Pulmonary alveolar epithelial inducible NO synthase gene expression: regulation by inflammatory mediators

1995 ◽  
Vol 268 (3) ◽  
pp. L501-L508 ◽  
Author(s):  
H. H. Gutierrez ◽  
B. R. Pitt ◽  
M. Schwarz ◽  
S. C. Watkins ◽  
C. Lowenstein ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Gene Expression Regulation ◽  
Interleukin 1 ◽  
Alveolar Epithelium ◽  
Cell Types ◽  
Oxidation Products ◽  
No Oxidation ◽  
Target Cells ◽  
Cell Permeabilization ◽  
Necrosis Factor Alpha

Nitric oxide (.NO) is a short-lived mediator that can be induced by different cytokines and lipopolysaccharide (LPS) in a variety of cell types and produces many physiological and metabolic changes in target cells. In the current study, we show that a combination of cytokines, LPS, and zymosan-activated serum (ZAS; called for convenience cytomix Z) induces production of high concentrations of the NO oxidation products nitrite (NO2-) and nitrate (NO3-) by cultured rat fetal lung epithelial type II cells in a time-dependent fashion. Interferon-gamma and tumor necrosis factor-alpha alone did not significantly affect .NO synthesis, whereas ZAS, LPS, and interleukin-1 beta caused only a modest increase in formation of .NO oxidation products. Production of NO2- and NO3- was inhibited by NG-monomethyl-L-arginine and cyclohexmide. After exposure of these cells to a combination of the above cytokines, Escherichia coli LPS, and ZAS (cytomix Z), enhanced inducible nitric oxide synthase (iNOS) expression was indicated by an elevation in steady-state mRNA specific for iNOS (via Northern blot analysis) and increased immunofluorescence for iNOS after cell permeabilization, incubation with anti-iNOS antibody, and treatment with Cy3.18-conjugated rabbit-specific antibody. The extent of inflammatory mediator-induced.NO production by alveolar epithelium, which exceeds that of other lung cell types, reveals new insight into mechanisms of pulmonary host defense and pathways of free radical-mediated lung injury.

Augmentation of cytokine-induced nitric oxide synthesis by hydrogen peroxide

1996 ◽  
Vol 271 (1) ◽  
pp. L114-L120 ◽  
Author(s):  
S. A. Milligan ◽  
M. W. Owens ◽  
M. B. Grisham
Keyword(s):  
Nitric Oxide ◽  
Interleukin 1 ◽  
Northern Blotting ◽  
Oxidation Products ◽  
Tnf Alpha ◽  
Inos Mrna ◽  
Transcriptional Level ◽  
Necrosis Factor Alpha ◽  
Steady State Levels ◽  
Stimulation Of

The inducible isoform of nitric oxide synthase (iNOS) is induced upon stimulation of cells with cytokines and lipopolysaccharide (LPS). Stimulation of rat pleural mesothelial cells with combinations of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and LPS induced the synthesis of nitric oxide as measured by the oxidation products nitrite (NO2-) and nitrate (NO3-). Addition of 25-50 microM H2O2 to the cytokines significantly augmented the synthesis of NO2- and NO3-. Stimulation with IL-1 beta and TNF-alpha plus H2O2 or IL-1 beta and LPS plus H2O2 increased the synthesis of NO2- and NO3- by 3.8- and 3.5-fold, respectively. These effects were inhibited by NG-nitro-L-arginine methyl ester and cycloheximide as well as by catalase. Immunoblotting demonstrated that H2O2 augmented cytokine-induced synthesis of iNOS protein. These effects were inhibited by certain antioxidants and metal chelators, suggesting that the hydroxyl radical may mediate the oxidant-induced effect. Northern blotting demonstrated that H2O2 greatly augmented steady-state levels of iNOS mRNA, suggesting that H2O2 acted in part at the transcriptional level.

scholarly journals Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin.

