MKK3 Mitogen-Activated Protein Kinase Pathway Mediates Carbon Monoxide-Induced Protection Against Oxidant-Induced Lung Injury

Otterbein, Leo E.; Otterbein, Sherrie L.; Ifedigbo, Emeka; Liu, Fang; Morse, Danielle; Fearns, Colleen; Ulevitch, Richard J.; Knickelbein, Roy G.; Flavell, Richard A.; Choi, Augustine M.K.

doi:10.1016/s0002-9440(10)63610-3

Cited by 175 publications

(174 citation statements)

References 29 publications

Supporting

Mentioning

166

Contrasting

Unclassified

Order By: Relevance

“…LPS and ventilation both induced activation of AP-1 and NF-B ( Figures 6A and 6B); however, CO treatment did not modulate the activation of AP-1-or NF-B-binding activity compared with ventilation or LPS/ventilation treatment. Another intracellular pathway that is activated in lung injury is p38 mitogen-activated protein kinase (MAPK) (23). In our model LPS and ventilation increased activation of p38 MAPK; CO significantly increased p38 MAPK activation when compared with ventilation and LPS (Figure 7).…”

Section: Mechanisms Of Co-induced Antiinflammatory Effectsmentioning

confidence: 79%

Inhaled Carbon Monoxide Confers Antiinflammatory Effects against Ventilator-induced Lung Injury

Dolinay

Szilasi

Liu

et al. 2004

Am J Respir Crit Care Med

138

127

View full text Add to dashboard Cite

Ventilator-induced lung injury (VILI) is a major cause of morbidity and mortality in intensive care units. The stress-inducible gene product, heme oxygenase-1, and carbon monoxide (CO), a major byproduct of heme oxygenase catalysis of heme, have been shown to confer potent antiinflammatory effects in models of tissue and cellular injury. In this study, we observed increased expression of heme oxygenase-1 mRNA and protein in a rat model of VILI. To assess the physiologic function of heme oxygenase-1 induction in VILI, we determined whether low concentration of inhaled CO could serve to protect the lung against VILI. Low concentration of inhaled CO significantly reduced tumor necrosis factor-␣ levels and total cell count in lavage fluid, while simultaneously elevating levels of antiinflammatory interleukin-10 levels. To better characterize the mechanism of CO-mediated antiinflammatory effects, we examined key signaling pathways, which may mediate CO-induced antiinflammatory effects. We demonstrate that inhaled CO exerts antiinflammatory effects in VILI via the p38 mitogen-activated protein kinase pathway but independent of activator protein-1 and nuclear factor-B pathways. Our data lead to a tempting speculation that inhaled CO might be useful in minimizing VILI. Keywords: cytokines; heme oxygenase-1; p38 MAPKAccording to an international study, an average of 39% of intensive care unit patients requires mechanical ventilation worldwide (1). Many of these patients develop ventilator-induced lung injury (VILI) (2). Eventually VILI contributes to acute respiratory distress syndrome (ARDS), which has a 40 to 50% mortality rate (3). Although clinical trials showed that ARDS/VILI-related mortality could be attenuated with lower tidal volume ventilation, positive end-expiratory pressure (PEEP) ventilation, and more recently, with recruitment maneuver combined with protective ventilation strategy, the syndrome remains a major problem in intensive care units (3)(4)(5).It is established that mechanical ventilators that apply high volumes and pressures can lead to increased alveolar-capillary permeability (6). This loss of compartmentalization results in increased fluid influx to the alveoli from the capillaries, causing pulmonary edema. The injured or ruptured cells attract neutrophil leukocytes and activate alveolar macrophages, causing inflammation in the lung (6). Tremblay and colleagues have suggested that ventilation can provoke an inflammatory response in the distal airway and alveolar cells (7), manifested by increased production of proinflammatory cytokines. It is speculated that the released proinflammatory cytokines could enter the circulation causing inflammation in other systemic organs. In addition, the previously diseased or injured lungs are more susceptible to subsequent mechanical ventilation, releasing more proinflammatory cytokines than healthy lungs, perhaps reflecting the cumulative effects of multiple injuries (8, 9). Lipopolysaccharide (LPS), acid aspiration, and cecal ligation/perforation-induced sep...

