Induction of nitric oxide synthase in asthma

doi:10.1016/S0140-6736(05)80083-2

The Lancet

Volume 342, Issues 8886–8887, 18–25 December 1993, Pages 1510-1513

https://doi.org/10.1016/S0140-6736(05)80083-2 Get rights and content

Summary

Nitric oxide (NO) is a mediator of vasodilatation and bronchodilatation synthesised from L-arginine by the enzyme NO synthase, which is either constitutive or induced by lipopolysaccharides and/or cytokines. The presence and function of NO synthase in normal or diseased lung is not yet clear.

Asthma is characterised by bronchial hyperresponsiveness, epithelial damage, inflammation, and increased cytokine production. To investigate the presence of NO synthase in asthma, we immunostained bronchial biopsies from non-steroid-treated people with asthma and non-asthmatic controls with specific polyvalent antisera to purified inducible NO synthase and to a selected peptide sequence of the same enzyme. Immunoreactivity was seen in the epithelium and some inflammatory cells in 22 of 23 biopsies from people with asthma, but in only 2 of 20 controls. To assess the relation of cytokines to NO synthase induction, bronchial epithelial cells in culture were stimulated with tumour necrosis factor (TNFα). Inducible enzyme immunoreactivity was found only in the treated cells.

The existence of inducible NO synthase in human lungs suggests that increased production of NO, probably induced by cytokines, may be relevant to the pathology of asthma.

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Cited by (753)

