Role of nitric oxide in acute lung inflammation: Lessons learned from the inducible nitric oxide synthase knockout mouse*

Shanley, Thomas P.; Zhao, Bin; Macariola, Demetrio; Denenberg, Alvin; Salzman, Andrew L.; Ward, Peter A.

doi:10.1097/00003246-200209000-00003

Cited by 44 publications

(33 citation statements)

References 31 publications

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“…Experiments utilizing NO synthase inhibitors or iNOS knockout mice in IT LPS or VILI models underscore the critical importance of iNOS in these injuries (24,31,33,42). For example, in IT LPS, NO production from iNOS was upstream of MIP-2 and TNF-␣ (31, 42) and contributed significantly to alveolar neutrophil influx (31,42), and alveolar-capillary barrier dysfunction (24,31,42). Indeed, NO synthase inhibition was more effective in blocking LPS-induced epithelial barrier dysfunction than either TNF-␣ antibody or neutrophil depletion (24).…”

Section: Discussionmentioning

confidence: 99%

“…LPS, through Toll-like receptor-4 signaling, was shown to cause increased NO from phosphorylated endothelial (eNOS) (11) and inducible nitric oxide synthase (iNOS) (24,31) in alveolar macrophages, neutrophils, epithelium, and endothelium. NO from both eNOS and iNOS was found to play a major pathogenic role in ALI from LPS (24,31,42) and in ventilator-induced lung injury (VILI) (33,39). These injurious effects of endogenous NO have been attributed to a reaction with superoxide to generate peroxynitrite (31,33).…”

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confidence: 99%

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Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Rentsendorj

Damarla

Aggarwal

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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is stimulated by cGMP to hydrolyze cAMP, a potent endothelial barrier-protective molecule. We previously found that lung PDE2A contributed to a mouse model of ventilator-induced lung injury (VILI). The purpose of the present study was to determine the contribution of PDE2A in a two-hit mouse model of 1-day intratracheal (IT) LPS followed by 4 h of 20 ml/kg tidal volume ventilation. Compared with IT water controls, LPS alone (3.75 g/g body wt) increased lung PDE2A mRNA and protein expression by 6 h with a persistent increase in protein through day 4 before decreasing to control levels on days 6 and 10. Similar to the PDE2A time course, the peak in bronchoalveolar lavage (BAL) neutrophils, lactate dehydrogenase (LDH), and protein concentration also occurred on day 4 post-LPS. IT LPS (1 day) and VILI caused a threefold increase in lung PDE2A and inducible nitric oxide synthase (iNOS) and a 24-fold increase in BAL neutrophilia. Compared with a control adenovirus, PDE2A knockdown with an adenovirus expressing a short hairpin RNA administered IT 3 days before LPS/VILI effectively decreased lung PDE2A expression and significantly attenuated BAL neutrophilia, LDH, protein, and chemokine levels. PDE2A knockdown also reduced lung iNOS expression by 53%, increased lung cAMP by nearly twofold, and improved survival from 47 to 100%. We conclude that in a mouse model of LPS/VILI, a synergistic increase in lung PDE2A expression increased lung iNOS and alveolar inflammation and contributed significantly to the ensuing acute lung injury.lipopolysaccharide; ventilator-induced; cyclic guanosine monophosphate; inducible nitric oxide synthase; cAMP SEVERE PNEUMONIA IS A FREQUENT cause of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) (49). ARDS is characterized by neutrophil infiltration, the generation of toxic cytokines and reactive oxygen species (ROS), increased NO production and the loss of endothelial and epithelial barrier function (4). These features can be reproduced in animal models by the installation of intratracheal (IT) LPS (10, 24, 31), a key component of the gram-negative bacterial cell wall. LPS, through Toll-like receptor-4 signaling, was shown to cause increased NO from phosphorylated endothelial (eNOS) (11) and inducible nitric oxide synthase (iNOS) (24, 31) in alveolar macrophages, neutrophils, epithelium, and endothelium. NO from both eNOS and iNOS was found to play a major pathogenic role in ALI from LPS (24, 31, 42) and in ventilator-induced lung injury (VILI) (33, 39). These injurious effects of endogenous NO have been attributed to a reaction with superoxide to generate peroxynitrite (31, 33). In both LPS-induced ALI (47) and VILI (39), however, NO also activates soluble guanylyl cyclase (sGC), increasing production of cGMP in multiple cell types including endothelium (39), epithelium (9, 17), and macrophages (3).The effects of cGMP signaling in ALI are complex, depending on cell type, intracellular compartmentalization, and the downstream cGMP targets (39). These targets include...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Rentsendorj

Damarla

Aggarwal

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In view of the fact that drugs currently used in the treatment of inflammatory bowel disease, such as steroids, do not substantially reduce intestinal NO synthesis (Leonard et al, 1998), the above effect of green tea may be of therapeutic relevance. Furthermore, in chronic inflammatory lung diseases, especially in neonates, the use of steroids has a number of undesired effects (Shanley et al, 2002). Therefore, in inflammatory diseases, green tea may be a suitable adjuvant to reduce the doses of steroids needed.…”