1992 ◽  
Vol 176 (1) ◽  
pp. 261-264 ◽  
Author(s):  
A K Nussler ◽  
M Di Silvio ◽  
T R Billiar ◽  
R A Hoffman ◽  
D A Geller ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Human Cell ◽  
Interleukin 1 ◽  
Cell Types ◽  
Human Hepatocytes ◽  
Target Cells ◽  
Cell Type ◽  
Oxide Synthase ◽  
Culture Supernatants ◽  
Stimulation Of

Nitric oxide (NO) is a short-lived biologic mediator that is shown to be induced in various cell types and to cause many metabolic changes in target cells. Inhibition of tumor cell growth and antimicrobial activity has been attributed to the stimulation of the inducible type of the NO synthase (NOS). However, there is limited evidence for the existence of such inducible NOS in a human cell type. We show here the induction of NO biosynthesis in freshly isolated human hepatocytes (HC) after stimulation with interleukin 1, tumor necrosis factor (TNF), IFN-gamma, and endotoxin. Increased levels of nitrite (NO2-) and nitrate (NO3-) in culture supernatants were associated with NADPH-dependent NOS activity in the cell lysates. The production of NO2- and NO3- was inhibited by NG-monomethyl L-arginine and was associated with an increase in cyclic guanylate monophosphate release. The data presented here provide evidence for the existence of typical inducible NO biosynthesis in a human cell type.

Regulation of inducible nitric oxide synthase in hepatic sinusoidal endothelial cells

1996 ◽  
Vol 271 (2) ◽  
pp. G260-G267 ◽  
Author(s):  
D. C. Rockey ◽  
J. J. Chung
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Interleukin 1 ◽  
Cell Types ◽  
Tnf Alpha ◽  
Inos Mrna ◽  
No Production ◽  
Sinusoidal Endothelial Cells ◽  
Necrosis Factor Alpha ◽  
Ifn Gamma

Nitric oxide (NO) has many important physiological effects that depend in part on its cellular source(s). In liver, NO is produced by all major cell types, including hepatocytes, Kupffer, stellate, and sinusoidal endothelial cells (SECs). Although endothelial cells have been commonly associated with constitutive NO production, recent evidence suggests that NO is inducible in this cell type. Here, we investigated the regulation of inducible NO synthase (iNOS) in SECs. Interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) as individual compounds induced iNOS mRNA in SECs. Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) had no effect when used alone but enhanced iNOS mRNA upregulation by IFN-gamma. iNOS transcription after LPS was present only for 4 h after exposure yet was more sustained after IFN-gamma/TNF-alpha, LPS was unique in that it transiently induced iNOS mRNA, whereas IFN-gamma/TNF-alpha resulted in prolonged increases in iNOS mRNA. Both LPS and IFN-gamma/TNF-alpha caused prolonged elevation of immunoreactive protein. However, when stimulated by LPS, iNOS remained enzymatically active for only 24-48 h. After IFN-gamma or IFN-gamma/TNF-alpha, iNOS activity declined only moderately. LPS added to IFN-gamma alone or IFN-gamma/TNF-alpha did not result in more rapid decay of iNOS enzymatic activity. These data indicate that induction of iNOS by sinusoidal endothelial cells is prominent and that it is regulated both transcriptionally and by its inactivation. Such complex regulation of iNOS has important implications for NO biology in liver disease.

Role of inflammation in the development of colorectal cancer

2020 ◽  
Vol 20 ◽  
Author(s):  
Sridhar Muthusami ◽  
R. Ileng Kumaran ◽  
Kokelavani Nampalli Babu ◽  
Sneha Krishnamoorthy ◽  
Akash Guruswamy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chronic Inflammation ◽  
Interleukin 1 ◽  
Cell Types ◽  
Model Systems ◽  
Cytokine Gene Expression ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Proinflammatory Molecules

