suffering from inflammatory bowel disease. We have, therefore, examined the relative influences of hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and N-chloramines such as NH2Cl, on the neurally stimulated and nonstimulated guinea pig ileum. In separate experiments the oxidants were tested in the presence and absence of the cyclooxygenase inhibitor piroxicam and the antioxidant glutathione. All three oxidants, in concentrations produced by activated neutrophils, increased the muscle tone (concentration-dependent, peak at 0.3 mM for NH2Cl and H2O2 and 1 mM for HOCl). Tetrodotoxin (0.5 microM) inhibited the NH2Cl and H2O2 effects by 50% and 70%, respectively. Piroxicam (5 microM) partially blocked maximal contractions induced by all three oxidants. The contractile response to carbachol (10 microM) was blocked by 0.3 mM NH2Cl, but not by H2O2 and HOCl. In electrically stimulated ileum the oxidants produced a concentration-dependent biphasic response (transient enhancement of neurally mediated twitch contraction followed by marked inhibition). This response was not modified by piroxicam, hexamethonium, atropine and pyrilamine. The inhibition of twitch contraction was irreversible for NH2Cl and HOCl, in contrast to H2O2, which was reversed by repeated washing. Neither the contractile effect nor the effects on nerve stimulation-induced contraction were affected by preincubation of the tissue with glutathione, whereas prior combination of NH2Cl with glutathione prevented the effects of NH2Cl. Oxidant-induced contraction of guinea pig ileum appears to be via release of prostaglandins and one or more neurotransmitters. High concentrations of reactive oxygen metabolites may alter receptor function.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The results indicate that NH2Cl generated during inflammation may decrease the biological activities of different agonists and antagonists of smooth muscle function.
Abstract: Neutrophil-derived oxidants such as hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and monochloramine (NH2Cl) may contribute to gallbladder inflammation in cholecystitis. We examined the influence of oxidants on the biological activity of different agonists and antagonists of gallbladder smooth muscle function. The concentration-response curves for cholecystokinin-octapeptide (CCK-OP) and carbachol were examined before and after incubation of the tissues with NH2Cl (30 microM). The 50% effective concentration of CCK-OP was shifted from 0.5 +/- 0.09 nM (control) to 4 +/- 1.2 nM in the presence of NH2Cl. The effect of carbachol was not affected by NH2Cl. The contractile effect of CCK-OP (3 nM) was abolished by prior exposure to HOCl or NH2Cl. These actions were prevented by 60 microM glutathione. Oxidant-induced degradation of CCK-OP was confirmed by high-performance liquid chromatography and thin-layer chromatography. NH2Cl also significantly reduced the contractile response to neurokinin A, bradykinin, leukotriene D4, and phorbol 12,13-dibutyrate and the relaxant response to isoproterenol. Prior exposure of acetylcholine, histamine, serotonin, prostaglandin E2, vasoactive intestinal polypeptide, or calcitonin gene-related peptide to NH2Cl had no effect on their activity. The results indicate that NH2Cl generated during inflammation may decrease the biological activities of different agonists and antagonists of smooth muscle function.