Abstract
Acute respiratory distress syndrome (ARDS) caused by severe sepsis remains a major challenge in intensive care medicine. ACE2 has been shown to protect against lung injury. However, the mechanisms of its protective effects on ARDS are largely unknown. Here, we report that ACE2 prevents LPS-induced ARDS by inhibiting MAPKs and NF-κB signaling pathway. Lentiviral packaged Ace2 cDNA or Ace2 shRNA was intratracheally administrated into the lungs of male SD rats. Two weeks after gene transfer, animals received LPS (7.5 mg/Kg) injection alone or in combination with Mas receptor antagonist A779 (10 μg/Kg) or ACE2 inhibitor MLN-4760 (1 mg/Kg) pretreatment. LPS-induced lung injury and inflammatory response were significantly prevented by ACE2 overexpression and deteriorated by Ace2 shRNA. A779 or MLN-4760 pretreatment abolished the protective effects of ACE2. Moreover, overexpression of ACE2 significantly reduced the Ang II/Ang-(1-7) ratio in BALF and up-regulated Mas mRNA expression in lung, which was reversed by A779. Importantly, the blockade of ACE2 on LPS-induced phosphorylation of ERK1/2, p38 and p50/p65 was also abolished by A779. Whereas, only the ERK1/2 inhibitor significantly attenuated lung injury in ACE2 overexpressing rats pretreated with A779. Our observation suggests that AEC2 attenuates LPS-induced ARDS via the Ang-(1-7)/Mas pathway by inhibiting ERK/NF-κB activation.
Highlights
Acute respiratory distress syndrome (ARDS) caused by severe sepsis remains a major challenge in intensive care medicine
There were no significant differences in Angiotensin-converting enzyme 2 (ACE2) mRNA and protein expression between the control group and Lv-NC group
Our results showed that LPS administration significantly reduced ACE2 expression in the rat lung, whereas overexpression ACE2 significantly attenuated LPS-induced lung injury and suppressed inflammatory response, which was abolished by ACE2 inhibitor
Summary
Acute respiratory distress syndrome (ARDS) caused by severe sepsis remains a major challenge in intensive care medicine. We report that ACE2 prevents LPS-induced ARDS by inhibiting MAPKs and NF-κB signaling pathway. LPS-induced lung injury and inflammatory response were significantly prevented by ACE2 overexpression and deteriorated by Ace shRNA. Our observation suggests that AEC2 attenuates LPS-induced ARDS via the Ang-(1-7)/Mas pathway by inhibiting ERK/NF-κB activation. The phosphorylation levels of p38 MAPK, extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) are all significantly increased in LPS-induced lung injury. AT1R blocker, telmisartan, exerts protective effects on heart failure through upregulating myocardial ACE2 level and inhibiting p38 MAPK, ERK and JNK phosphorylation. Our previous in vitro study demonstrated that ACE2 prevented rat pulmonary microvascular endothelial cells (PMVECs) from LPS-induced apoptosis and inflammation through inhibiting the activation of JNK and NF-κB pathways. We hypothesize that ACE2 may protect against LPS-induced acute lung injury by inhibiting the MAPKs/ NF-κB pathway
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