P38 mitogen-activated protein kinase inhibition attenuates pulmonary inflammatory response in a rat cardiopulmonary bypass model

Dong, Xiao; Liu, Yinglong; Du, Ming; Wang, Qiang; Yu, Cun Tao; Xia, Fan

doi:10.1016/j.ejcts.2006.02.040

Cited by 22 publications

(16 citation statements)

References 22 publications

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“…Furthermore, in reperfused rat lungs, the phosphorylation of p38 MAPK and ERK was also upregulated (13). Our previous study demonstrated that p38 MAPK was activated in rat lungs following CPB and that the inhibitor of p38 MAPK restrained CPB-triggered inflammation (14). Therefore, MAPK signaling serves an important role in acute lung injury and the associated inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that MAPK signaling was activated in the rat lung tissue following CPB (13). However, this signaling was blocked following MAPK signaling inhibitor treatment, and simultaneously, the release of inflammatory factors and infiltration were restrained (14). Therefore, MAPK signaling may participate in CPB-induced lung injury, although whether NAMPT regulates CPB-triggered inflammation and cellular permeability enhancement of lung tissue through MAPK signaling remains unknown.…”

Section: Introductionmentioning

confidence: 92%

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Promotion of anoxia‑reoxygenation‑induced inflammation and permeability enhancement by nicotinamide phosphoribosyltransferase‑activated MAPK signaling in human umbilical vein endothelial cells

et al. 2017

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Abstract. Previous studies have demonstrated that nicotinamide phosphoribosyltransferase (NAMPT) promoted inflammation and permeability of vascular endothelial cells following cardiopulmonary bypass (CPB). In addition, mitogen-activated protein kinase (MAPK) signaling was activated and contributed to these cell responses. However, the mechanism by which NAMPT regulates cellular inflammation and permeability remains unknown, and whether NAMPT regulates MAPK signaling during this process is also not clear. The present study established an anoxia-reoxygenation (A-R) model using human umbilical vein endothelial cells (HUVECs) and investigated the regulation of MAPK signaling by NAMPT by using small RNA transfection, ELISA and western blot analysis. The results demonstrated that A-R significantly induced the expression levels of NAMPT and cellular permeability-associated proteins, and the release of several inflammatory factors. Furthermore, calcium and MAPK signaling were evidently increased. When the A-R cells were transfected with NAMPT small interfering RNA, the expression of cellular permeability-associated proteins was downregulated, the release of inflammatory factors was decreased, and calcium and MAPK signaling was blocked. These data suggest that NAMPT may activate MAPK signaling to promote A-R-induced inflammation and permeability enhancement of HUVECs. Therefore, the current study indicates that NAMPT may be a potential drug target for A-R-induced endothelial cell injury subsequent to CPB.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Promotion of anoxia‑reoxygenation‑induced inflammation and permeability enhancement by nicotinamide phosphoribosyltransferase‑activated MAPK signaling in human umbilical vein endothelial cells

et al. 2017

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“…The transcription of proinflammatory genes associated with these signaling pathways is dependent on the activation of SAPKs and NF-B (16,28). Chemical inhibitors such as SB-203580 have been frequently used to study the requirement for activation of p38 MAPK in many inflammatory models, including lung inflammation following cardiopulmonary bypass (14), cystic fibrosis (55), and ovalbumin-induced allergy in the airway (18). The role of NF-B in airway inflammation was confirmed by the demonstration that the adenoviral vector-mediated overexpression of IKK in airway epithelial cells of mice was sufficient for NF-B activation, production of inflammatory mediators, and recruitment of neutrophils to the lungs (58).…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory responses of human airway cells to ricin involve stress-activated protein kinases and NF-κB

