p38β-regulated induction of the heat shock response by carbon monoxide releasing molecule CORM-2 mediates cytoprotection in lung cells in vitro

Schallner, Nils; Schwemmers, Sven; Schwer, Christian I.; Froehlich, Christian; Stoll, Patrick; Humar, Matjaž; Pahl, Heike L.; Hoetzel, Alexander; Loop, Torsten; Goebel, Ulrich

doi:10.1016/j.ejphar.2011.08.028

Cited by 17 publications

(19 citation statements)

References 27 publications

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“…ALF186 does not carry such attributes, yet does clearly demonstrate the feasibility of parenteral delivery. ALF186 is one of a family of CORMs that are orally active leading to similar elevations in COHb as when given intraperitoneally or intravenously (data not shown) similar to other CORMs [4], [13], [17], [33]–[39]. Therefore CORMs represent a safe alternative for potential clinical application of CO [32].…”

Section: Discussionmentioning

confidence: 92%

“…Staining with Annexin V-FITC and propidiumiodide (Becton Dickinson, Heidelberg, Germany) and flow-cytometric analyses were done as previously described [17]. Western Blots were done as previously described [17] using antibodies against cleaved Caspase-3 (#9664 from Cell Signaling Technology, Danvers, MA, USA) and GAPDH (#CSA-335 from Enzo Lifesciences, Plymouth, PA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Western Blots were done as previously described [17] using antibodies against cleaved Caspase-3 (#9664 from Cell Signaling Technology, Danvers, MA, USA) and GAPDH (#CSA-335 from Enzo Lifesciences, Plymouth, PA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Carbon Monoxide Abrogates Ischemic Insult to Neuronal Cells via the Soluble Guanylate Cyclase-cGMP Pathway

et al. 2013

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PurposeCarbon monoxide (CO) is an accepted cytoprotective molecule. The extent and mechanisms of protection in neuronal systems have not been well studied. We hypothesized that delivery of CO via a novel releasing molecule (CORM) would impart neuroprotection in vivo against ischemia-reperfusion injury (IRI)-induced apoptosis of retinal ganglion cells (RGC) and in vitro of neuronal SH-SY5Y-cells via activation of soluble guanylate-cyclase (sGC).MethodsTo mimic ischemic respiratory arrest, SH-SY5Y-cells were incubated with rotenone (100 nmol/L, 4 h) ± CORM ALF186 (10–100 µmol/L) or inactivated ALF186 lacking the potential of releasing CO. Apoptosis and reactive oxygen species (ROS) production were analyzed using flow-cytometry (Annexin V, mitochondrial membrane potential, CM-H2DCFDA) and Western blot (Caspase-3). The impact of ALF186± respiratory arrest on cell signaling was assessed by measuring expression of nitric oxide synthase (NOS) and soluble guanylate-cyclase (sGC) and by analyzing cellular cGMP levels. The effect of ALF186 (10 mg/kg iv) on retinal IRI in Sprague-Dawley rats was assessed by measuring densities of fluorogold-labeled RGC after IRI and by analysis of apoptosis-related genes in retinal tissue.ResultsALF186 but not inactivated ALF186 inhibited rotenone-induced apoptosis (Annexin V positive cells: 25±2% rotenone vs. 14±1% ALF186+rotenone, p<0.001; relative mitochondrial membrane potential: 17±4% rotenone vs. 55±3% ALF186+rotenone, p<0.05). ALF186 increased cellular cGMP levels (33±5 nmol/L vs. 23±3 nmol/L; p<0.05) and sGC expression. sGC-inhibition attenuated ALF186-mediated protection (relative mitochondrial membrane potential: 55±3% ALF186+rotenone vs. 20±1% ODQ+ALF186+rotenone, p<0.05). ALF186 protected RGC in vivo (IRI 1255±327 RGC/mm2 vs. ALF186+IRI 2036±83; p<0.05) while sGC inhibition abolished the protective effects of ALF186 (ALF186+IRI 2036±83 RGC/mm2 vs. NS-2028+ALF186+IRI 1263±170, p<0.05).ConclusionsThe CORM ALF186 inhibits IRI-induced neuronal cell death via activation of sGC and may be a useful treatment option for acute ischemic insults to the retina and the brain.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

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Carbon Monoxide Abrogates Ischemic Insult to Neuronal Cells via the Soluble Guanylate Cyclase-cGMP Pathway

et al. 2013

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“…Phosphorylation of p38 was suppressed by CO inhalation up to 48 h after I/R injury. Depending on which p38 kinase isoform is predominantly involved, either promotion or inhibition of apoptosis may be fostered [25], [28], [29]. Postconditioning with inhaled CO in our model of I/R seemed to suppress p38 signaling, whereas ERK-1/2 activation was increased in CO-treated animals.…”

