Abstract
The oxidative stresses are a major insult in pulmonary injury such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), two clinical manifestations of acute respiratory failure with substantially high morbidity and mortality. Mesenchymal stem cells (MSCs) hold a promise in treatments of many human diseases, mainly owing to their capacities of immunoregulation and antioxidative activity. The strong immunoregulatory role of human placental MSCs of fetal origin (hfPMSCs) has been previously demonstrated; their antioxidant activity, however, has yet been interrogated. In this report, we examined the antioxidative activity of hfPMSCs by accessing the ability to scavenge oxidants and radicals and to protect alveolar epithelial cells from antioxidative injury using both a cell coculture model and a conditioned culture medium (CM) of hfPMSCs. Results showed a comparable antioxidative capacity of the CM with 100 μM of vitamin C (VC) in terms of the total antioxidant capacity (T-AOC), scavenging abilities of free radicals DPPH, hydroxyl radical (·OH), and superoxide anion radical (O2 −), as well as activities of antioxidant enzymes of SOD and GSH-PX. Importantly, both of the CM alone and cocultures of hfPMSCs displayed a protection of A549 alveolar epithelial cells from oxidative injury of 600 μM hydrogen peroxide (H2O2) exposure, as determined in monolayer and transwell coculture models, respectively. Mechanistically, hfPMSCs and their CM could significantly reduce the apoptotic cell fraction of alveolar epithelial A549 cells exposed to H2O2, accompanied with an increased expression of antiapoptotic proteins Bcl-2, Mcl-1, Nrf-2, and HO-1 and decreased proapoptotic proteins Bax, caspase 3, and Keap1, in comparison with naïve controls. Furthermore, hfPMSCs-CM (passage 3) collected from cultures exposed an inhibition of the Nrf2/Keap1/ARE signaling pathway which led to a significant reduction in caspase 3 expression in A549 cells, although the addition of Nrf2 inhibitor ML385 had no effect on the antioxidative activity of hfPMSCs-CM. These data clearly suggested that hfPMSCs protected the H2O2-induced cell oxidative injury at least in part by regulating the Nrf2-Keap1-ARE signaling-mediated cell apoptosis. Our study thus provided a new insight into the antioxidative mechanism and novel functions of hfPMSCs as antioxidants in disease treatments, which is warranted for further investigations.
Highlights
The imbalance between oxidant and antioxidant is mainly caused by the increased production of reactive oxygen species (ROS), which may result in oxidative stress in the body
In order to assess the antioxidative capacity of the hfPMSC-conditioned medium from passage 2 (P2) to P6, the total antioxidant capacity (T-AOC), free radical scavenging ability of DPPH, the inhibitory ability to hydroxyl radical (·OH), superoxide anion radical (O2-), and antioxidant enzyme activity were evaluated
This result implied that hfPMSCs-conditioned medium (CM), especially in the CM from passage 3 (P3) cells, had a comparable antioxidant activity with 100 μmol/L of vitamin C (VC) (Figure 1)
Summary
The imbalance between oxidant and antioxidant is mainly caused by the increased production of reactive oxygen species (ROS), which may result in oxidative stress in the body. The oxidative stress usually leads to cell necrosis and apoptosis and causes systemic inflammatory responses and diseases including chronic heart failure [1], Alzheimer’s disease [2], atherosclerosis, diabetes [3], systemic lupus erythematosus (SLE), and cancer [4] In this regard, an oxidative injury has been recognized as a major inducer of pulmonary injury, which is associated with the development and progression of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Recently studies have demonstrated that the nuclear factor erythroidderived 2-like 2- (Nrf2-) Kelch-like ECH-associated protein 1- (keap1-) antioxidant response element (ARE) signaling pathway is one of the most important cellular defense mechanisms against oxidative stress [15, 16] In this respect, MSCs modified with heme oxygenase-1 (HO-1) could enhance paracrine production of hepatocyte growth factor (HGF), interleukin- (IL-) 10, and the activity of Nrf to attenuate lipopolysaccharide- (LPS-) induced oxidative damage in pulmonary microvascular endothelial cells (PVECs) [16]. The underlying mechanism by which the secretome of hfPMSC attenuated the degree of ALI has not been fully understood
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