Clinical review: Ventilator-induced diaphragmatic dysfunction - human studies confirm animal model findings!

Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation. However, the use of controlled mechanical ventilation in animal models results in a major reduction of diaphragmatic force-generating capacity together with structural injury and atrophy of diaphragm muscle fibers, a condition termed ventilator-induced diaphragmatic dysfunction (VIDD). Increased oxidative stress and exaggerated proteolysis in the diaphragm have been linked to the development of VIDD in animal models, but much less is known about the extent to which these phenomena occur in humans undergoing mechanical ventilation in the ICU. In the present review, we first briefly summarize the large body of evidence demonstrating the existence of VIDD in animal models, and outline the major cellular mechanisms that have been implicated in this process. We then relate these findings to very recently published data in critically ill patients, which have thus far been found to exhibit a remarkable degree of similarity with the animal model data. Hence, the human studies to date have indicated that mechanical ventilation is associated with increased oxidative stress, atrophy, and injury of diaphragmatic muscle fibers along with a rapid loss of diaphragmatic force production. These changes are, to a large extent, directly proportional to the duration of mechanical ventilation. In the context of these human data, we also review the methods that can be used in the clinical setting to diagnose and/or monitor the development of VIDD in critically ill patients. Finally, we discuss the potential for using different mechanical ventilation strategies and pharmacological approaches to prevent and/or to treat VIDD and suggest promising avenues for future research in this area

Ultrasound increases plasmid-mediated gene transfer to dystrophic muscles without collateral damage

Studies have shown that ultrasound, used either alone or in combination with microbubble contrast agents, can increase cell membrane permeability to plasmid DNA. Because ultrasound is a non-painful and well-established tool in clinical medicine, its potential to enhance DNA uptake into the muscles of patients with muscular dystrophy is conceptually attractive. Therefore, we evaluated the ability of ultrasound pulses (1 MHz; 1.5 W/cm2) to increase exogenous (LacZ) gene expression in normal wild-type and dystrophic Dmd(mdx/mdx) mice after plasmid DNA injection into muscle. We also ascertained whether co-injection of lipid-encapsulated perfluoropropane microbubbles (Definity) or pretreatment with hyaluronidase could further increase the level of gene transfer to ultrasound-treated muscles. The use of ultrasound did not increase transfection efficiency in normal mice. In contrast, dystrophic mice demonstrated an increase in the number of transfected fibers (threefold) as well as the amount of LacZ protein (22-fold) after ultrasound exposure, provided that Definity was also co-injected with the DNA. Pretreatment of muscles with hyaluronidase before ultrasound exposure was not effective in augmenting the level of gene transfer. Under the optimal conditions for dystrophic muscle transfection (ultrasound + Definity), there was no associated increase in muscle damage. Hence ultrasound may provide a safe and effective method for enhancing gene transfer to dystrophic muscles, thereby increasing the prospects for therapeutic application of naked DNA in muscular dystrophy patients.Peer reviewed: YesNRC publication: N

Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation

Ventilator-induced diaphragmatic dysfunction (VIDD) refers to the diaphragm muscle weakness that occurs following prolonged controlled mechanical ventilation (MV). The presence of VIDD impedes recovery from respiratory failure. However, the pathophysiological mechanisms accounting for VIDD are still not fully understood. Here, we show in human subjects and a mouse model of VIDD that MV is associated with rapid remodeling of the sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor (RyR1) in the diaphragm. The RyR1 macromolecular complex was oxidized, S-nitrosylated, Ser-2844 phosphorylated, and depleted of the stabilizing subunit calstabin1, following MV. These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by MV and stimulation of adrenergic signaling resulting from the anesthesia. We demonstrate in the murine model that such abnormal resting SR Ca2+ leak resulted in reduced contractile function and muscle fiber atrophy for longer duration of MV. Treatment with β-adrenergic antagonists or with S107, a small molecule drug that stabilizes the RyR1–calstabin1 interaction, prevented VIDD. Diaphragmatic dysfunction is common in MV patients and is a major cause of failure to wean patients from ventilator support. This study provides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD (i.e., loss of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention