Induced Pluripotent Stem Cell Therapy Ameliorates Hyperoxia-Augmented Ventilator-Induced Lung Injury through Suppressing the Src Pathway

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.

Suppression of plasminogen activator inhibitor-1 by inhaled nitric oxide attenuates the adverse effects of hyperoxia in a rat model of acute lung injury

“…Hyperoxia can damage normal lung tissue and cause neutrophil infiltration, pulmonary edema, destruction of the alveolar epithelial barrier, hyaline membrane formation and interstitial fibrosis [30]. Hyperoxia can also augment ventilator-induced lung injury [31]. However, in the present study, histological changes in the lungs of control rats exposed to a high concentration of oxygen remained constant or showed a slight degree of injury during 24 h of oxygen treatment.…”

Annexin A1 peptide Ac2-26 mitigates ventilator-induced lung injury in acute respiratory distress syndrome rats by enhancing endothelial nitric oxide synthase activity

“…Oxidative stress can promote lipid peroxidation to produce MDA [39] and it can also be enhanced by increased NADPH oxidase and MPO [40][41][42]. In this study, we found that Ac2-26 significantly reduced the levels of MDA, NADPH oxidase and MPO activities in the lungs of rats, which were partially attenuated by L-NIO.…”

Developmental pathways in lung regeneration

“…The biggest hurdle in the study of ESC or iPSC derived lung epithelium is that the resulting cells are immature and do not represent a fully functional differentiated cell. Despite this and other limitations, such differentiation protocols have been used in various models to explore the differentiation potential of human and mouse ESCs and iPSCs including the kidney capsule formation assay (Mou, Zhao et al 2012, Liu, Li et al 2014), lung-on-a-chip type models such as air liquid interface (ALI) culture (Wong, Bear et al 2012, Firth, Dargitz et al 2014), and in bioengineered models such as culture within the decellularized lung (Longmire, Ikonomou et al 2012). The major benefit of patient derived iPSCs is their capacity to harbor genetic mutations that affect respiratory function such as cystic fibrosis or alpha-1 anti-trypsin deficiency.…”