Anti-inflammatory effect of augmented nitric oxide production in chronic lung infection

Abstract

Chronic infection of the lungs with Pseudomonas aeruginosa complicates many long-term lung diseases including cystic fibrosis, bronchiectasis, chronic obstructive lung disease, and mechanical ventilation. In acute inflammatory lung diseases, increased nitric oxide synthase (NOS-2) expression leads to excess nitric oxide (NO) production, resulting in the production of reactive nitrogen intermediates, which contribute to tissue damage. In contrast, the contribution of NO to pulmonary damage in chronic Pseudomonas infection of the lung has not been directly examined and is unclear. Although NOS-2 expression is increased in this condition, NO production is not abnormally elevated. It was hypothesized that chronic infection of the airways does not cause increased NO production but, in contrast, leads to inappropriately low NO concentrations that are pro-inflammatory. A rodent model of chronic airway infection was used to examine the effects on lung damage of augmenting or inhibiting NO production after airway infection with P. aeruginosa was well established. Three days post-infection, L-arginine, which augments NO production, or L-NAME, an inhibitor of NO production, was administered in drinking water. Lung damage was assessed 12 days later. L-arginine treatment reduced tissue damage, inhibited neutrophil recruitment, and reduced the pro-inflammatory cytokine interleukin (IL)-1beta. Treatment with L-NAME caused loss of alveolar walls, greater vascular damage, and increased levels of the pro-inflammatory cytokine IL-6. Thus, in chronic airway infection, inhibition of NO production worsened lung damage, whereas augmenting NO ameliorated this damage. This is the first demonstration that augmenting endogenous NO production in chronic infective lung disease caused by P. aeruginosa is anti-inflammatory. Given that infection with this organism complicates many chronic lung diseases, most notoriously cystic fibrosis, these findings have important clinical implications.

Effect of Arginase Inhibition on Pulmonary L-Arginine Metabolism in Murine Pseudomonas Pneumonia

“…Studies in CF patients for instance have shown that low levels of airway NO are a risk factor for acquisition of this pathogen [7]. In addition, in a rat model of chronic P. aeruginosa lung infection, supplementation with L-arginine reduced the pro-inflammatory cytokine interleukin (IL)-1β in airways, inhibited neutrophil recruitment, and ameliorated lung tissue damage, while pharmacological inhibition of NOS in this model significantly worsened lung damage [3].…”

“…Infection of the lung with bacteria leads to increased expression of the inducible nitric oxide synthase (iNOS or NOS2) and NO production [1]–[3], as does intra-tracheal instillation of lipopolysaccharide (LPS) [4], [5]. NO production from NOS depends on the availability of substrate and co-factors, as well as the presence of endogenous inhibitors including asymmetric dimethylarginine (ADMA) [6].…”

Antibiotic and Anti-Inflammatory Therapies for Cystic Fibrosis

“…Arginase activity is increased in blood and sputum of CF patients and may further decrease NO by degrading L-arginine, an NO substrate (Grasemann et al 2005a). In a rodent model, L-arginine was associated with reduced tissue damage, decreased neutrophil recruitment, and reduced IL-1b (Hopkins et al 2006). A small study of L-arginine in CF was associated with increased eNO (Grasemann et al 2005b).…”

Cystic Fibrosis – a Multiorgan Protein Misfolding Disease

“…These include enhancing thiocyanate levels [19] and direct [20,21] or indirect [22,23] methods for supplementing nitric oxide in the lungs (which is reduced in CF patients [24,25]). Some groups are also investigating the possibility of promoting autophagy via pharmacological means, as this is also known to be dysregulated in people with CF [26].…”