Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 Mediates Apoptosis during Lung Vascular Permeability by Regulating Movement of Cleaved Caspase 3

Damarla, Mahendra; Parniani, Ahmad; Johnston, Laura; Maredia, Hasina; Serebreni, Leonid; Omar, Hamdan; Sidhaye, Venkataramana K.; Shimoda, Larissa A.; Myers, Allen C.; Crow, Michael T.; Schmidt, Eric P.; Machamer, Carolyn E.; Gaestel, Matthias; Rane, Madhavi J.; Kolb, Todd M.; Kim, Bo; Damico, Rachel; Hassoun, Paul M.

doi:10.1165/rcmb.2013-0361oc

Cited by 37 publications

(44 citation statements)

References 51 publications

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“…Bronchoalveolar lavage fluid (BALF) was collected for assessment of cell counts and protein concentration, as previously described (Damarla et al. ; Singer et al. ).…”

Section: Methodsmentioning

confidence: 99%

XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis

et al. 2017

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Sepsis is a leading cause of death among patients in the intensive care unit, resulting from multi‐organ failure. Activity of xanthine oxidoreductase (XOR), a reactive oxygen species (ROS) producing enzyme, is known to be elevated in nonsurvivors of sepsis compared to survivors. We have previously demonstrated that XOR is critical for ventilator‐induced lung injury. Using febuxostat, a novel nonpurine inhibitor of XOR, we sought to determine the role of XOR inhibition in a murine model of sepsis‐induced lung injury and mortality. C57BL/6J mice were subjected to intravenous (IV) lipopolysaccharide (LPS) for various time points, and lungs were harvested for analyses. Subsets of mice were treated with febuxostat, pre or post LPS exposure, or vehicle. Separate groups of mice were followed up for mortality after LPS exposure. After 24 hr of IV LPS , mice exhibited an increase in XOR activity in lung tissue and a significant increase in pulmonary endothelial barrier disruption. Pretreatment of animals with febuxostat before exposure to LPS, or treatment 4 h after LPS, resulted in complete abrogation of XOR activity. Inhibition of XOR with febuxostat did not prevent LPS‐induced pulmonary vascular permeability at 24 h, however, it accelerated recovery of the pulmonary endothelial barrier integrity in response to LPS exposure. Furthermore, treatment with febuxostat resulted in significant reduction in mortality. Inhibition of XOR with febuxostat accelerates recovery of the pulmonary endothelial barrier and prevents LPS‐induced mortality, whether given before or after exposure to LPS.

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“…Bronchoalveolar lavage fluid (BALF) was collected for assessment of cell counts and protein concentration, as previously described (Damarla et al. ; Singer et al. ).…”

Section: Methodsmentioning

confidence: 99%

XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis

et al. 2017

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“…The assay was used according to the manufacturer's directions (Damarla et al. ). Lung edema was assessed by determining the ratio of right lung wet weight to total body weight, as described previously (Aggarwal et al.…”

Section: Methodsmentioning

confidence: 99%

The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice

et al. 2015

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Severe sepsis and septic shock are frequent causes of the acute respiratory distress syndrome, and important sources of human mortality. Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, plays a major role in the pathogenesis of severe sepsis and septic shock. LPS exposure induces the production of harmful reactive oxygen species, and the resultant oxidant injury has been implicated in the pathogenesis of both severe sepsis and ARDS. We previously showed that the tyrosine kinase inhibitor imatinib increases lung endothelial antioxidant enzymes and protects against pulmonary endothelial antioxidant injury. In the present study, we tested the hypothesis that imatinib would protect against lung injury and systemic inflammation caused by intravenous LPS in an intact mouse model of endotoxemia mimicking early sepsis. We found that intravenous LPS induced a significant increase in the activity of lung xanthine oxidoreductase (XOR), an enzyme which is a major source of reactive oxygen species and implicated in the pathogenesis of acute lung injury. Imatinib had no effect of LPS-induced XOR activity. However, pretreatment of mice with imatinib increased lung catalase activity and decreased intravenous LPS-induced lung oxidant injury as measured by γ-H2AX, a marker of oxidant-induced DNA damage, lung apoptosis, and pulmonary edema. Imatinib also attenuated systemic cytokine expression after intravenous LPS exposure. Finally, imatinib completely prevented mortality in an in vivo, intravenous LPS mouse model of endotoxemia and lung injury. These results support the testing of imatinib as a novel pharmacologic agent in the treatment of Gram-negative sepsis and sepsis-induced ARDS.

