Abstract
BackgroundDiaphragm weakness occurs rapidly in adult animals treated with mechanical ventilation (MV), but the effects of MV on the neonatal diaphragm have not been determined. Furthermore, it is unknown whether co-existent lung disease exacerbates ventilator-induced diaphragmatic dysfunction (VIDD). We investigated the impact of MV (mean duration = 7.65 h), either with or without co-existent respiratory failure caused by surfactant deficiency, on the development of VIDD in newborn lambs.MethodsNewborn lambs (1–4 days) were assigned to control (CTL, non-ventilated), mechanically ventilated (MV), and MV + experimentally induced surfactant deficiency (MV+SD) groups. Immunoblotting and quantitative PCR assessed inflammatory signaling, the ubiquitin-proteasome system, autophagy, and oxidative stress. Immunostaining for myosin heavy chain (MyHC) isoforms and quantitative morphometry evaluated diaphragm atrophy. Contractile function of the diaphragm was determined in isolated myofibrils ex vivo.ResultsEqual decreases (25–30%) in myofibrillar force generation were found in MV and MV+SD diaphragms compared to CTL. In comparison to CTL, both MV and MV+SD diaphragms also demonstrated increased STAT3 transcription factor phosphorylation. Ubiquitin-proteasome system (Atrogin1 and MuRF1) transcripts and autophagy indices (Gabarapl1 transcripts and the ratio of LC3B-II/LC3B-I protein) were greater in MV+SD relative to MV alone, but fiber type atrophy was not observed in any group. Protein carbonylation and 4-hydroxynonenal levels (indices of oxidative stress) also did not differ among groups.ConclusionsIn newborn lambs undergoing controlled MV, there is a rapid onset of diaphragm dysfunction consistent with VIDD. Superimposed lung injury caused by surfactant deficiency did not influence the severity of early diaphragm weakness.
Highlights
Diaphragm weakness occurs rapidly in adult animals treated with mechanical ventilation (MV), but the effects of MV on the neonatal diaphragm have not been determined
The total duration of ventilation was longer in the surfactant-depleted lambs after taking into account the additional time required for intrapulmonary lavage (MV = 6.80 + 0.16 h, MV + experimentally induced surfactant deficiency (MV+SD) = 8.55 + 0.57 h; p < 0.05)
Levels of the non-lipidated (LC3B-I) and lipidated (LC3B-II) forms of LC3B revealed that the LC3B-II/ LC3B-I ratio, considered an index of autophagy activation, was increased in the MV+SD group (Fig. 2c). These results suggest that MV+SD may have led to a higher level of autophagy pathway induction compared to the other groups
Summary
Diaphragm weakness occurs rapidly in adult animals treated with mechanical ventilation (MV), but the effects of MV on the neonatal diaphragm have not been determined It is unknown whether coexistent lung disease exacerbates ventilator-induced diaphragmatic dysfunction (VIDD). In critically ill children, a complete cessation of diaphragm electromyographic activity is frequently observed during MV [12] Taken together, these observations suggest that neonates could be at especially high risk for the development of VIDD. A frequent indication for MV in neonatal intensive care is the presence of lung injury secondary to surfactant deficiency, which could in theory further exacerbate diaphragm weakness via increased local or systemic inflammation [13,14,15]
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