show abstract

Section: Mechanisms Of Co-induced Antiinflammatory Effectsmentioning

confidence: 79%

Inhaled Carbon Monoxide Confers Antiinflammatory Effects against Ventilator-induced Lung Injury

Dolinay

Szilasi

Liu

et al. 2004

Am J Respir Crit Care Med

138

127

View full text Add to dashboard Cite

show abstract

“…Some of the potential candidates include Fas, p53, caspases, Bcl-2 family members, cytokines (IL-6, IL-11, IL-1β and TNF-α), growth factors (Vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF) and keratinocytes growth factor (KGF)), heme oxygenase 1 (HO-1), and Toll-like receptor 4 (TLR4) [56,57,63]. First, exposure to hyperoxia induces an altered expression of many of Bcl-2 family members, including both proapoptotic (Bax, Bad, Bak) and antiapoptotic (Bcl-k L, Bclw, Bfl-1 and Bcl-2).…”

Section: Expression Of Regulatory Genes In Hyperoxic Cell Deathmentioning

confidence: 99%

“…Carbon monoxide (CO), a byproduct of HO degradation of heme, protects epithelial cells from hyperoxic damage. Using dominant negative mutants and mice deficient in different MAPKs, Otterbein et al demonstrated the cytoprotective effects of CO is mediated by specific MKK3/p38β pathways [57]. TLR4, a principal receptor for bacterial lipopolysaccharides (LPS), can be activated by noninfectious stimuli including hyperoxia [63].…”

Section: Expression Of Regulatory Genes In Hyperoxic Cell Deathmentioning

confidence: 99%

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

Zaher

Miller

Morrow

et al. 2007

Free Radical Biology and Medicine

120

View full text Add to dashboard Cite

Mechanical ventilation with hyperoxia is necessary to treat critically ill patients. However, prolonged exposure to hyperoxia leads to the generation of excessive reactive oxygen species (ROS), which can cause acute inflammatory lung injury. One of the major effects of hyperoxia is the injury and death of pulmonary epithelium, which is accompanied by increased levels of pulmonary proinflammatory cytokines and excessive leukocyte infiltration. A thorough understanding of the signaling pathways leading to pulmonary epithelial cell injury/death may provide some insights into the pathogenesis of hyperoxia-induced acute inflammatory lung injury. This review focuses on epithelial responses to hyperoxia and some of the major factors regulating pathways to epithelial cell injury/death, and proinflammatory responses upon exposure to hyperoxia. We discuss in detail some of the most interesting players, such as, NF-κB, that can modulate both proinflammatory responses and cell injury/death of lung epithelial cells. A better appreciation for the functions of these factors will no doubt help us to delineate the pathways to hyperoxic cell death and proinflammatory responses.

show abstract

“…The CO exposed animals also had improved gastrointestinal transit and no animal deaths after the operation, compared to a survival of 58 % for the nonexposed rats (Nakao et al, 2003). In a model of acute lung injury in mice, CO showed cytoprotective effects and an attenuation of the lung injury, along with prolonged survival during exposure to lethal hyperoxia (Otterbein et al, 2003). All of these studies indicate that CO has anti-inflammatory effects.…”

Section: Inflammationmentioning

confidence: 78%

Carbon monoxide in biological systems: an experimental and clinical study

Åberg¹

2008

Acta Anaesthesiol Scand

View full text Add to dashboard Cite

MKK3 Mitogen-Activated Protein Kinase Pathway Mediates Carbon Monoxide-Induced Protection Against Oxidant-Induced Lung Injury

Cited by 175 publications

References 29 publications

Inhaled Carbon Monoxide Confers Antiinflammatory Effects against Ventilator-induced Lung Injury

Inhaled Carbon Monoxide Confers Antiinflammatory Effects against Ventilator-induced Lung Injury

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

Carbon monoxide in biological systems: an experimental and clinical study

Contact Info

Product

Resources

About