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“…In I/R animal models, p38 over-activation is detrimental and, as such, the pharmacological inhibition of p38 prevents I/R induced MI and improves cardiac function after reperfusion [7, 8]. The over-activation of p38 MAPK phosphorylates MK2, promotes the activation of caspase-3 and subsequently contributes to apoptosis and cell death [9]. There are four isoforms (α, β, γ, and δ) of p38 MAPKs.…”

Section: Introductionmentioning

confidence: 99%

Modulation of p38 kinase by DUSP4 is important in regulating cardiovascular function under oxidative stress

Barajas-Espinosa

Basye

Angelos

2015

Free Radical Biology and Medicine

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Over-activation of p38 is implicated in many cardiovascular diseases (CVDs), including myocardial infarction, hypertrophy, heart failure, and ischemic heart disease. Numerous therapeutic interventions for CVDs have been directed towards the inhibition of the p38 mitogen-activated protein kinase activation that contributes to the detrimental effect after ischemia/reperfusion (I/R) injuries. However, the efficacy of these treatments is far from ideal as they lack specificity and are associated with high toxicity. Previously, we demonstrated that N-acetyl cysteine (NAC) pre-treatment up-regulates DUSP4 expression in endothelial cells, regulating p38 and ERK1/2 activities, thus providing a protective effect against oxidative stress. Here, endothelial cells under hypoxia/reoxygenation (H/R) insult and isolated heart I/R injury were used to investigate the role of DUSP4 on the modulation of the p38 pathway. In rat endothelial cells, DUSP4 is time-dependently degraded with H/R (0.25 ± 0.07 fold change of control after 2 h H/R). Its degradation is closely associated with hyper-phosphorylation of p38 (2.1 ± 0.36 fold change) and cell apoptosis, as indicated by the increase in cells immunopositive for cleaved caspase-3 (12.59% ± 3.38%) or TUNEL labeling (29.46% ± 3.75%). The inhibition of p38 kinase activity with 20 µM SB203580 during H/R prevents H/R-induced apoptosis, assessed via TUNEL (12.99% ± 1.89%). Conversely, DUSP4 gene silencing in endothelial cells augments their sensitivity to H/R-induced apoptosis (45.81% ± 5.23%). This sensitivity is diminished via the inhibition of p38 activity (total apoptotic cells drop to 17.47% ± 1.45%). Interestingly, DUSP4 gene silencing contributes to the increase in superoxide generation from cells. Isolated Langendorff-perfused mouse hearts were subjected to global I/R injury. DUSP4−/− hearts had significantly larger infarct size than WT. The increase in I/R-induced infarct in DUSP4−/− mice significantly correlates with reduced functional recovery (assessed by: RPP%, LVDP%, HR%, and dP/dtmax) as well as lower CF% and a higher initial LVEDP. From immunoblotting analysis, it is evident that p38 is significantly over-activated in DUSP4−/− mice after I/R injury. The activation of cleaved caspase-3 is seen in both WT and DUSP4−/− I/R hearts. Infusion of a p38 inhibitor prior to ischemia and during the reperfusion improves both WT and DUSP4−/− cardiac function. Therefore, the identification of p38 kinase modulation by DUSP4 provides a novel therapeutic target for oxidant-induced diseases, especially myocardial infarction.

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Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 Mediates Apoptosis during Lung Vascular Permeability by Regulating Movement of Cleaved Caspase 3

Cited by 37 publications

References 51 publications

XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis

XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis

The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice

Modulation of p38 kinase by DUSP4 is important in regulating cardiovascular function under oxidative stress

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