Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

Schellekens, Willem-Jan M.; Hees, Hieronymus W. H. van; Vaneker, Michiel; Linkels, Marianne; Dekhuijzen, P.N.R.; Scheffer, Gert Jan; Hoeven, Johannes G. van der; Heunks, Leo

doi:10.1097/aln.0b013e3182608cc0

Cited by 42 publications

(80 citation statements)

References 46 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A recent report reveals that prolonged MV increases the expression of key autophagy proteins (e.g., ATG5, ATG7, and beclin 1) and the number of autophagosomes in the human diaphragm (45). Furthermore, emerging evidence reveals an increase in autophagy biomarkers in rodent diaphragms following 8 -18 h of full support MV (97,107). Together, these results suggest that full support MV increases the rate of autophagy in both human and animal diaphragms.…”

Section: Mv-induced Proteolysis In the Diaphragmmentioning

confidence: 52%

“…This original observation has been confirmed in numerous animal and human studies using full support MV. Indeed, abundant evidence demonstrates that prolonged full support MV increases the activity of all four major proteolytic systems in the diaphragm of both animals and humans exposed to 12 or more hours of MV (9,22,44,45,47,57,58,63,70,97,106,117). A brief overview of these proteolytic pathways along with evidence for their activation in the diaphragm during prolonged MV follows.…”

Section: Mv-induced Proteolysis In the Diaphragmmentioning

confidence: 99%

See 1 more Smart Citation

Ventilator-induced diaphragm dysfunction: cause and effect

Powers

Wiggs

Sollanek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

143

156

View full text Add to dashboard Cite

Powers SK, Wiggs MP, Sollanek KJ, Smuder AJ. Ventilator-induced diaphragm dysfunction: cause and effect. Am J Physiol Regul Integr Comp Physiol 305: R464 -R477, 2013. First published July 10, 2013 doi:10.1152/ajpregu.00231.2013 is used clinically to maintain gas exchange in patients that require assistance in maintaining adequate alveolar ventilation. Common indications for MV include respiratory failure, heart failure, drug overdose, and surgery. Although MV can be a life-saving intervention for patients suffering from respiratory failure, prolonged MV can promote diaphragmatic atrophy and contractile dysfunction, which is referred to as ventilator-induced diaphragm dysfunction (VIDD). This is significant because VIDD is thought to contribute to problems in weaning patients from the ventilator. Extended time on the ventilator increases health care costs and greatly increases patient morbidity and mortality. Research reveals that only 18 -24 h of MV is sufficient to develop VIDD in both laboratory animals and humans. Studies using animal models reveal that MV-induced diaphragmatic atrophy occurs due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, autophagy, and the ubiquitin-proteasome system as key proteases that participate in MV-induced diaphragmatic proteolysis. The challenge for the future is to define the MV-induced signaling pathways that promote the loss of diaphragm protein and depress diaphragm contractility. Indeed, forthcoming studies that delineate the signaling mechanisms responsible for VIDD will provide the knowledge necessary for the development of a pharmacological approach that can prevent VIDD and reduce the incidence of weaning problems. respiratory muscle; atrophy; mechanical ventilation; weaning; muscle wasting MECHANICAL VENTILATION (MV) is used clinically to achieve sufficient pulmonary gas exchange in patients unable to sustain adequate alveolar ventilation on their own. Common indications for MV include respiratory failure due to chronic obstructive pulmonary disease, status asthmaticus, and/or heart failure. In addition, MV is often an essential intervention in patients suffering from acute drug overdose, neuromuscular diseases, sepsis, and during surgery along with postsurgical recovery.The number of patients receiving prolonged MV in the United States exceeds more than 300,000 each year in the intensive care unit (ICU) (20). Although MV can be a lifesaving measure, prolonged MV results in the rapid development of diaphragmatic weakness due to both atrophy and contractile dysfunction. This detrimental impact of prolonged MV on the diaphragm has been termed ventilator-induced diaphragmatic dysfunction (VIDD) and VIDD is predicted to be a major contributor to problems in weaning patients from the ventilator (26, 114). Although previous reports describing the impact of prolonged MV on the diaphragm have appeared in the literature, advances in our understanding of the mechanisms responsible for VIDD h...

