Abstract
BackgroundHigh tidal volume (VT) mechanical ventilation (MV) can induce the recruitment of neutrophils, release of inflammatory cytokines and free radicals, and disruption of alveolar epithelial and endothelial barriers. It is proposed to be the triggering factor that initiates ventilator-induced lung injury (VILI) and concomitant hyperoxia further aggravates the progression of VILI. The Src protein tyrosine kinase (PTK) family is one of the most critical families to intracellular signal transduction related to acute inflammatory responses. The anti-inflammatory abilities of induced pluripotent stem cells (iPSCs) have been shown to improve acute lung injuries (ALIs); however, the mechanisms regulating the interactions between MV, hyperoxia, and iPSCs have not been fully elucidated. In this study, we hypothesize that Src PTK plays a critical role in the regulation of oxidants and inflammation-induced VILI during hyperoxia. iPSC therapy can ameliorate acute hyperoxic VILI by suppressing the Src pathway.MethodsMale C57BL/6 mice, either wild-type or Src-deficient, aged between 2 and 3 months were exposed to high VT (30 mL/kg) ventilation with or without hyperoxia for 1 to 4 h after the administration of Oct4/Sox2/Parp1 iPSCs at a dose of 5×107 cells/kg of mouse. Nonventilated mice were used for the control groups.ResultsHigh VT ventilation during hyperoxia further aggravated VILI, as demonstrated by the increases in microvascular permeability, neutrophil infiltration, macrophage inflammatory protein-2 (MIP-2) and plasminogen activator inhibitor-1 (PAI-1) production, Src activation, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and malaldehyde (MDA) level. Administering iPSCs attenuated ALI induced by MV during hyperoxia, which benefited from the suppression of Src activation, oxidative stress, acute inflammation, and apoptosis, as indicated by the Src-deficient mice.ConclusionThe data suggest that iPSC-based therapy is capable of partially suppressing acute inflammatory and oxidant responses that occur during hyperoxia-augmented VILI through the inhibition of Src-dependent signaling pathway.
Highlights
Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema, increased alveolocapillary permeability, leukocyte infiltration, and the release of cytokines [1,2,3]
We previously demonstrated that hyperoxia augmented ventilator-induced lung injury (VILI) through the activation of plasminogen activator inhibitor-1 (PAI-1), which was mediated by redoxsensitizing transcription factor nuclear factor-kappaB (NF-kB) in mice [19]
The roles of induced pluripotent stem cells (iPSCs) therapy in hyperoxia-augmented VILI have not been fully delineated and require further exploration. In this mouse model of hyperoxia-augmented VILI, we examine the relationships among high VT ventilation and hyperoxia, iPSCs, macrophage inflammatory protein-2 (MIP-2) and PAI-1 production, intracellular oxidative stress, and activation of Src and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase signaling using Src knock-out mice
Summary
Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema, increased alveolocapillary permeability, leukocyte infiltration, and the release of cytokines (because of severe epithelial and endothelial injury) [1,2,3]. The management of ARDS often necessitates the use of mechanical ventilation (MV) with high levels of oxygen, especially in the first few hours after intubation This allows for adequate maintenance of the oxygenation of vital organs. High tidal volume (VT) mechanical ventilation (MV) can induce the recruitment of neutrophils, release of inflammatory cytokines and free radicals, and disruption of alveolar epithelial and endothelial barriers. It is proposed to be the triggering factor that initiates ventilator-induced lung injury (VILI) and concomitant hyperoxia further aggravates the progression of VILI. The anti-inflammatory abilities of induced pluripotent stem cells (iPSCs) have been shown to improve acute lung injuries (ALIs); the mechanisms regulating the interactions between MV, hyperoxia, and iPSCs have not been fully elucidated. We hypothesize that Src PTK plays a critical role in the regulation of oxidants and inflammation-induced VILI during hyperoxia. iPSC therapy can ameliorate acute hyperoxic VILI by suppressing the Src pathway
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