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

Gironella

Laboratory Investigation

et al. 2002

SUMMARY:Nitric oxide (NO) synthesis is up-regulated in inflammatory bowel disease. However, its role in the pathophysiology of this condition is controversial. The aims of this study were to assess whether nitric oxide administration ameliorates experimental colitis and to determine the possible mechanisms underlying its effects on intestinal inflammation. For this purpose, the NO donor diethylamine NONOate (DETA/NO; 0.01, 0.1, 1, 5, or 10 mg/kg/day), or the DETA moiety, was administered daily to mice with dextran sulfate sodium-induced colitis. Daily body weight and colonic pathologic alterations at Day 10 were determined. Leukocyte endothelial cell interactions in colonic venules were assessed with intravital microscopy, and expression of endothelial cell adhesion molecules was determined using radiolabeled antibodies. IL-12 and IFN-␥ production were measured in intestinal tissue. Colitis induced a significant loss of body weight, reduction of colon length, and increase in colon weight and myeloperoxidase activity. Administration of 1 mg/kg/day DETA/NO significantly attenuated these pathologic changes. The marked increase in leukocyte rolling and adhesion in colonic venules of colitic mice were significantly reduced by administration of 1 mg/kg/day DETA/NO. Development of colitis was associated with a marked increase in endothelial expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. Supplementation with NO significantly attenuated the up-regulation of endothelial intercellular adhesion molecule-1 and P-selectin, but not vascular cell adhesion molecule-1, in colonic tissue. NO abrogated the increase in IL-12 and IFN-␥ mRNA expression in the colon of colitic mice. The DETA moiety alone did not have any effect on any of the parameters studied. In conclusion, exogenous NO supplementation significantly ameliorates dextran sulfate sodium-induced colitis. This effect is related to a reduction in leukocyte recruitment and proinflammatory cytokine production. (Lab Invest 2002, 82:597-607).

Section: No Treatment In Experimental Colitiscontrasting

confidence: 99%

Section: Salas Et Almentioning

confidence: 82%

Nitric Oxide Supplementation Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice

Gironella

Laboratory Investigation

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

“…For example, NO nonsteroidal antiinflammatory drugs are known to suppress neutrophil adherence to the vascular endothelium in response to chemotaxins (36); this might account for the reduction in the flow of myeloid cells at the tumor site observed in mice orally treated with NO aspirin (Fig. 6).…”

Section: Discussionmentioning

confidence: 99%

Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination

Santo¹,

Serafini²,

Marigo³

et al. 2005

262

192

Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine: arginase and nitric oxide (NO) synthase. NO-releasing aspirin is a classic aspirin molecule covalently linked to a NO donor group. NO aspirin does not possess direct antitumor activity. However, by interfering with the inhibitory enzymatic activities of myeloid cells, orally administered NO aspirin normalized the immune status of tumorbearing hosts, increased the number and function of tumorantigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination. Because cancer vaccines and NO aspirin are currently being investigated in independent phase I͞II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases.arginase ͉ immunosuppression ͉ myeloid cells ͉ nitric oxide ͉ immunotherapy I dentifying effective treatments for cancer is a clinical priority.Despite the plethora of evidence in preclinical models, the most advanced immunotherapy, either active or passive, has had limited success in human clinical trials (1). Basis for this conclusion appears to involve at least in part the progressive accumulation of myeloid cells, which exert a powerful inhibitory activity on antitumor lymphocytes as a function of tumor growth. In tumor-bearing hosts, for example, tumor progression is often associated with altered hematopoiesis, which leads to the accumulation of myeloid cells at the tumor site and in blood, secondary lymphoid organs, and bone marrow (2-4).Mouse myeloid cells express the CD11b and Gr-1 markers, have a mixed mature-immature myeloid phenotype, and are responsible for the induction of tumor-specific and nonspecific T cell dysfunctions, which are frequently observed not only in transplantable tumors but also in tumors spontaneously arising with transgenic expression of tissue-restricted oncogenes (2, 5). These cells have been termed myeloid suppressor cells (MSCs) and arise from bone marrow and other hematopoietic organs exposed to systemically released factors acting on myelomonocytic precursors (reviewed in refs. 2, 3, and 6). Moreover, MSCs are the final effectors of a circuit that negatively affects tumor immunity and that requires participation of natural killer T cells. Cytotoxic T lymphocyte (CTL)-mediated tumor immunosurveillance was recently shown to be down-regulated by TGF-␤ released by CD11b ϩ ͞Gr-1 ϩ cells, an event driven by cytokine IL-13 release from CD1d-restricted natural killer T cells (7). This circuit is activated very early in tumor progression and ...

Mem. Inst. Oswaldo Cruz

“…The potential of NO-releasing drugs as therapeutics for inflammatory conditions has been reviewed in detail (Muscara & Wallace 1999). The addition of a NO-releasing moiety to several nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to greatly reduce their toxicity while enhancing their efficacy and potency , 1997, Davies et al 1997.…”

Section: Therapeutic Potential Of No In Inflammationmentioning

confidence: 99%

Nitric oxide as a regulator of inflammatory processes

Wallace

2005

117