Abstract
Mechanical ventilation (MV) is the main supportive treatment of acute respiratory distress syndrome (ARDS), but it may lead to ventilator-induced lung injury (VILI). Large epidemiological studies have found that obesity was associated with lower mortality in mechanically ventilated patients with acute lung injury, which is known as “obesity paradox.” However, the effects of obesity on VILI are unknown. In the present study, wild-type mice were fed a high-fat diet (HFD) and ventilated with high tidal volume to investigate the effects of obesity on VILI in vivo, and pulmonary microvascular endothelial cells (PMVECs) were subjected to 18% cyclic stretching (CS) to further investigate its underlying mechanism in vitro. We found that HFD protects mice from VILI by alleviating the pulmonary endothelial barrier injury and inflammatory responses in mice. Adipose-derived exosomes can regulate distant tissues as novel adipokines, providing a new mechanism for cell-cell interactions. We extracted three adipose-derived exosomes, including HFD mouse serum exosome (S-Exo), adipose tissue exosome (AT-Exo), and adipose-derived stem cell exosome (ADSC-Exo), and further explored their effects on MV or 18% CS-induced VILI in vivo and in vitro. Administration of three exosomes protected against VILI by suppressing pulmonary endothelial barrier hyperpermeability, repairing the expression of adherens junctions, and alleviating inflammatory response in vivo and in vitro, accompanied by transient receptor potential vanilloid 4 (TRPV4)/Ca2+ pathway inhibition. Collectively, these data indicated that HFD-induced obesity plays a protective role in VILI by alleviating the pulmonary endothelial barrier injury and inflammatory response via adipose-derived exosomes, at least partially, through inhibiting the TRPV4/Ca2+ pathway.
Highlights
Acute respiratory distress syndrome (ARDS)-related research has been ongoing for more than 40 years, mortality due to the disease is still high, and there are no effective treatment measures
We investigated whether there was a difference in the response to ventilatorinduced lung injury (VILI) in high-fat diet (HFD) mice compared with normal chow diet (NCD) mice and whether the difference was favorable or harmful
Significant increases in pulmonary leakage were observed in the Mechanical ventilation (MV) group compared with that of the spontaneously breathing (SB) group, whereas pulmonary leakage was significantly decreased in HFD ϩ MV mice compared with that in NCD ϩ MV mice (Fig. 1, B and C)
Summary
Acute respiratory distress syndrome (ARDS)-related research has been ongoing for more than 40 years, mortality due to the disease is still high, and there are no effective treatment measures. Relevant studies have found that obese patients have a higher risk of ARDS than normal weight patients. Those who were obese had higher survival rates [41]. Obesity and overweight are often associated with an increased risk of death in the general population, but in some critical diseases such as ARDS, mortality is reduced, which is known as the “obesity paradox” [3, 31]. A recent animal study found that a high-fat diet (HFD) can protect mice from VILI via neutrophil-independent mechanisms [51], driving us to further explore the protective effects and mechanisms of obesity on VILI
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