Role of nitric oxide in regulation of leucocyte‐endothelial cell interactions

Hickey, Michael J.; Kubes, Paul

doi:10.1113/expphysiol.1997.sp004029

Cited by 62 publications

(33 citation statements)

References 25 publications

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“…37,38 Similarly, mice that are genetically deficient in critical protein subunits (eg, p47 phox ) of NAD(P)H oxidase or transgenic mice that overexpress SOD exhibit attenuated leukocyte adhesion responses in models of oxidative stress. 39 Studies demonstrating that treatment of otherwise normal animals with inhibitors of NOS 40 and endothelial NOS-knockout mice 41 exhibit increased leukocyte adhesion support the view that a critical determinant of whether the vasculature assumes a proinflammatory or an antiinflammatory (and therefore, a prothrombogenic or an antithrombogenic) phenotype is the balance between ROS and NO. Although NO and superoxide per se are often ascribed anti-inflammatory and proinflammatory (and antithrombogenic and prothrombogenic) roles, respectively, the products of their chemical interaction (RNOS) can yield either phenotype, depending on whether there is net oxidation or nitrosation of specific molecular targets that regulate the inflammatory response (Figure 1).…”

Section: Oxidative Stressmentioning

confidence: 98%

Modulation of the Inflammatory Response in Cardiovascular Disease

2004

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Abstract-There is a growing body of evidence that inflammation might play an important role in the initiation and progression of cardiovascular diseases (CVDs). The designation of CVD as a chronic inflammatory process is further supported by evidence that the risk factors for CVD cause endothelial cells throughout the vascular tree to assume an inflammatory phenotype. These activated endothelial cells characteristically exhibit oxidative stress and increased adhesiveness for circulating leukocytes. Although initial efforts to define the mechanisms underlying the inflammatory phenotype in diseased endothelial cells have focused on the linkage between oxidative stress and adhesion molecule activation/expression, recent work has implicated a variety of additional factors that can modulate the magnitude and/or nature of the inflammatory responses in CVD. Platelets, angiotensin II, and the CD40/CD40 ligand signaling system are gaining recognition as contributors to the pathogenesis of CVD. These factors appear to converge with known pathways that link oxidative stress with adhesion molecule expression and help to explain the apparent integration of coagulation with inflammation in CVD. These factors also hold the promise of offering multiple sites for therapeutic intervention in CVD. Key Words: oxidative stress Ⅲ integrins Ⅲ angiotensin II Ⅲ adhesion molecules I nflammation is gaining widespread attention for its role in the initiation and progression of cardiovascular disease (CVD). Epidemiological studies have revealed strong associations between biochemical markers of systemic inflammation and both the presence of and future risk for symptomatic CVD. Animal experimentation as well as clinical studies has provided convincing evidence that the known risk factors for CVD (hypertension, diabetes, hypercholesterolemia, and smoking) can elicit both an inflammatory and a prothrombogenic phenotype in the vascular system. The phenotypic changes are more pronounced in endothelial cells and can include oxidative stress, increased expression of endothelial cell adhesion molecules (CAMs), activation of cell signaling pathways (eg, the CD40/CD40 ligand [CD40L] dyad), and the consequent adhesion and activation of leukocytes and platelets. In the microcirculation, the inflammatory manifestations of CVD are more readily visible in postcapillary venules. There is growing evidence, however, that the endothelium-dependent arteriolar dysfunction often associated with CVD is also linked to the systemic inflammatory response. [1][2][3][4] Because the expression of adhesion glycoproteins by activated endothelial cells is a rate-determining step in the recruitment of inflammatory cells, much attention has been devoted to the role of endothelial CAMs in CVD. This attention has produced considerable evidence for the: (1) altered endothelial CAM expression in animal models of CVD 2,5 ; (2) use of circulating levels of soluble endothelial CAMs (eg, soluble intercellular adhesion molecule-1 [sICAM-1]) as a marker for the severity of inflammati...

