Inhibition by nitric oxide‐donors of human polymorphonuclear leucocyte functions

Abstract

The study was designed to test the hypothesis that nitric oxide (NO)‐releasing compounds increase guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) production in human polymorphonuclear leucocytes (PMNs) and concomitantly inhibit PMN functions, i.e. leukotriene B4 (LTB4) synthesis, degranulation, chemotaxis and superoxide anion (O2−) release. The effects of two new NO‐releasing compounds, GEA 3162 and GEA 5024 were compared to 3‐morpholino‐sydnonimine (SIN‐1) and S‐nitroso‐N‐acetyl‐penicillamine (SNAP). GEA 3162 and GEA 5024 (1–100 μm) inhibited Ca ionophore A23187‐induced LTB4 and β‐glucuronidase release, chemotactic peptide FMLP‐induced chemotaxis and opsonized zymosan‐triggered chemiluminescence dose‐dependently in human PMNs. SIN‐1 and SNAP were weaker inhibitors. Cellular cyclic GMP production was increased after exposure to NO‐donors concomitantly with the inhibition of PMN functions. No alterations in the levels of adenosine 3′:5′‐cylic monophosphate (cyclic AMP) were detected. The results suggest that NO, possibly through increased cyclic GMP, inhibits the activation of human PMNs and may thus act as a local modulator in inflammatory processes.

Effects of Reactive Oxygen and Nitrogen Metabolites on RANTES. and IL-5-Induced Eosinophil Chemotactic Activity in vitro

“…Inflammatory cell chemotactic factors, including RANTES and IL-5, are likely to encounter high local concentrations of NO, superoxide, and peroxynitrite in inflammatory sites. Several studies have examined the effects of NO on neutrophil, monocyte, and eosinophil chemotaxis, [33][34][35][36][37][38] but few have examined the effects on chemotactic factors.…”

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

“…However, it is known that NO induces a rise in cGMP in neutrophils through activation of sGC. 8,83 Given that the cell permeable analogues of cAMP (db-cAMP) and cGMP (db-cGMP) can delay constitutive neutrophil apoptosis, 10 and that a rise in cGMP has been postulated to at least partially account for NOmediated inhibition of apoptosis in other cell types, 84,85 it is possible that an increase in one or other of these cyclic nucleotides mediates the inhibition of apoptosis in neutrophils exposed to low concentrations of NO. A role for cyclic nucleotide (cGMP or cAMP) signalling has also been proposed in NO-mediated inhibition of both constitutive and Fas-triggered eosinophil apoptosis.…”

“…7 NO is capable of inducing inflammatory cell apoptosis and also possesses several other anti-inflammatory properties, including direct downregulation of leukocyte functions, such as neutrophil and monocyte adhesion, and neutrophil chemotaxis, degranulation and superoxide anion (O 2 À ) generation. [8][9][10] It also acts to maintain the impermeable nature of the vascular endothelium to leukocytes. 9 Thus, manipulation of NO concentrations is a particularly promising candidate to alter leukocyte function and rates of apoptosis in inflammatory conditions.…”

Nitric oxide production by tumour tissue: impact on the response to photodynamic therapy

“…Photodynamic therapy (PDT), used for the treatment of various types of cancer (Dougherty et al, 1998), induces a strong oxidative stress and triggers the vascular-mediated response with a massive neutrophil recruitment (Krosl et al, 1995;Gollnick et al, 1997), and these events are prone to be highly sensitive to NO mediation (Moilanen et al, 1993;Schmidt and Walter, 1994;Hirst and Flitney, 1997). In tumours producing high levels of NO, the PDTinduced reduction in tumour blood flow, vascular occlusion and consequent ischaemia may be diminished, while the inflammatory reaction triggered by PDT may be suppressed .…”