During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from iNOS seems to be a proinflammatory mediator with immunomodulatory effects. The concentration of this molecule in exhaled air is abnormal in activated states of different inflammatory airway diseases, and its monitoring is potentially a major advance in the management of, e.g., asthma. Finally, the production of NO under oxidative stress conditions secondarily generates strong oxidizing agents (reactive nitrogen species) that may modulate the development of chronic inflammatory airway diseases and/or amplify the inflammatory response. The fundamental mechanisms driving the altered NO bioactivity under pathological conditions still need to be fully clarified, because their regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways.

/pdf/nitric-oxide-in-health-and-disease-of-the-respiratory-system-3cwysenbku.pdf

Nitric Oxide in Health and Disease of the Respiratory System

Chronic asthma is an inflammatory airways disease characterized by pathological changes in the airway smooth muscle (ASM) bundle that contribute to airway obstruction and hyperresponsiveness. Remodeling of the ASM is associated with an increased smooth muscle mass, involving components of cellular hypertrophy and hyperplasia, and changes in the phenotype of the muscle that facilitate proliferative, synthetic and contractile functions. These changes are considered major contributing factors to the pathophysiology of asthma, because of their role in exaggerated airway narrowing. The mechanisms that regulate changes in ASM mass and phenotype are incompletely understood, but likely involve the regulatory role of mediators and growth factors secreted from inflammatory cells on ASM cell proliferation and phenotype. An alternative hypothesis is that cellular and structural components that together constitute the airway wall, such as the airway epithelium, airway nerves, and the extracellular matrix, interact with the ASM bundle to facilitate changes in smooth muscle phenotype and function that drive remodeling under inflammatory conditions. This review discusses the mechanisms by which structural components of the airway wall communicate with the ASM bundle to regulate remodeling and discusses these mechanisms in the context of the pathophysiology of asthma.

https://www.atsjournals.org/doi/pdf/10.1513/pats.200907-056DP

Airway Structural Components Drive Airway Smooth Muscle Remodeling in Asthma

Recent studies have indicated that arginase, which converts l-arginine into l-ornithine and urea, may play an important role in the pathogenesis of various pulmonary disorders. In asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis, increased arginase activity in the airways may contribute to obstruction and hyperresponsiveness of the airways by inducing a reduction in the production of bronchodilatory nitric oxide (NO) that results from its competition with constitutive (cNOS) and inducible (iNOS) NO synthases for their common substrate. In addition, reduced l-arginine availability to iNOS induced by arginase may result in the synthesis of both NO and the superoxide anion by this enzyme, thereby enhancing the production of peroxynitrite, which has procontractile and pro-inflammatory actions. Increased synthesis of l-ornithine by arginase may also contribute to airway remodelling in these diseases. l-Ornithine is a precursor of polyamines and l-proline, and these metabolic products may promote cell proliferation and collagen production, respectively. Increased arginase activity may also be involved in other fibrotic disorders of the lung, including idiopathic pulmonary fibrosis. Finally, through its action of inducing reduced levels of vasodilating NO, increased arginase activity has been associated with primary and secondary forms of pulmonary hypertension. Drugs targeting the arginase pathway could have therapeutic potential in these diseases.

/pdf/arginase-and-pulmonary-diseases-156al6nr08.pdf

Arginase and pulmonary diseases.

Allergic asthma is a chronic inflammatory airways' disease, characterized by allergen-induced early and late bronchial obstructive reactions, airway hyperresponsiveness (AHR), airway inflammation and airway remodelling. Recent ex vivo and in vivo studies in animal models and asthmatic patients have indicated that arginase may play a central role in all these features. Thus, increased arginase activity in the airways induces reduced bioavailability of L-arginine to constitutive (cNOS) and inducible (iNOS) nitric oxide synthases, causing a deficiency of bronchodilating and anti-inflammatory NO, as well as increased formation of peroxynitrite, which may be involved in allergen-induced airways obstruction, AHR and inflammation. In addition, both via reduced NO production and enhanced synthesis of L-ornithine, increased arginase activity may be involved in airway remodelling by promoting cell proliferation and collagen deposition in the airway wall. Therefore, arginase inhibitors may have therapeutic potential in the treatment of acute and chronic asthma. This review focuses on the pathophysiological role of arginase in allergic asthma and the emerging effectiveness of arginase inhibitors in the treatment of this disease.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.2009.00374.x

Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives

The precise role of each nitric oxide (NO) synthase (NOS) isoform in the pathobiology of asthma is not well established. Our objective was to investigate the contribution of constitutive NO synthase (cNOS) and inducible NOS (iNOS) isoforms to lung mechanics and inflammatory and remodeling responses in an experimental model of chronic allergic pulmonary inflammation. Guinea pigs were submitted to seven ovalbumin exposures with increasing doses (1 ∼ 5 mg/ml) for 4 wk. The animals received either chronic l-NAME (N-nitro-l-arginine methyl ester, in drinking water) or 1400W (iNOS-specific inhibitor, intraperitoneal) treatments. At 72 h after the seventh inhalation of ovalbumin solution, animals were anesthetized, mechanically ventilated, exhaled NO was collected, and lung mechanical responses were evaluated before and after antigen challenge. Both l-NAME and 1400W treatments increased baseline resistance and decreased elastance of the respiratory system in nonsensitized animals. After challenge, l-NAME increas...

https://www.atsjournals.org/doi/pdf/10.1165/rcmb.2005-0391OC

Effects of nitric oxide synthases in chronic allergic airway inflammation and remodeling.

Pharmacological evidence supports a role of a transient decreased endogenous nitric oxide (NO) synthesis in ovalbumin (OVA)-induced early airway hyperresponsiveness in guinea pigs. However, no data are available regarding the expression and activity of the constitutive NO synthases (cNOS; NOS1 and NOS3, nNOS and eNOS, respectively) in this model. Therefore, we evaluated cNOS activity (conversion of l-[3H]arginine to l-[3H]citrulline in the presence of Ca2 + and calmodulin), nitrate and nitrite (NOx) concentration (modified Griess method), and NOS1 and NOS3 protein expression (Western blot) in lung homogenates and in the tracheal smooth muscle from OVA-immunized and multiple aerosol-challenged guinea pigs (six challenges, once daily). The expression and activity of the inducible NOS isoform (NOS2), the levels of exhaled NO, and the in vivo airway reactivity were also determined. Constitutive NOS activity and NO x concentration were significantly lower 6 h after the last OVA challenge as compared with salin...

Decreased pulmonary and tracheal smooth muscle expression and activity of type 1 nitric oxide synthase (nNOS) after ovalbumin immunization and multiple aerosol challenge in guinea pigs.

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Decreased pulmonary and tracheal smooth muscle expression and activity of type 1 nitric oxide synthase (nNOS) after ovalbumin immunization and multiple aerosol challenge in guinea pigs.