Nitric oxide as a double-edged sword in pulmonary viral infections: Mechanistic insights and potential therapeutic implications
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In the face of the global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), researchers are tirelessly exploring novel therapeutic approaches to combat coronavirus disease 2019 (COVID-19) and its associated complications. Nitric oxide (NO) has appeared as a multifaceted signaling mediator with diverse and often contrasting biological activities. Its intricate biochemistry renders it a crucial regulator of cardiovascular and pulmonary functions, immunity, and neurotransmission. Perturbations in NO production, whether excessive or insufficient, contribute to the pathogenesis of various diseases, encompassing cardiovascular disease, pulmonary hypertension, asthma, diabetes, and cancer. Recent investigations have unveiled the potential of NO donors to impede SARS-CoV- 2 replication, while inhaled NO demonstrates promise as a therapeutic avenue for improving oxygenation in COVID-19-related hypoxic pulmonary conditions. Interestingly, NO's association with the inflammatory response in asthma suggests a potential protective role against SARS-CoV-2 infection. Furthermore, compelling evidence indicates the benefits of inhaled NO in optimizing ventilation-perfusion ratios and mitigating the need for mechanical ventilation in COVID-19 patients. In this review, we delve into the molecular targets of NO, its utility as a diagnostic marker, the mechanisms underlying its action in COVID-19, and the potential of inhaled NO as a therapeutic intervention against viral infections. The topmost significant pathway, gene ontology (GO)-biological process (BP), GO-molecular function (MF) and GO-cellular compartment (CC) terms associated with Nitric Oxide Synthase (NOS)1, NOS2, NOS3 were arginine biosynthesis (p-value = 1.15 x 10–9) regulation of guanylate cyclase activity (p-value = 7.5 x 10–12), arginine binding (p-value = 2.62 x 10–11), vesicle membrane (p-value = 3.93 x 10–8). Transcriptomics analysis further validates the significant presence of NOS1, NOS2, NOS3 in independent COVID-19 and pulmonary hypertension cohorts with respect to controls. This review investigates NO's molecular targets, diagnostic potentials, and therapeutic role in COVID-19, employing bioinformatics to identify key pathways and NOS isoforms' significance.
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La medición de la fracción exhalada de óxido nítrico (FE_NO) ha demostrado utilidad para diagnosticar el asma y predecir la respuesta a glucocorticoides, riesgo de exacerbaciones o el cumplimiento con el tratamiento. Se recomienda su uso en la mayoría de las guías de práctica clínica. En los últimos años hemos asistido a la proliferación de múltiples dispositivos para su medición en el mercado que tienen características distintas y plantean dudas a los profesionales al momento de adquirir el más apropiado para el manejo del paciente con asma. En esta revisión se recogen las características más importantes de los principales medidores de FE_NO y se analizan los estudios comparativos y farmacoeconómicos existentes. La intención es que la evidencia existente en la actualidad sirva de ayuda para la elección del dispositivo más adecuado.
The use of devices for measuring the exhaled fraction of nitric oxide has proven to be very useful, especially in the diagnosis of asthma, prediction of response to corticosteroids, risk of exacerbations or compliance with treatment, among others, and their use is recommended by important clinical practice guidelines. In recent years we have witnessed a proliferation of options on the market with different characteristics. To help in choosing a device that suits the needs of the professionals involved in the management of asthma, this review presents some of the important characteristics of the most common devices. In addition, the existing comparative and pharmacoeconomic studies are analyzed so that professionals can make the choice of device guided by the most current evidence.
Intranasal micellar curcumin for the treatment of chronic asthma
2022, Journal of Drug Delivery Science and Technology
Citation Excerpt :
Nitric oxide is one of the potential makers of inflammation and higher levels of nitric oxide are produced in asthamatic condition. Three isoforms (two constitutive and one inducible) of nitric oxide enzyme are responsible for production of neuronal or type I (nNOS), inducible isoform or type II (iNOS), and the endothelial isoform or type 3 (eNOS) [26–31]. Studies have shown that curcumin acts as a scavenger of nitric oxide and modulates signaling pathways mediated via (NF-KB)and mitogen-activated protein kinase, which prevent bronchial inflammation in asthmatic patients [30].
Curcumin is a natural phytoconstituent obtained from the rhizomes of Curcuma longa (turmeric) and is known for its diverse anti-oxidant and anti-inflammatory benefits, but its clinical utility is limited by its poor aqueous solubility and rapid metabolism, which ultimately affects its bioavailability. The present study is focused on the formulation of curcumin loaded micellar dispersion for intranasal delivery for the treatment of chronic asthma. Micellar dispersion was prepared by film formation method using poly-(ethylene oxide)-block-distearoyl phosphatidyl-ethanolamine (mPEG5000-DSPE) as lipid surfactant and characterized for its physic-chemical properties. The curcumin micelles were evaluated for their anti-asthmatic action in ovalbumin (OVA)-induced allergic asthma model in male wistar rats against standard drug dexamethasone. The micelles showed mean particle size in the range of 20.03 nm–26.48 nm. The micellar dispersion exhibited negative zeta potential in the range of −26.22 to −25.52 mV. Incorporation of curcumin into micelles helped in enhancing the solubility of curcumin besides providing it protection against degradation. In vitro studies showed sustained relase of curcumin up to 36 h. A 14- fold increase in the bioaviability of the curcumin was measured when administered as micelles. In addition, 4.4- fold higher concentration of drug was measured in the lungs for micellar curcumin. Comparable reduction in the levels of intracellular ROS was observed for i.n. curcumin-micelles (approx.57.6%) and dexamethasone (59.3%). Also, micellar curcumin produced significant supression (p < 0.05) in the release of nitric oxide. Through the present study, we can suggest the potential application of curcumin micelles in the treatment of asthma.
Diagnosing, Monitoring and Treating Asthma
2021, Encyclopedia of Respiratory Medicine, Second Edition
Asthma is the most common long term condition in childhood, yet the frequency with which it is diagnosed belies the complexity and heterogeneity of asthma and the challenges in management. Although most children respond well to low levels of inhaled steroids a significant proportion experience frequent attacks and symptoms which impact on their quality of life. Advances have been made in recent years in understanding the underlying pathobiology of childhood asthma, particularly in those with severe asthma, affording the opportunity for more effective targeted treatments. This article will discuss the important considerations in diagnosing childhood asthma, explore the underlying pathophysiology, describe phenotypes of asthma and how they can be used to direct treatment and finally discuss the key components of asthma monitoring.
Exhaled nitric oxide and its predictive power related to lung function and bronchial inflammation
2020, Biochemical Pharmacology
Design, synthesis and crystal structure of six macrocyclic complexes as efficient and effective nitric oxide scavengers
2018, Polyhedron
Citation Excerpt :
NO exhibits an important role in maintaining the vasodilatory tone of tumors by regulating tumor blood flow and is closely linked to the growth and progression of several human tumors [3–6]. Overproduction of NO contributes significantly to various diseases such as sepsis, arthritis, diabetes and epilepsy [7–9]. Hence the molecules which could donate as well as those compounds which could scavenge NO are extremely important for the treatment of diseases caused by unusual concentration of NO [10].
Four new complexes of Robson-type macrocycles, [CuH(L¹)]₂(ClO₄)₂(H₂O)₂ (1), [CuH(L²)] ClO₄ (2), [Cu H(L³)]₂(ClO₄)₂ (3), [Cu H(L⁴)]₂(ClO₄)₂(CH₃CH₂OH)₂(CH₃CN)₂(4) and two reported Robson-type macrocycles polymers {[CuL⁵](H₂O)₂}_n(5), {[MnL⁵](H₂O)₂}_n (6) were obtained. The ligands (H₂L¹, H₂L², H₂L³) are the products from the condensation between bata and N,N′-bis(3-formyl-5-X-salicylimine)-1,2-ethylenediimine (X = CH₃, Cl, F), respectively. Ligands H₂L⁴ and H₂L⁵ are the products of N,N′-bis(3-formyl-5-methylsalicylimine)-1,2-propylenediimineand condensation with bafa and bapa, respectively. All the metal ions have unsaturated coordinated sites, which are available for NO binding. The binding of the complexes with NO molecules have been confirmed by UV–Vis spectrophotometry. The binding constants were calculated to be 1.28 × 10³ M⁻¹, 8.9 × 10² M⁻¹, 7.7 × 10³ M⁻¹, 1.2 × 10³ M⁻¹, 1.2 × 10³ M⁻¹, 1.3 × 10³ M⁻¹ for 1, 2, 3, 4, 5 and 6, respectively. The control experiments revealed there was non-reversible binding of NO, which can be ascribed to specially coordination environment of the central ions. Moreover, the interactions of the complexes with calf thymus DNA (CT-DNA) have been measured by agarose gel electrophoresis, and unobvious DNA cleavage ability of complexes 1, 3 and 4 indicating no damage to DNA. The results reveal that complexes 1, 3 and 4 can be served as potential NO scavengers.

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ArticleInduction of nitric oxide synthase in asthma

Summary

Biochem Pharmacol

J Biol Chem

Biochem Biophys Res Commun

Lancet

Biochem Biophys Res Commun

Eur J Pharmacol

FEBS Lett

Lancet

J Allergy Clin Immunol

Lancet

Nitric oxide: physiology, pathophysiology, and pharmacology

Pharm Revs

Localization of nitric oxide synthase indicating a neural role for nitric oxide

Nature

Immunological detection of nitric oxide synthase(s) in human tissues using heterologous antibodies suggesting different isoforms

Histochemistry

Hepatocytes produce nitrogen oxides from L-arginine in response to inflammatory products from Kupffer cells

J Exp Med

Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide

J Exp Med

Article
Induction of nitric oxide synthase in asthma