Abstract
Sepsis-induced diaphragm dysfunction (SIDD) which is mainly characterized by decrease in diaphragmatic contractility has been identified to cause great harms to patients. Therefore, there is an important and pressing need to find effective treatments for improving SIDD. In addition, acetylcholinesterase (AChE) activity is a vital property of the diaphragm, so we evaluated both diaphragmatic contractility and AChE activity. Though neuregulin-1β (NRG-1β) is known to exert organ-protective effects in some inflammatory diseases, little is known about the potential of NRG-1β therapy in the diaphragm during sepsis. Our study was aimed at exploring the effects of NRG-1β application on diaphragmatic contractility and AChE activity during sepsis. Proinflammatory cytokines, muscle injury biomarkers in serum, contractile force, AChE activity, proinflammatory cytokines, oxidative parameters, histological condition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling proteins in the diaphragm were measured and compared between nonseptic and septic groups with or without NRG-1β treatment. In vitro, the effects of NRG-1β on reactive oxygen species (ROS) production in the lipopolysaccharide- (LPS-) stimulated L6 rat muscle skeletal cells with or without the Akt inhibitor MK-2206 were detected. NRG-1β inhibited proinflammatory cytokine release and muscle injury biomarkers soaring in serum and improved the sepsis-induced diaphragm dysfunction and AChE activity decrease significantly during sepsis. Meanwhile, the inflammatory response, oxidative stress, pathological impairment, and cell apoptosis in the diaphragm were mitigated by NRG-1β. And NRG-1β activated the PI3K/Akt signaling in the diaphragm of septic rats. Elevated ROS production in the LPS-stimulated L6 rat skeletal muscle cells was reduced after treatment with NRG-1β, while MK-2206 blocked these effects of NRG-1β. In conclusion, our findings underlined that NRG-1β could reduce circulating levels of proinflammatory cytokines in rats with sepsis, adjust diaphragmatic proinflammatory cytokine level, mitigate diaphragmatic oxidative injury, and lessen diaphragm cell apoptosis, thereby improving diaphragmatic function, and play a role in diaphragmatic protection by activating PI3K/Akt signaling.
Highlights
Sepsis is a series of clinical syndromes induced by severe infection, causing multiple organ dysfunctions [1]
We firstly offered the evidence that NRG-1β may provide a therapeutic option for curing sepsis-induced diaphragm dysfunction (SIDD) via suppressing oxidative stress and inflammation by activating the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway
Than NRG-1α [15, 16]; we chose to use NRG-1β in this study. Proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 have been verified to participate in and promote sepsis in previous studies; our study suggested that sepsis-induced diaphragmatic dysfunction and AChE activity decrease were associated with an increased exposure of the diaphragm to proinflammatory cytokines
Summary
Sepsis is a series of clinical syndromes induced by severe infection, causing multiple organ dysfunctions [1]. It is often accompanied by acute respiratory failure, in which the weakness of respiratory muscles is an important factor [2]. Inflammatory cytokine infiltration and recessive reactive oxygen species (ROS) generated from oxidative stress during sepsis could do damage to the skeletal muscle contractility-associated proteins such as sarco(endo)plasmic reticulum calcium-ATPases (SERCA) and/or sarcomere, subsequently causing diaphragmatic weakness [9]. Our previous study verified that AChE activity decreased at the NMJ in the diaphragm during sepsis and oxidative stress was a vital contributor [13]. Drugs could inhibit the inflammation, and/or oxidative stress is theoretically useful for maintaining diaphragmatic contractile function and AChE activity during sepsis
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