: Chronic inflammation can lead to the development of many diseases including cancer. Inflammatory bowel disease (IBD) that includes both ulcerative colitis (UC) and Crohn's disease (CD) are risk factors for the development of colorectal cancer (CRC). Many cytokines produced primarily by the gut immune cells either during or in response to localized inflammation in the colon and rectum are known to stimulate the complex interactions between the different cell types in the gut environment resulting in acute inflammation. Subsequently, chronic inflammation together with genetic and epigenetic changes has been shown to lead to the development and progression of CRC. Various cell types present in the colon such as enterocytes, Paneth cells, goblet cells and macrophages express receptors for inflammatory cytokines and respond to tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6 and other cytokines. Among the several cytokines produced, TNF-α and IL-1β are the key proinflammatory molecules that play critical roles in the development of CRC. The current review is intended to consolidate the published findings to focus on the role of proinflammatory cytokines, namely TNF-α and IL-1β, on inflammation (and the altered immune response) in the gut, to better understand the development of CRC in IBD, using various experimental model systems, preclinical and clinical studies. Moreover, this review also highlights the current therapeutic strategies available (monotherapy and combination therapy), to alleviate the symptoms or treat inflammationassociated CRC by using monoclonal antibodies or aptamers to block proinflammatory molecules, inhibitors of tyrosine kinases in inflammatory signaling cascade, competitive inhibitors of proinflammatory molecules, and the nucleic acid drugs like small activating RNAs (saRNAs) or microRNA (miRNA) mimics to activate tumor suppressor or repress oncogene/proinflammatory cytokine gene expression.

scholarly journals Inducible Nitric Oxide Synthase Is Not Essential for Control of Trypanosoma cruzi Infection in Mice

2004 ◽  
Vol 72 (7) ◽  
pp. 4081-4089 ◽  
Author(s):  
Kara L. Cummings ◽  
Rick L. Tarleton
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Trypanosoma Cruzi ◽  
Inducible Nitric Oxide Synthase ◽  
Interleukin 1 ◽  
Mouse Strains ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACT Immune control of many intracellular pathogens, including Trypanosoma cruzi, is reported to be dependent on the production of nitric oxide. In this study, we show that mice deficient in inducible nitric oxide synthase (iNOS or NOS2) exhibit resistance to T. cruzi infection that is comparable to that of wild-type mice. This is the case for two iNOS-deficient mouse strains, Nos2tm1Lau and Nos2 N5, infected with the Brazil or Tulahuen strain of T. cruzi. In all cases, blood parasitemia, tissue parasite load, and survival rates are similar between wild-type and iNOS-deficient mice. In contrast, both wild-type and Nos2tm1Lau mice died within 32 days postinfection when treated with the nitric oxide synthase inhibitor aminoguanidine. Increased transcription of NOS1 or NOS3 is not found in iNOS-knockout (KO) mice, indicating that the absence of nitric oxide production through iNOS is not compensated for by increased production of other NOS isoforms. However, Nos2tm1Lau mice exhibit enhanced expression of tumor necrosis factor alpha, interleukin-1, and macrophage inflammatory protein 1α compared to that of wild-type mice, and these alterations may in part compensate for the lack of iNOS. These results clearly show that iNOS is not required for control of T. cruzi infection in mice.

Oxymatrine inhibits lipopolysaccharide-induced inflammation by down-regulating Toll-like receptor 4/nuclear factor-kappa B in macrophages

2015 ◽  
Vol 93 (4) ◽  
pp. 253-260 ◽  
Author(s):  
Yu Zhang ◽  
Ruhong Yan ◽  
Yae Hu
Keyword(s):  
Nitric Oxide ◽  
Interleukin 1 ◽  
Chinese Herb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Anti Inflammatory

Oxymatrine (OMT) is the quinolizidine alkaloid extracted from the Chinese herb Sophora flavescens Ait. that has many pharmacological effects and is used for the treatment of some inflammatory diseases. In this study, RAW264.7 cells and THP-1 differentiated macrophages were pretreated with various concentrations of OMT at 2 h prior to treatment with lipopolysaccharide (LPS) (1.0 μg/mL) for different durations. We detected the anti-inflammatory effect of OMT in LPS-stimulated macrophages and investigated the molecular mechanism. We showed that OMT pretreatment significantly inhibited the LPS-induced secretion of nitric oxide (NO), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) in supernatant, attenuated the mRNA levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and Toll-like receptor 4 (TLR4), increased TLR4 and phosphorylation of inhibitor of kappa B-alpha (p-IBα) in cytosol, and decreased the nuclear level of nuclear factor-κB (NF-κB) p65 in macrophages. In conclusion, OMT exerts anti-inflammatory properties in LPS-stimulated macrophages by down-regulating the TLR4/NF-κB pathway.