Wong¹,

Korcheva²,

Jacoby

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Furthermore, our findings may also be relevant to other forms of systemic inflammatory activation such as burns [49], ischemia-reperfusion [50] and cardiopulmonary bypass [51,52], where p38MAPK activation and its relation to multi-organ dysfunction is becoming increasingly clear. Inhibitors of the p38MAPK pathway are being investigated in animal and human studies of sepsis and other pro-15 inflammatory disease states [52][53][54][55][56]. Modulation of up-or downstream regulators of this pathway could also be of interest therapeutically.…”

mentioning

confidence: 96%

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase*

Pathan

Franklin

Eleftherohorinou

et al. 2011

Critical Care Medicine

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2 At a glance commentary: Myocardial dysfunction is a major feature in the pathophysiology of septic shock. IL-6 has been identified as a key mediator of a negative inotropic state in meningococcal sepsis. In this study we demonstrate that the p38MAPK pathway is a central regulator in the negative inotropic activity of interleukin 6 and is highly dysregulated in meningococcal septic shock. Modulators of the p38MAPK pathway could have therapeutic potential for patients with cardiac dysfunction in meningococcal and other forms of septic shock. 2 Abstract: Objectives: Myocardial failure, leading to inotrope-unresponsive shock, is the predominant cause of death in meningococcal and other forms of septic shock. Pro-inflammatory cytokines released in septic shock are known to have myocardial depressant effects. We previously showed that Interleukin 6 (IL-6) is a major myocardial depressant factor in children with meningococcal septicaemia. In the current study, we aimed to investigate the mechanisms by which IL-6 induces myocardial failure in meningococcal sepsis, and to identify potential novel therapeutic targets. Design: Laboratory based study Setting: University hospital and laboratories Patients: Children with a clinical diagnosis of meningococcal septic shock Methods: We studied IL-6-induced signaling events, both in vitro using isolated rat ventricular cardiac myocytes as a model of myocardial contractility, and in whole blood from children with meningococcal sepsis. Measurements and Main results: We demonstrated involvement of JAK2, PI3K, Akt and p38MAPK in IL-6-induced negative inotropy in isolated cardiac myocytes. Inhibition of p38MAPK not only reversed IL-6-induced myocardial depression in both rat and human myocytes, but restored inotrope responsiveness. Cardiomyocytes transduced with dominant-negative p38MAPK showed no IL-6-induced myocardial depression. To investigate p38MAPK in vivo, we profiled global RNA expression patterns in peripheral blood of children with meningococcal septicaemia. Transcripts for genes mapping to the p38MAPK pathway showed significantly altered levels of abundance, with a high proportion of genes of this pathway affected. Conclusions: Our findings demonstrate an integral role of the p38MAPK pathway in IL-6-mediated cardiac contractile dysfunction and inotrope insensitivity. Dysregulation of the p38MAPK pathway in meningococcal septicemia suggests that this pathway may be an important target for novel therapies to 3 reverse myocardial dysfunction in patients with meningococcal septic shock who are not responsive to inotropic support. (273 words) 4 Introduction: Sepsis and septic shock remain major causes of morbidity and mortality worldwide, with reported mortality rates of 10-50% [1-4]. An important feature in the pathophysiology of septic shock is the development of progressive hemodynamic and cardiovascular instability and depressed myocardial contractility [5, 6]. Over the past three decades, intense efforts to develop immunomodulatory treatments for septic shock have target...

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P38 mitogen-activated protein kinase inhibition attenuates pulmonary inflammatory response in a rat cardiopulmonary bypass model

Cited by 22 publications

References 22 publications

Promotion of anoxia‑reoxygenation‑induced inflammation and permeability enhancement by nicotinamide phosphoribosyltransferase‑activated MAPK signaling in human umbilical vein endothelial cells

Promotion of anoxia‑reoxygenation‑induced inflammation and permeability enhancement by nicotinamide phosphoribosyltransferase‑activated MAPK signaling in human umbilical vein endothelial cells

Proinflammatory responses of human airway cells to ricin involve stress-activated protein kinases and NF-κB

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase*

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