Abstract

EZETIMIBE MITIGATES LIPOPOLYSACCHARIDE-INDUCED LUNG INJURY IN MICE: ATTENTION TO NLRP3/CASPASE-1/IL-1? AND NF-?B SIGNALING PATHWAYS

Abeer G. Sakr*, Hoda E. Kafl, Dalia H. El-Kashef

ABSTRACT

Ezetimibe (Eze), is an azetidinone derivative, has been extensively used as a hypolipidemic drug either alone or combined with statins to protect against cardiovascular complications. The pleotropic activity of this compound is still under investigation to explore its potential anti-inflammatory and anti-oxidative activity. This research investigated the capacity of Eze to protect against lipopolysaccharide (LPS)-induced acute lung injury (ALI) and its fundamental mechanisms in a mouse model. Results revealed that Eze efficiently protects against LPS-induced ALI. It effectively reduced protein content and LDH activity in bronchoalveolar lavage fluid and attenuated LPS-induced inflammatory cell infiltration into the pulmonary tissues resulting in reduction of pulmonary edema. Eze improved LPS-induced histopathological lesions and suppressed oxidative stress presented by low levels of malondialdehyde (MDA) and high levels of reduced glutathione (GSH) in lung tissues. The anti-inflammatory potential ofEze against LPS-induced ALI was obviously confirmed through the inhibition of toll like receptor4 (TLR4)-mediated nuclear factor kappa B (NF-κB) signaling which causes the activation of NOD-LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome and Caspase 1 (Casp-1). Additionally, Eze effectively attenuated the levels of pro inflammatory cytokines namely, tumor necrosis factor-α (TNF-α) and Interleukin-1beta (IL-1β). Collectively, Eze has anti-oxidant and anti-inflammatory potentials against LPS-induced ALI.

Keywords: Ezetimibe; LPS; inflammation; TLR4/ NF-?B/ NLRP3/Casp-1.