Hypoxia inhibits nitric oxide synthesis in isolated rabbit lung

1997 ◽  
Vol 272 (6) ◽  
pp. L1167-L1173 ◽  
Author(s):  
S. P. Kantrow ◽  
Y. C. Huang ◽  
A. R. Whorton ◽  
E. N. Grayck ◽  
J. M. Knight ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Competitive Inhibitor ◽  
Oxidation Products ◽  
No Oxidation ◽  
Severe Hypoxia ◽  
No Production ◽  
Rabbit Lung ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Oxide Synthase

Nitric oxide (NO.) has been proposed to modulate hypoxic vasoconstriction in the lung. The activity of nitric oxide synthase (NOS) can be inhibited by hypoxia because molecular oxygen is a necessary substrate for the enzyme. On the basis of this mechanism, we hypothesized that NOS activity has a key role in regulation of pulmonary vascular tone during hypoxia. We measured oxidation products of NO. released into the vasculature of isolated buffer-perfused rabbit lung ventilated with normoxic (21% O2), moderately hypoxic (5% O2), or anoxic (0% O2) gas using two methods. Mean PO2 in perfusate exiting the lung was 25 Torr during anoxic ventilation and 47 Torr during moderately hypoxic ventilation. We found that the amount of the NO. oxidation product nitrite released into the perfusate was suppressed significantly during ventilation with anoxic but not moderately hypoxic gas. During normoxic ventilation, nitrite release was inhibited by pretreatment with NG-monomethyl-L-arginine, a competitive inhibitor of NOS. To confirm that changes in nitrite concentration reflected changes in NO. release into the perfusate, major oxidation products of NO. (NOx) were assayed using a method for reduction of these products to NO. by vanadium(III) Cl. Release of NOx into the perfusate was suppressed by severe hypoxia (anoxic ventilation), and this effect was reversed by normoxia. Pulmonary vasoconstriction was observed during severe but not moderate hypoxia and was related inversely to the rate of nitrite release. These observations provide evidence that decreased NO. production contributes to the pulmonary vasoconstrictor response during severe hypoxia.

scholarly journals Basal and stimulated nitric oxide in control of kidney function in the aging rat

1997 ◽  
Vol 272 (6) ◽  
pp. R1747-R1753 ◽  
Author(s):  
C. Hill ◽  
A. M. Lateef ◽  
K. Engels ◽  
L. Samsell ◽  
C. Baylis
Keyword(s):  
Nitric Oxide ◽  
Vascular Resistance ◽  
Pressor Response ◽  
Renal Vascular Resistance ◽  
Oxidation Products ◽  
No Oxidation ◽  
No Production ◽  
Sprague Dawley ◽  
Vasoconstrictor Response ◽  
Renal Vascular

To investigate the activity of nitric oxide (NO) in control of renal hemodynamics during aging, studies were conducted on conscious Sprague-Dawley rats aged 3-5 mo (young, Y) and 18-22 mo (old, O). Blood pressure (BP) and renal vascular resistance (RVR) were higher in O vs. Y in control, and acute systemic NO synthesis inhibition (NOSI) increased BP and RVR, with an enhanced renal vasoconstrictor response in O. Infusion of the NO substrate L-arginine produced similar, selective renal vasodilation in both groups. The endothelium-dependent vasodilator acetylcholine caused similar falls in BP and RVR, whereas sodium nitroprusside produced an exaggerated depressor response in O vs. Y without falls in RVR in either age group. Urinary excretion of the stable NO oxidation products (NOx) decreased with age, suggesting a decline in the overall somatic NO production. In conclusion, basal tonically produced NO has a more pronounced role in maintenance of renal perfusion in aging, whereas L-arginine- and agonist-stimulated renal vasodilation is not impaired with age. NO production from some source may be reduced with aging, as indicated by falls in 24-h NOX excretion, although the similarity in pressor response and enhanced renal vasoconstrictor response to NOSI suggests that the role of NO in control of total peripheral and renal vascular resistance is maintained.