show abstract

Section: Mv-induced Proteolysis In the Diaphragmmentioning

confidence: 52%

Section: Mv-induced Proteolysis In the Diaphragmmentioning

confidence: 99%

Ventilator-induced diaphragm dysfunction: cause and effect

Powers

Wiggs

Sollanek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

143

156

View full text Add to dashboard Cite

show abstract

“…But the study of LEVINE et al [10] in ventilated brain-dead organ donors, which revealed rapid diaphragm fibre atrophy and enhanced proteolysis, as in animal models, highlighted the fact that the mechanical ventilation effect was not exclusive to laboratory models. Subsequent studies in animal models, and also in humans, have further documented the impact of controlled mechanical ventilation on the diaphragm [11][12][13][14][15][16][17][18][19][20].…”

Section: @Erspublicationsmentioning

confidence: 99%

Ventilator-induced diaphragm dysfunction: time for (contr)action!

Gayan‐Ramirez

2013

Eur Respir J

View full text Add to dashboard Cite

@ERSpublicationsNew studies indicate that diaphragm pacing techniques could protect against ventilator-induced diaphragm injury http://ow.ly/kTvSo During the past 10 years, intensive experimental research has focused on the effects of mechanical ventilation on the diaphragm. Whatever the animal species studied, all these studies have consistently shown that mechanical ventilation impaired diaphragm function, resulting in the so-called ventilatorinduced diaphragm dysfunction (VIDD) [1][2][3][4][5][6][7][8][9]. The development of this effect is rapid and worsens with the time spent on the ventilator [5]. It is associated with early diaphragm fibre atrophy leading, ultimately, to diaphragm weight loss and to diaphragm ultrastructural alterations, with disorganisation of the sarcomere's architecture [8]. Oxidative stress, decreased protein synthesis and increased proteolysis have been all reported in the diaphragm after mechanical ventilation [8]. These data revealed that a healthy diaphragm was made diseased after mechanical ventilation.For a long time, the importance of these data has been neglected, probably because of the experimental nature of the studies. But the study of LEVINE et al. [10] in ventilated brain-dead organ donors, which revealed rapid diaphragm fibre atrophy and enhanced proteolysis, as in animal models, highlighted the fact that the mechanical ventilation effect was not exclusive to laboratory models. Subsequent studies in animal models, and also in humans, have further documented the impact of controlled mechanical ventilation on the diaphragm [11][12][13][14][15][16][17][18][19][20].Despite this evidence, the impact of VIDD as an important component of diaphragm disability during mechanical ventilation remains questioned. It has been claimed that the available data pertain to controlled mechanical ventilation, a ventilation mode which is not the preferential mode of ventilation in patients. Well, this is true, although this ventilation mode is a necessary tool in particular situations (e.g. in patients treated with neuromuscular blocking agents, in attempts to minimise oxygen consumption, and in patients with central neurological problems) and is therefore still being used in the intensive care unit [21]. But other ventilation modes may not be as innocent as it is believed. Experimental data showed that 3 days of assist-control mechanical ventilation in healthy animals resulted in about 15% loss in maximal diaphragm force, which is obviously far less than the 45% reduction seen with controlled mechanical ventilation [22], but still indicative that it is also harmful. Along the same lines, pressure support ventilation that did not affect diaphragm proteolysis or synthesis, in contrast to controlled mechanical ventilation, induced as much diaphragmatic oxidative stress as controlled mechanical ventilation did [23].Because the debate on whether VIDD is a myth or a reality is still going on, little has been done to develop strategies to minimise these effects, except for the use of pharmacologica...

show abstract

“…In this month's issue of ANESTHESIOLOGY, Schellekens et al present the results of an animal study that tested the role of Toll-like receptor 4 (TLR4) in the development of ventilator-induced diaphragm atrophy. 2 In their experiments, wild-type and TLR4 knockout mice were ventilated for 8 h. Controlled MV in wild-type mice resulted in a reduction of the diaphragm myosin heavy chain content by approximately 50% as compared with spontaneously breathing mice, which was associated with increased local concentrations of the inflammatory mediators interleukin-6 and keratinocyte-derived chemokine, the mouse analog of human interleukin-8. In TLR4 knockout mice, MV neither affected myosin content nor diaphragm interleukin-6 and keratinocyte-derived chemokine levels.…”

mentioning

confidence: 99%

“…Schellekens et al hypothesize that these endogenous TLR4 ligands might be responsible for activation of TLR4 in ventilator-induced diaphragm atrophy. 2 But how can these damage-associated molecular patterns reach the diaphragm? Are these ligands also present in plasma?…”

mentioning

confidence: 99%