Abstract
Mechanical ventilation (MV) is a major life support technique for the management of trauma-associated hemorrhagic shock (HS). Ventilator-induced diaphragm dysfunction (VIDD), one of the most common complications of MV, has been well demonstrated in animal and human studies. However, few data are available concerning the effects of MV on diaphragm function in HS victims. In the present study, we found diaphragm muscle atrophy and weakness in HS but not in healthy animals after 4 hours of MV. The inhibition of autophagy resulted in reduced muscle fiber atrophy and improved forces. In addition, we observed diaphragmatic interleukin- (IL-) 6 overexpression and activation of its downstream signaling JAK/STAT in HS animals after MV, and either the neutralization of IL-6 or the inhibition of the JAK/STAT pathway attenuated autophagy, diaphragm atrophy, and weakness. Importantly, treatment with nonselective antioxidant exerted no protective effects against VIDD in HS animals. In addition, in vitro study showed that exogenous IL-6 was able to induce activation of JAK/STAT signaling and to increase autophagy in C2C12 cells. Moreover, the inhibition of JAK/STAT signaling abolished IL-6-induced cell autophagy. Together, our results suggested that HS sensitized the diaphragm to ventilator-induced atrophy and weakness through the activation of IL-6/JAK/STAT signaling-mediated autophagy in rats.
Highlights
Hemorrhagic shock (HS) is a severe outcome of traumatic injury
These results indicated that short-term Mechanical ventilation (MV) was unable to induce diaphragm atrophy in healthy rats
Western blots showed that the autophagic marker LC3B II/I ratio was markedly upregulated in the hemorrhagic shock (HS)+MV group as compared to other groups (Figures 1(g) and 1(h))
Summary
Patients who survive the initial phase of HS are at risk of multiple organ dysfunction syndrome (MODS), systemic inflammation, and oxidative stress [1]. A recent study reported that diaphragm function was preserved during HS in a rat model, and HS did not induce apparent inflammation in diaphragmatic tissues [9]. MV use leads to diaphragm muscle atrophy and weakness, which has been linked to weaning difficulties and has been termed as ventilator-induced diaphragm dysfunction (VIDD) [10]. Since HS is able to induce systemic inflammation and oxidative stress, it is reasonable to speculate that HS possibly worsens diaphragm atrophy and weakness during MV. We aim to test the hypothesis that short-time ventilation was able to induce diaphragm dysfunction in HS rats and to determine its underlying molecular mechanisms
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