Acute effect of insulin on nitric oxide synthesis in humans: a precursor-product isotopic study

2007 ◽  
Vol 293 (3) ◽  
pp. E776-E782 ◽  
Author(s):  
Paolo Tessari ◽  
Anna Coracina ◽  
Lucia Puricelli ◽  
Monica Vettore ◽  
Alessandra Cosma ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Effect ◽  
Oxidation Products ◽  
No Oxidation ◽  
Metabolic Effects ◽  
Whole Body ◽  
Fasting State ◽  
Isotopic Study ◽  
Euglycemic Hyperinsulinemic Clamp

Nitric oxide (NO) is a key regulatory molecule with wide vascular, cellular, and metabolic effects. Insulin affects NO synthesis in vitro. No data exist on the acute effect of insulin on NO kinetics in vivo. By employing a precursor-product tracer method in humans, we have directly estimated the acute effect of insulin on intravascular NOx (i.e., the NO oxidation products) fractional (FSR) and absolute (ASR) synthesis rates in vivo. Nine healthy male volunteers were infused iv with l-[15N2-guanidino]arginine ([15N2]arginine) for 6 h. Timed measurements of 15NOx and [15N2]arginine enrichments in whole blood were performed in the first 3 h in the fasting state and then following a 3-h euglycemic-hyperinsulinemic clamp (with plasma insulin raised to ≈1,000 pmol/l). In the last 60 min of each experimental period, at ≈steady-state arginine enrichment, a linear increase of 15NOx enrichment (mean r = 0.9) was detected in both experimental periods. In the fasting state, NOx FSR was 27.4 ± 4.3%/day, whereas ASR was 0.97 ± 0.36 mmol/day, accounting for 0.69 ± 0.27% of arginine flux. Following hyperinsulinemia, both FSR and ASR of NOx increased (FSR by ≈50%, to 42.4 ± 6.7%/day, P < 0.005; ASR by ≈25%, to 1.22 ± 0.41 mmol/day, P = 0.002), despite a ≈20–30% decrease of arginine flux and concentration. The fraction of arginine flux used for NOx synthesis was doubled, to 1.13 ± 0.35% ( P < 0.003). In conclusion, whole body NOx synthesis can be directly measured over a short observation time with stable isotope methods in humans. Insulin acutely stimulates NOx synthesis from arginine.

Gigantol Alleviates IL-1β-Induced Inflammation and Catabolism in Mouse Osteoarthritis via PI3K/Akt/NF-κB Pathways In Vivo and In Vitro

2021 ◽  
Author(s):  
Gaosheng Zhu ◽  
Keze Miao ◽  
Mingwei Dong ◽  
Jie Cai ◽  
Zhihao Shen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Therapeutic Option ◽  
Interleukin 1 ◽  
Cartilage Degradation ◽  
Research Society ◽  
Necrosis Factor Alpha ◽  
Persistent Inflammation ◽  
Anti Inflammatory

Abstract Osteoarthritis (OA), a prevalent disabling disease, is characterized by irreversible cartilage degradation and persistent inflammation. The etiology as well as pathogenesis of OA are not completely unclear and need further investigation. Gigantol, is a bibenzyl derivative extracted from Dendrobium plants and has been found exhibit multiple effects such as anti-inflammatory effects. Nevertheless, the biological function of gigantol on osteoarthritis (OA) is still uncertain. This study aimed at examining the anti-inflammatory effects and latent mechanisms of gigantol in IL-1β-mediated OA progression. In vitro, we identified that gigantol treatment suppressed tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6) in interleukin-1 beta (IL-1β) mediated mouse OA chondrocytes. Gigantol was also shown to dose dependently downregulate the metalloproteinase 13 (MMP13) as well as thrombospondin motifs 5 (ADAMTS5) levels. Moreover, IL-1β-mediated AKT and PI3K phosphorylation as well as NF-κB activation were inhibited by gigantol. Meanwhile, in vivo, we detected that gigantol treatment inhibited degradation of the cartilage degradation and lowered the Osteoarthritis Research Society International scores (OARSI) in OA mouse. Therefore, gigantol is a promising therapeutic option for OA.

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