The JAK-STAT Pathway Is Critical in Ventilator-Induced Diaphragm Dysfunction

Abstract

INTRODUCTION Mechanical ventilation (MV) is an important component of modern medical practice which allows support of breathing in the intensive care unit (ICU) and during surgery requiring general anesthesia. Many patients, however, fail initial weaning from the ventilator and enter the difficult realm of prolonged ventilation. Patients who develop this ventilator dependence, though a diverse group, share the common underlying problem of substantial dysfunction of the major inspiratory muscle, the diaphragm (1-8). The development of ventilator-induced diaphragm dysfunction (VIDD) appears to be a major underlying cause of prolonged ventilator-dependence with its attendant dramatic increase in morbidity and mortality (9-14). The pathogenesis of VIDD includes both atrophy of diaphragmatic myofibers and loss of diaphragmatic contractile function (that is, specific force) unrelated to atrophy (15-17). In previous studies, MV with diaphragm inactivity has been shown to elicit significant dysfunction and/or atrophy of myofibers in the diaphragm of humans (18-21), rats (22), mice (23-25), rabbits (26) and piglets (27). With regard to the atrophy, several proteolytic events, such as activation of the ubiquitin proteasome system (UPS) (28-30), autophagy (24,25,31) and apoptosis (32-35), and upregulation of calpain (36), have been demonstrated in MV models. We and others have re

Ventilator‐induced diaphragmatic dysfunction in MDX mice

“…20 In this regard, inhibition of STAT3 phosphorylation was recently reported to prevent oxidative stress, proteolysis, and specific force loss in rat diaphragms exposed to MV. 21,22 In keeping with the above, mdx diaphragms subjected to MV exhibited increases in protein carbonylation (an index of oxidative stress) as well as elevated levels of phosphorylated STAT3. Furthermore, the observed upregulation of both SIRT1 and mGPAT may represent compensatory responses to combat MV-induced oxidative stress.…”

“…Furthermore, it has been hypothesized that STAT3 activation could act as an upstream mediator of mitochondria‐derived reactive oxygen species generation . In this regard, inhibition of STAT3 phosphorylation was recently reported to prevent oxidative stress, proteolysis, and specific force loss in rat diaphragms exposed to MV . In keeping with the above, mdx diaphragms subjected to MV exhibited increases in protein carbonylation (an index of oxidative stress) as well as elevated levels of phosphorylated STAT3.…”

Dysfunction of respiratory muscles in critically ill patients on the intensive care unit

“…Proteolysis is mediated by the calpain and caspase system, as well as the ubiquitin–proteasome complex and the autophagy–lysosomal system . The biochemical changes of VIDD, mainly examined in healthy murine models, may be augmented or even triggered by oxidative stress pathways, nuclear factor kB (NFkB), or JAK–Stat signalling pathways . Similar to patients with severe sepsis and septic shock, distinct cytokine cascades are upregulated.…”

“…42 The biochemical changes of VIDD, mainly examined in healthy murine models, may be augmented or even triggered by oxidative stress pathways, 19,[43][44][45] nuclear factor kB (NFkB), 46,47 or JAK-Stat signalling pathways. 48 Similar to patients with severe sepsis and septic shock, distinct cytokine cascades are upregulated. This includes interleukin (IL)-6, tumour necrosis factor-α, and IL-1β in rat diaphragmatic tissue exposed to mechanical ventilation 47 and may further amplify major inflammatory signalling pathways including NFkB.…”

Ventilator-induced diaphragmatic dysfunction

“…A particularly intriguing finding is that phosphorylated STAT3 appears to translocate into the mitochondria during mechanical ventilation[25 && ], indicating a possible direct effect in promoting mitochondrial dysfunction[26 …”