Role of PARP on iNOS pathway during endotoxin-induced acute lung injury

Kiefmann, Rainer; Heckel, Kai; Doerger, Martina; Schenkat, Sonja; Kupatt, Christian; Stoeckelhuber, Mechthild; Węsierska‐Gądek, Józefa; Goetz, Alwin E.

doi:10.1007/s00134-004-2301-x

Cited by 48 publications

(49 citation statements)

References 40 publications

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“…These studies have shown that PARP inhibition can completely abrogate the release of cytokines and also led to the attenuated the recruitment of neutrophils. [9,26] It was also shown that PARP inhibition attenuates nitrite/nitrate production in a model of systemic endotoxemia, [25,27] as also seen in the current study. Thus, we speculate that ameliorated oxidative and nitrosative stress in rats received 3-AB might be attributed to its regulation of transcription and inflammatory response.…”

Section: Effects Of 3-aminobenzamide On Renal I/rsupporting

confidence: 84%

3-Aminobenzamide, a Poly ADP Ribose Polymerase Inhibitor, Attenuates Renal Ischemia/Reperfusion Injury

et al. 2009

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Introduction. This study was designed to investigate whether 3-amino benzamide (3-AB), a poly (ADP-ribose) polymerase (PARP) inhibitor, has a protective effect on kidney injury induced by renal ischemia/reperfusion (I/R) by decreasing oxidative and nitrosative stress on renal dysfunction and injury. Materials and Methods. Thirty-two male SpragueDawley rats were divided into four groups: sham-operated, sham-operated + 3-AB, I/R, I/R + 3-AB. Rats were given 3-AB (100 mg/kg/day ip) 14 days prior to I/R. I/R and I/R + 3-AB groups underwent 60 min of bilateral renal ischemia followed by 6 h of reperfusion. After reperfusion, kidneys and blood were obtained for evaluation. Superoxide dismutase, glutathione peroxidase, malondialdehide, protein carbonyl content, and nitrite/nitrate level (NO x ) were determined in the renal tissue. Serum creatinine (S Cr ), blood urea nitrogen (BUN), and aspartate aminotransferase (AST) were determined in the blood. Additionally, renal sections were used for histological grade of renal injury. Results. 3-AB significantly reduced the I/R-induced increases in S Cr , BUN, and AST. In addition, 3-AB markedly reduced elevated oxidative stress product, restored decreased antioxidant enzymes, and attenuated histological alterations. Moreover, 3-AB attenuated the tissue NO x levels, indicating reduced NO production. Conclusions. 3-AB has beneficial effect on renal glomerular and tubular dysfunction in rats' kidneys subjected to I/R injury. Moreover, 3-AB has ameliorating effect on both oxidative stress and nitrosative stress of the kidneys, which correlated with histopathological evaluation.

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Section: Effects Of 3-aminobenzamide On Renal I/rsupporting

confidence: 84%

3-Aminobenzamide, a Poly ADP Ribose Polymerase Inhibitor, Attenuates Renal Ischemia/Reperfusion Injury

et al. 2009

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“…Excessive NO production can lead to cellular injury by several mechanisms, including loss of membrane integrity through direct lipid peroxidation, altered protein function through NT formation, or energy depletion through PARP activation (40). Studies with PARP-1 KO mice and chemical PARP inhibitors have consistently shown that lack of PARP activation following severe oxidative injury with NO, hydrogen peroxide, and ONOO -results in significantly reduced neuronal death (22).…”

Section: Discussionmentioning

confidence: 99%

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis

Kaplin

Deshpande

Scott

et al. 2005

Journal of Clinical Investigation

115

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Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.

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“…Inhibition of PARP activity reduces the I/R injury of the heart, skeletal muscle and brain [6,7]. In addition, PARP inhibition with 3-aminobenzamide attenuates the acute lung injury induced by endotoxin [8]. The inhibitory effects of nicotinamide or its related substances, niacinamide and nicotinic acid, on PARP activity are protective to organ dysfunction and/or cell damage caused by oxidative stress [9,10].…”

mentioning

confidence: 99%

Nicotinamide abrogates acute lung injury caused by ischaemia/reperfusion

Su¹,

Liu²,

Kao³

et al. 2007

Eur Respir J

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Poly (ADP-ribose) synthase or polymerase (PARS and PARP, respectively) is a cytotoxic enzyme which causes cellular damage. Nicotinamide, a compound of vitamin B complex, has been reported to exert an inhibitory effect on PARS or PARP. The present study tests the effects of nicotinamide on acute lung injury and associated alterations following ischaemia/reperfusion (I/R) of the isolated perfused rat's lung.I/R increased the lung weight (LW) to body weight ratio, LW gain, protein and dye tracer leakage, pulmonary arterial pressure and capillary permeability. The insult also increased nitrate/ nitrite, methyl guanidine, tumour necrosis factor-a and interleukin-1b in lung perfusate, while it decreased adenosine triphosphate content with an increase in PARP activity in lung tissue.Most of the I/R-induced changes were abrogated by post-treatment (30 min after I/R) with nicotinamide (100 mg?kg -1 body weight). However, the increase in pulmonary arterial pressure was enhanced by nicotinamide post-treatment. Following I/R, the inducible nitric oxide synthase (iNOS) mRNA expression was enhanced. Nicotinamide reduced the iNOS expression. The results suggest that nicotinamide exerted a protective effect on the acute lung injury caused by ischaemia/reperfusion. The mechanisms may be mediated through the inhibition on the poly (adenosine diphosphate-ribose) polymerase activity, inducible nitric oxide synthase expression and the subsequent suppression of nitric oxide, free radicals and pro-inflammatory cytokines with restoration of adenosine triphosphate.

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Role of PARP on iNOS pathway during endotoxin-induced acute lung injury

Abstract: PARP regulates the pulmonary NO pathway during endotoxemia via AP-1 and not NF-kappaB. Thus, pharmacological inhibition of PARP might be an effective intervention to prevent endotoxin-induced lung injury, interrupting the vicious circle of NO production and PARP activation.

Cited by 48 publications

References 40 publications

3-Aminobenzamide, a Poly ADP Ribose Polymerase Inhibitor, Attenuates Renal Ischemia/Reperfusion Injury

3-Aminobenzamide, a Poly ADP Ribose Polymerase Inhibitor, Attenuates Renal Ischemia/Reperfusion Injury

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis

Nicotinamide abrogates acute lung injury caused by ischaemia/reperfusion

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