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Section: Oxidative Stressmentioning

confidence: 98%

Modulation of the Inflammatory Response in Cardiovascular Disease

2004

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“…First, we investigated whether NO inhibits the adhesion of neutrophils to endothelial cells. Earlier in vivo and in vitro results have shown that NOS inhibitors increase the adhesion of neutrophils to endothelial cells (25,27). In our model using an intravital microscopy assay, we demonstrated that animals subjected to L-CLP surgery had a significant reduction in leukocyte rolling and adherence in postcapillary venules of the mesentery.…”

Section: Discussionmentioning

confidence: 99%

“…Investigating the mechanism involved in this phenomenon, we observed that inhibitors of nitric oxide synthase (NOS), such as aminoguanidine (AG) and N G -mono-methyl-L-arginine, protected animals from impairment of neutrophil migration, suggesting that NO mediates this phenomenon (5,50). Accordingly, NO reduces leukocyte-endothelial cell adhesion (25,26,27). In the CLP-sepsis model, treatment of mice with AG at doses of up to 30 mg kg Ϫ1 were shown to protect animals from lethality.…”

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confidence: 99%

Inhibition of Leukocyte Rolling by Nitric Oxide during Sepsis Leads to Reduced Migration of Active Microbicidal Neutrophils

et al. 2002

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We developed two models of sepsis with different degrees of severity, sublethal and lethal sepsis, induced by cecal ligation and puncture. Lethal sepsis induced by cecal ligation and puncture (L-CLP) resulted in failure of neutrophil migration to the infection site and high mortality. Treatment of septic animals with aminoguanidine (AG), a nitric oxide (NO) synthase inhibitor, precluded the failure of neutrophil migration and protected the animals from death. However, cytokine-induced NO synthase (iNOS)-deficient (iNOS ؊/؊ ) mice subjected to L-CLP did not present neutrophil migration failure, but 100% lethality occurred. iNOS ؊/؊ mice subjected to sublethal sepsis induced by cecal ligation and puncture (SL-CLP) also suffered high mortality despite the occurrence of neutrophil migration. This apparent paradox could be explained by the lack of microbicidal activity in neutrophils of iNOS ؊/؊ mice present at the infection site due to their inability to produce NO. Notably, SL-and L-CLP iNOS ؊/؊ mice showed high bacterial numbers in exudates. The inhibition of neutrophil migration by NO is due to inhibition of a neutrophil/endothelium adhesion mechanism, since a reduction in leukocyte rolling, adhesion, and emigration was observed in L-CLP wild-type mice. These responses were prevented by AG treatment and were not observed in the iNOS ؊/؊ L-CLP group. There was no significant change in L-selectin expression in neutrophils from L-CLP mice. Thus, it seems that the decrease in leukocyte rolling is due to a defect in the expression of adhesion molecules on endothelial surfaces mediated by iNOS-derived NO. In conclusion, the results indicate that despite the importance of NO in neutrophil microbicidal activity, its generation in severe sepsis reduces neutrophil migration by inhibiting leukocyte rolling and their firm adhesion to the endothelium, in effect impairing the migration of leukocytes and consequently their fundamental role in host cell defense mechanisms.

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“…NO also modulates vascular permeability [6][7][8], angiogenesis [9,10], platelet adhesion and aggregation [11][12][13], and leukocyte adhesion [14][15][16]. Thus, NO bioavailabilty is important in maintaining several aspects of homeostasis and its dysfunction contributes to a large variety of diseased states [17][18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin

Azarov

Jeffers

et al. 2008

Free Radical Biology and Medicine

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Release of hemoglobin from the erythrocyte during intravascular hemolysis contributes to the pathology of a variety of diseased states. This effect is partially due to the enhanced ability of cellfree plasma hemoglobin, which is primarily found in the ferrous, oxygenated state, to scavenge nitric oxide. Oxidation of the cell-free hemoglobin to methemoglobin, which does not effectively scavenge nitric oxide, using inhaled nitric oxide has been shown to be effective in limiting pulmonary and systemic vasoconstriction. However, the ferric heme species may be reduced back to ferrous hemoglobin in plasma and has the potential to drive injurious redox chemistry. We propose that compounds that selectively convert cell-free hemoglobin to ferric, and ideally iron-nitrosylated heme species that do not actively scavenge nitric oxide would effectively treat intravascular hemolysis. We show here that nitroxyl, generated by Angeli's salt (Sodium α-oxyhyponitrite, Na 2 N 2 O 3 ), preferentially reacts with cell-free hemoglobin compared to that encapsulated in the red blood cell under physiologically relevant conditions. Nitroxyl oxidizes oxygenated ferrous hemoglobin to methemoglobin and can convert the methemoglobin to a more stable, less toxic species, iron-nitrosyl hemoglobin. These results support the notion that Angeli's salt or a similar compound could be used to effectively treat conditions associated with intravascular hemolysis.

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Role of nitric oxide in regulation of leucocyte‐endothelial cell interactions

Cited by 62 publications

References 25 publications

Modulation of the Inflammatory Response in Cardiovascular Disease

Modulation of the Inflammatory Response in Cardiovascular Disease

Inhibition of Leukocyte Rolling by Nitric Oxide during Sepsis Leads to Reduced Migration of Active Microbicidal Neutrophils

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin

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