Section: Discussionmentioning

confidence: 99%

Green Tea Inhibits Human Inducible Nitric-Oxide Synthase Expression by Down-Regulating Signal Transducer and Activator of Transcription-1α Activation

Tedeschi¹,

Menegazzi²,

Yao³

et al. 2004

Mol Pharmacol

104

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Green tea has been reported to show anti-inflammatory properties because of its inhibitory effects on the expression of several pro-inflammatory genes. Because the inducible nitricoxide synthase (iNOS) plays an important role in chronic inflammatory diseases, we have focused our attention on the regulation of iNOS expression by green tea in two different human epithelial cell lines, alveolar A549/8 and colon DLD-1 cells. With the use of electrophoretic mobility shift assays, we found a green tea-mediated down-regulation of the DNA binding activity of the transcription factor signal transducer and activator of transcription-1␣ (STAT-1␣), but not of nuclear factor-B. This down-regulation of the STAT-1␣ DNA binding was shown to result from reduced tyrosine phosphorylation of the STAT-1␣ protein and not from antioxidative effects of the green tea extract. Green tea extract inhibited human iNOS expression in a concentration-dependent manner, quantified in terms of iNOS mRNA, iNOS protein, and nitric oxide production in both cell lines. This inhibitory effect of green tea resulted from transcriptional inhibition as shown in reporter gene experiments. These data suggest that green tea extracts may be promising at least as an auxiliary anti-inflammatory principle in chronic inflammatory diseases.

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“…In one of these [262], a speci�c inhibitor of iNOS was shown to greatly lower PAH development, arguing for a causal role of iNOS induction in PAH. An iNOS knockout mouse was less sensitive to exacerbation of PAH, including in�ammatory responses, as discussed above [263].…”

Section: Inos Inductionmentioning

confidence: 81%

“…Wedgwood et al [212] showed a role for both increased ONOO − and superoxide in the rebound response following NO inhalation. Shanley et al [263] showed in�ammatory responses following NO inhalation, responses that were greatly lowered in an iNOS knockout mouse, showing that such in�ammatory responses were not only produced by such NO inhalation, but were lowered by blocking an important part of the NO/ONOO − cycle, namely iNOS induction. e Lakshminrusimha et al study [231] showed that inhaled NO produced increases in ONOO − .…”

Section: No Elevation?mentioning

confidence: 99%

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

Pall

2013

ISRN Hypertension

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e NO/ONOO − cycle is a primarily local biochemical/physiological vicious cycle that appears to cause a series of chronic in�ammatory diseases. is paper focuses on whether the cycle causes pulmonary arterial hypertension (PAH) when located in the pulmonary arteries. e cycle involves 12 elements, including superoxide, peroxynitrite (ONOO − ), nitric oxide (NO), oxidative stress, NF-B, in�ammatory cytokines, iNOS, mitochondrial dysfunction, intracellular calcium, tetrahydrobiopterin depletion, NMDA activity, and TRP receptor activity. 10 of the 12 are elevated in PAH (NMDA?, NO?) and 11 have documented causal roles in PAH. Each stressor that initiates cases of PAH acts to raise cycle elements, and may, therefore, initiate the cycle in this way. PAH involves a primarily local mechanism as required by the cycle and the symptoms and signs of PAH are generated by elements of the cycle. Endothelin-1, which acts as a causal factor in PAH, acts as part of the cycle; its synthesis is stimulated by cycle elements, and it, in turn, increases each element of the cycle. is extraordinary �t to the principles of the NO/ONOO − cycle allows one to conclude that PAH is a NO/ONOO − cycle disease, and this �t supports the cycle as a ma�or paradigm of chronic in�ammatory disease.

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Role of nitric oxide in acute lung inflammation: Lessons learned from the inducible nitric oxide synthase knockout mouse*

Abstract: Induction of NO may be a key mediator in driving the cytokine response to endotoxin toward an increased type-2 (interleukin-10) response and a diminished type-1 (interleukin-12) response.

Cited by 44 publications

References 31 publications

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Green Tea Inhibits Human Inducible Nitric-Oxide Synthase Expression by Down-Regulating Signal Transducer and Activator of Transcription-1α Activation

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

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Role of nitric oxide in acute lung inflammation: Lessons learned from the inducible nitric oxide synthase knockout mouse*

Abstract: Induction of NO may be a key mediator in driving the cytokine response to endotoxin toward an increased type-2 (interleukin-10) response and a diminished type-1 (interleukin-12) response.

Cited by 44 publications

References 31 publications

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Green Tea Inhibits Human Inducible Nitric-Oxide Synthase Expression by Down-Regulating Signal Transducer and Activator of Transcription-1α Activation

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

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Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review