Research Letters

Impairment of bronchoprotection by nitric oxide in severe asthma

Nitric oxide (NO) is a ubiquitous signaling molecule with a variety of biological functions in the pulmonary system. NO induces relaxation of airway and vascular smooth muscle, and is involved in host defense during inflammation mainly by reacting with superoxide to peroxynitrite. NO is produced from l-arginine by NO synthases, which activity is regulated by cellular transport and production of l-arginine, substrate competition by arginases and enzyme inhibition by endogenous methylarginines. Since aberrant NO homeostasis contributes to the pathophysiology of pulmonary diseases like asthma, COPD, cystic fibrosis and pulmonary hypertension, the NO/l-arginine homeostasis is pharmacologically targeted to treat these diseases.

Bradykinin, a pro-inflammatory molecule, and its related peptides have been studied for their effects on acute reactions in upper and lower airways, where they can be synthesised and metabolized after exposure to different stimuli including allergens and viral infection. Bradykinin B₁ and B₂ receptors are constitutively expressed in the airways on several residential and/or immune cells. Their expression can also be induced by inflammatory mediators, usually associated with eosinophil and neutrophil recruitment, such as IL-4, IL-13, TNF-α, IL-6 and IL-8, via intracellular MAPK and NF-κB signalling. In turn, the latters up-regulate both bradykinin receptors. Bradykinin activates epithelial/endothelial and immune cells, neurons and mesenchymal cells (such as fibroblasts, myofibroblasts and smooth muscle cells), which are implicated in the development of airway chronic inflammation, responsiveness and remodelling (a major feature of severe asthma). This review highlights the role of bradykinin and its receptors in respect to chronic inflammatory response involving eosinophils/neutrophils and to vascular/matrix-related airway remodelling in asthmatic airways. This scenario is especially important for understanding the mechanisms involved in the pathogenesis of eosinophilic and/or neutrophilic asthma and hence their therapeutic approach.

AgNPs have been used to manufacture nanomaterials with new biophysical properties and functions. However, few experimental approaches have been used to assess their potential toxic or beneficial effects on human health, in association with the size, concentration, and biological target. The aim of this work was to evaluate the effects of the AgNPs on the smooth muscle of rat trachea. A single administration of AgNPs did not modify the smooth muscle tone, but, when the trachea rings were pre-treated with acetylcholine (ACh), AgNPs produced a contractile effect. Simultaneous administration of AgNPs and ACh resulted in a slight increase of smooth muscle contractility induced by ACh. AgNPs pretreatment followed by ACh administration showed that AgNPs exerted an important contraction effect induced by ACh after which muscle tone did not return to the basal level. This effect was associated with an increase in the production of nitric oxide (NO). The contractile response of the AgNPs induced by ACh was completely blocked when the rings were incubated, after the ACh but before the AgNPs administration, with 1400 W (NO blocker). The contractile effect was also abolished by atropine, which suggests that AgNPs alter ACh muscarinic receptor signaling. These data also show that AgNPs modify the contractile action of ACh through NO production and possibly induce hyper-reactivity of tracheal smooth muscle.

Exhaled breath nitric oxide (NO) is an accepted asthma biomarker. Lung concentrations of NO and its amino acid precursor, L-arginine, are regulated by the relative expressions of the NO synthase (NOS) and arginase iso-forms. Increased expression of arginase I and NOS2 occurs in murine models of allergic asthma and in biopsies of asthmatic airways. Although clinical trials involving the inhibition of NO-producing enzymes have shown mixed results, small molecule arginase inhibitors have shown potential as a therapeutic intervention in animal and cell culture models. Their transition to clinical trials is hampered by concerns regarding their safety and potential toxicity. In this review, we discuss the paradigm of arginase and NOS competition for their substrate L-arginine in the asthmatic airway. We address the functional role of L-arginine in inflammation and the potential role of arginase inhibitors as therapeutics

This chapter describes the localization and synthesis of nitric oxide (NO) in airways, pathophysiological roles of NO in lung diseases, signaling pathways of NO in airways, and interaction between NO and reactive oxygen species in the lung, focusing on NO as a new molecular therapeutic target in airway inflammation. NO is a diffusible, short-lived, highly reactive gaseous molecule produced from L-arginine by the NO synthase family. Biological effects of NO are mediated through the reaction of NO with a number of targets such as heme groups, cysteine residues, and iron and zinc clusters. NO is a critical player in the development of various airway inflammatory diseases and is a part of complex signaling systems associated with airway inflammatory diseases. Although the role of NO in biological processes is so complex, bidirectional, and still somewhat controversial, the interrelationship between NO and various signaling networks, as well as oxidative stress involved in airway inflammation and remodeling, has made NO more attractive for therapeutic strategy in airway inflammatory diseases. Hence, NO has a very wide range of roles in various biological systems. Although NO is known to have protective effects—antimicrobial, antiinflammatory, and antioxidative—against the pathogenesis of various disease states, there is increasing evidence regarding the deleterious impact of NO in a number of respiratory disorders including airway inflammatory diseases. Recent studies have introduced NO as a key reactive signaling molecule, suggesting that NO is located at the switching point of various molecular signals in the respiratory system.

This chapter describes the localization and synthesis of nitric oxide (NO) in airways, pathophysiological roles of NO in lung diseases, signaling pathways of NO in airways, and interaction between NO and reactive oxygen species in the lung, focusing on NO as a new molecular therapeutic target in airway inflammation. NO is a diffusible, short-lived, highly reactive gaseous molecule produced from L-arginine by the NO synthase family. Biological effects of NO are mediated through the reaction of NO with a number of targets such as heme groups, cysteine residues, and iron and zinc clusters. NO is a critical player in the development of various airway inflammatory diseases and is a part of complex signaling systems associated with airway inflammatory diseases. Although the role of NO in biological processes is so complex, bidirectional, and still somewhat controversial, the interrelationship between NO and various signaling networks, as well as oxidative stress involved in airway inflammation and remodeling, has made NO more attractive for therapeutic strategy in airway inflammatory diseases. Hence, NO has a very wide range of roles in various biological systems. Although NO is known to have protective effects—antimicrobial, antiinflammatory, and antioxidative—against the pathogenesis of various disease states, there is increasing evidence regarding the deleterious impact of NO in a number of respiratory disorders including airway inflammatory diseases. Recent studies have introduced NO as a key reactive signaling molecule, suggesting that NO is located at the switching point of various molecular signals in the respiratory system.