Abstract
Acute lung injury (ALI) and the subsequent acute respiratory distress syndrome remain devastating diseases with high mortality rates and poor prognoses among patients in intensive care units. The present study is aimed at investigating the role and underlying mechanisms of microRNA-31-5p (miR-31-5p) on lipopolysaccharide- (LPS-) induced ALI. Mice were pretreated with miR-31-5p agomir, antagomir, and their negative controls at indicated doses for 3 consecutive days, and then they received a single intratracheal injection of LPS (5 mg/kg) for 12 h to induce ALI. MH-S murine alveolar macrophage cell lines were cultured to further verify the role of miR-31-5p in vitro. For AMP-activated protein kinase α (AMPKα) and calcium-binding protein 39 (Cab39) inhibition, compound C or lentiviral vectors were used in vivo and in vitro. We observed an upregulation of miR-31-5p in lung tissue upon LPS injection. miR-31-5p antagomir alleviated, while miR-31-5p agomir exacerbated LPS-induced inflammation, oxidative damage, and pulmonary dysfunction in vivo and in vitro. Mechanistically, miR-31-5p antagomir activated AMPKα to exert the protective effects that were abrogated by AMPKα inhibition. Further studies revealed that Cab39 was required for AMPKα activation and pulmonary protection by miR-31-5p antagomir. We provide the evidence that endogenous miR-31-5p is a key pathogenic factor for inflammation and oxidative damage during LPS-induced ALI, which is related to Cab39-dependent inhibition of AMPKα.
Highlights
Acute lung injury (ALI) and the subsequent acute respiratory distress syndrome are devastating diseases manifested as severe refractory hypoxemia and multiple organ failure, which cause high mortality rates and poor prognoses among patients in the intensive care units
Our present study indicates that miR-31-5p is upregulated in murine lungs upon LPS stimulation and that this upregulation is instrumental for the provocation of inflammation and oxidative damage both in mice and in cultured macrophages. miR-31-5p antagomir attenuates, while miR-31-5p agomir exacerbates pulmonary injury and dysfunction in LPS-treated mice
The associated speck-like protein (ASC) adaptor interacts with the Nucleotide-binding domain-like receptor protein 3 (NLRP3) scaffold to activate caspase-1, which proteolytically cleaves the precursors of multiple proinflammatory cytokines and releases the mature forms, including IL-1β and IL-18 [3, 4, 14]
Summary
Acute lung injury (ALI) and the subsequent acute respiratory distress syndrome are devastating diseases manifested as severe refractory hypoxemia and multiple organ failure, which cause high mortality rates and poor prognoses among patients in the intensive care units. Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome acts as a molecular scaffold for the maturation of various procytokines that contributes to inflammatory injury during sepsis-related ALI [3, 4] These leukocytes and excessive inflammation promote an overproduction of reactive oxygen species (ROS) and elicit oxidative damage to pulmonary cells. Lv et al found that AMPKα activation suppressed intrapulmonary inflammation and oxidative damage, thereby preventing LPS-induced ALI, while AMPKα inhibition exacerbated lung injury in mice [10, 11] Taken together, these findings provide a basis for targeting AMPKα as the promising strategy to treat sepsisrelated ALI. We supposed that miR-31-5p might be involved in the pathogenesis of LPS-induced ALI
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