Section: Discussionmentioning

confidence: 80%

Postconditioning with Inhaled Carbon Monoxide Counteracts Apoptosis and Neuroinflammation in the Ischemic Rat Retina

et al. 2012

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PurposeIschemia and reperfusion injury (I/R) of neuronal structures and organs is associated with increased morbidity and mortality due to neuronal cell death. We hypothesized that inhalation of carbon monoxide (CO) after I/R injury (‘postconditioning’) would protect retinal ganglion cells (RGC).MethodsRetinal I/R injury was performed in Sprague-Dawley rats (n = 8) by increasing ocular pressure (120 mmHg, 1 h). Rats inhaled room air or CO (250 ppm) for 1 h immediately following ischemia or with 1.5 and 3 h latency. Retinal tissue was harvested to analyze Bcl-2, Bax, Caspase-3, HO-1 expression and phosphorylation of the nuclear transcription factor (NF)-κB, p38 and ERK-1/2 MAPK. NF-κB activation was determined and inhibition of ERK-1/2 was performed using PD98059 (2 mg/kg). Densities of fluorogold prelabeled RGC were analyzed 7 days after injury. Microglia, macrophage and Müller cell activation and proliferation were evaluated by Iba-1, GFAP and Ki-67 staining.ResultsInhalation of CO after I/R inhibited Bax and Caspase-3 expression (Bax: 1.9±0.3 vs. 1.4±0.2, p = 0.028; caspase-3: 2.0±0.2 vs. 1.5±0.1, p = 0.007; mean±S.D., fold induction at 12 h), while expression of Bcl-2 was induced (1.2±0.2 vs. 1.6±0.2, p = 0.001; mean±S.D., fold induction at 12 h). CO postconditioning suppressed retinal p38 phosphorylation (p = 0.023 at 24 h) and induced the phosphorylation of ERK-1/2 (p<0.001 at 24 h). CO postconditioning inhibited the expression of HO-1. The activation of NF-κB, microglia and Müller cells was potently inhibited by CO as well as immigration of proliferative microglia and macrophages into the retina. CO protected I/R-injured RGC with a therapeutic window at least up to 3 h (n = 8; RGC/mm2; mean±S.D.: 1255±327 I/R only vs. 1956±157 immediate CO treatment, vs. 1830±109 1.5 h time lag and vs. 1626±122 3 h time lag; p<0.001). Inhibition of ERK-1/2 did not counteract the CO effects (RGC/mm2: 1956±157 vs. 1931±124, mean±S.D., p = 0.799).ConclusionInhaled CO, administered after retinal ischemic injury, protects RGC through its strong anti-apoptotic and anti-inflammatory effects.

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“…On the other hand, p38β has been reported to be important in protecting mesangial cells from TNFα toxicity, and appears to be involved in the cytoprotective effect of carbon monoxide in vitro [14], [15], [16]. Recent studies demonstrated a role for p38β MAPK during sympathetic neuron transdifferentiation [17], as well as reducing sensitivity to pain following spinal cord injury [18], suggesting that p38β MAPK may have specific functions in the CNS that are not seen in the periphery.…”

Section: Introductionmentioning

confidence: 99%

Deficiency in p38β MAPK Fails to Inhibit Cytokine Production or Protect Neurons against Inflammatory Insult in In Vitro and In Vivo Mouse Models

2013

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The p38 MAPK pathway plays a key role in regulating the production of proinflammatory cytokines, such as TNFα and IL-1β, in peripheral inflammatory disorders. There are four major isoforms of p38 MAPK (p38α, β, δ, γ), with p38α and p38β the targets of most p38 MAPK inhibitor drugs. Our previous studies demonstrated that the p38α MAPK isoform is an important contributor to stressor-induced proinflammatory cytokine up-regulation and neurotoxicity in the brain. However, the potential role of the p38β MAPK isoform in CNS proinflammatory cytokine overproduction and neurotoxicity is poorly understood. In the current studies, we used primary microglia from wild type (WT) and p38β knockout (KO) mice in co-culture with WT neurons, and measured proinflammatory cytokines and neuron death after LPS insult. We also measured neuroinflammatory responses in vivo in WT and p38β KO mice after administration of LPS by intraperitoneal or intracerebroventricular injection. WT and p38β KO microglia/neuron co-cultures showed similar levels of TNFα and IL-1β production in response to LPS treatment, and no differences in LPS-induced neurotoxicity. The in vitro results were confirmed in vivo, where levels of TNFα and IL-1β in the CNS were not significantly different between WT or p38β KO mice after LPS insult. Our results suggest that, similar to peripheral inflammation, p38α is critical but p38β MAPK is dispensable in the brain in regards to proinflammatory cytokine production and neurotoxicity induced by LPS inflammatory insult.

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p38β-regulated induction of the heat shock response by carbon monoxide releasing molecule CORM-2 mediates cytoprotection in lung cells in vitro

Cited by 17 publications

References 27 publications

Carbon Monoxide Abrogates Ischemic Insult to Neuronal Cells via the Soluble Guanylate Cyclase-cGMP Pathway

Carbon Monoxide Abrogates Ischemic Insult to Neuronal Cells via the Soluble Guanylate Cyclase-cGMP Pathway

Postconditioning with Inhaled Carbon Monoxide Counteracts Apoptosis and Neuroinflammation in the Ischemic Rat Retina

Deficiency in p38β MAPK Fails to Inhibit Cytokine Production or Protect Neurons against Inflammatory Insult in In Vitro and In Vivo Mouse Models

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