scholarly journals Potential of Inducible Nitric Oxide Synthase as a Therapeutic Target for Allergen-Induced Airway Hyperresponsiveness: A Critical Connection to Nitric Oxide Levels and PARP Activity

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Salome’ V. Ibba ◽  
Mohamed A. Ghonim ◽  
Kusma Pyakurel ◽  
Matthew R. Lammi ◽  
Anil Mishra ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Therapeutic Target ◽  
Airway Hyperresponsiveness ◽  
Mononuclear Cells ◽  
Inos Expression ◽  
Parp Inhibition ◽  
Protein Nitration ◽  
Parp Activation ◽  
Peripheral Blood Mononuclear ◽  
Inos Inhibitors

Although expression of inducible NO synthase (iNOS) in the lungs of asthmatics and associated nitrosative damage are established, iNOS failed as a therapeutic target for blocking airway hyperresponsiveness (AHR) and inflammation in asthmatics. This dichotomy calls for better strategies with which the enzyme is adequately targeted. Here, we confirm iNOS expression in the asthmatic lung with concomitant protein nitration and poly(ADP-ribose) polymerase (PARP) activation. We show, for the first time, that iNOS is highly expressed in peripheral blood mononuclear cells (PBMCs) of asthmatics with uncontrolled disease, which did not correspond to protein nitration. Selective iNOS inhibition with L-NIL protected against AHR upon acute, but not chronic, exposure to ovalbumin or house dust mite (HDM) in mice. Supplementation of NO by nitrite administration significantly blocked AHR in chronically HDM-exposed mice that were treated with L-NIL. Protection against chronic HDM exposure-induced AHR by olaparib-mediated PARP inhibition may be associated with the partial but not the complete blockade of iNOS expression. Indeed, L-NIL administration prevented olaparib-mediated protection against AHR in chronically HDM-exposed mice. Our study suggests that the amount of iNOS and NO are critical determinants in the modulation of AHR by selective iNOS inhibitors and renews the potential of iNOS as a therapeutic target for asthma.

scholarly journals Unchanged interleukin 6 level of protein and energy restricted goats during late gestation: the role of elevated blood nitric oxide

2012 ◽  
Vol 213 (1) ◽  
pp. 59-65 ◽  
Author(s):  
Zhixiong He ◽  
Zhiliang Tan ◽  
Zhihong Sun ◽  
Karen A Beauchemin ◽  
Shaoxun Tang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Interleukin 2 ◽  
Metabolizable Energy ◽  
Late Gestation ◽  
No Donor ◽  
Peripheral Blood Mononuclear ◽  
Synthase Inhibitor

Twelve pregnant goats were assigned to three dietary treatments during late gestation, namely control (C: metabolizable energy, 5.75 MJ/kg; crude protein, 12.6% and dry matter basis), 40% protein restricted (PR) and 40% energy restricted (ER), to examine the effects of nutrient restriction on the immune status of pregnant goats. Plasma was sampled on day 90, 125 and 145 from pregnant goats to determine cytokine production (interleukin 2 (IL2), IL6) and tumor necrosis factor α (TNFα)). Peripheral blood mononuclear cells were obtained on day 145 and activated by lipopolysaccharide to determine cytokine production, and then exposed (PR and ER) to sodium nitroprusside (SNP), a nitric oxide (NO) donor, or control to NG-nitro-l-arginine methyl ester hydrochloride (l-NAME), an NO synthase inhibitor to explore the role of NO in regulating cytokine production. Plasma IL2, IL6 and TNFα were not altered during gestation, but NO was increased (P<0.05) at gestation day 145 for PR and ER.In vitro, compared with control, NO was lower for PR and ER (P<0.001), but IL6 was higher for PR (P<0.001) and ER (P=0.11). The addition of SNP decreased IL6 (P<0.001, PR;P=0.12, ER) in the malnourished group, andl-NAME increased (P<0.001) IL6 in control compared to those treatments without SNP orl-NAME. The results indicate that plasma NO acted as a regulator of cytokine function exhibiting negative feedback to maintain steady plasma IL6 concentration in PR or ER goats during late gestation.

Evaluation of the potential anti-allergic effects of heat-inactivated Lactobacillus paracasei V0151 in vitro, ex vivo, and in vivo

2015 ◽  
Vol 6 (5) ◽  
pp. 697-705 ◽  
Author(s):  
Y.W. Liu ◽  
T.Y. Fu ◽  
W.S. Peng ◽  
Y.H. Chen ◽  
Y.M. Cao ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Human Peripheral Blood ◽  
Lactobacillus Paracasei ◽  
Raw 264.7 Cells ◽  
Inflammatory Factors ◽  
T Helper ◽  
T Helper 1 ◽  
Peripheral Blood Mononuclear

The efficacy of Lactobacillus paracasei V0151 (V0151), isolated from the faeces of a child, to modulate immune responses was investigated. In RAW 264.7 cells expressing an inducible nitric oxide synthase (iNOS)-directed luciferase gene, heat-inactivated V0151 stimulated iNOS expression followed by nitric oxide production. V0151 significantly elevated interferon gamma, interleukin (IL)-10, tumour necrosis factor alpha, and IL-1β production in human peripheral blood mononuclear cells. In splenocytes isolated from ovalbumin (OVA)-sensitised BALB/c mice treated with OVA and V0151 at different bacterium-to-cell ratios (1:1, 10:1, and 20:1) for 96 h, IL-2, IL-4, IL-5, and IL-13 production was dose-dependently downregulated, whereas IL-12 was dose-dependently upregulated. Collectively, our findings indicate that V0151 might regulate pro-inflammatory factors in macrophages and splenocytes. Furthermore, the T helper 1/T helper 2 (Th1/Th2) balance was also skewed toward Th1 dominance through the elevation of Th1 cytokine production.

scholarly journals IL-10 and TGF-β Induced Arginase Expression Contributes to Deficient Nitric Oxide Response in Human Visceral Leishmaniasis

2021 ◽  
Vol 10 ◽  
Author(s):  
Manu Kupani ◽  
Smriti Sharma ◽  
Rajeev Kumar Pandey ◽  
Rajiv Kumar ◽  
Shyam Sundar ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
No Production ◽  
Peripheral Blood Mononuclear ◽  
Before And After ◽  
Plasma Nitrite

Nitric oxide (NO) is an anti-microbial effector of the innate immune system which plays major role in non-specific killing of various pathogens including protozoan parasites. However, due to subversion of the host’s immune processes by pathogens, suboptimal production of NO is frequently found in many infection models. Previous studies have shown suppressed NO production during Leishmania donovani infection, the causative agent of visceral leishmaniasis (VL). Availability of L-Arginine, a semi-essential amino acid is required for inducible nitric oxide synthase (iNOS) mediated NO production. However, arginase is another enzyme, which if expressed concomitantly, may strongly compete for L-Arginine, and suppress NO production by iNOS. In the present study, plasma nitrite and arginase levels were measured in VL patients before and after successful drug treatment, endemic and non-endemic healthy donors. We observed significantly lower NO levels in the plasma of VL patients as compared to endemic controls, which improved significantly post-treatment. Significantly elevated arginase activity was also observed in the plasma of VL patients, which may be associated with NO deficiency. VL patients also showed significantly higher levels of IL-10 and TGF-β, which are known to regulate expression of arginase in various immune cells. In vitro studies with human peripheral blood mononuclear cells (PBMCs) further corroborated the role of IL-10 and TGF-β in arginase mediated suppression of NO production.

Sign in / Sign up

Export Citation Format

Share Document