Inhibition of microsomal prostaglandin E synthase-1 ameliorates acute lung injury in mice

Abstract

Background To examine the effects of BI 1029539 (GS-248), a novel selective human microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor, in experimental models of acute lung injury (ALI) and sepsis in transgenic mice constitutively expressing the mPGES1 (Ptges) humanized allele. Methods Series 1: Lipopolysaccharide (LPS)-induced ALI. Mice were randomized to receive vehicle, BI 1029539, or celecoxib. Series 2: Cecal ligation and puncture-induced sepsis. Mice were randomized to receive vehicle or BI 1029539. Results Series 1: BI 1029539 or celecoxib reduced LPS-induced lung injury, with reduction in neutrophil influx, protein content, TNF-ɑ, IL-1β and PGE2 levels in bronchoalveolar lavage (BAL), myeloperoxidase activity, expression of mPGES-1, cyclooxygenase (COX)-2 and intracellular adhesion molecule in lung tissue compared with vehicle-treated mice. Notably, prostacyclin (PGI2) BAL concentration was only lowered in celecoxib-treated mice. Series 2: BI 1029539 significantly reduced sepsis-induced BAL inflammatory cell recruitment, lung injury score and lung expression of mPGES-1 and inducible nitric oxide synthase. Treatment with BI 1029539 also significantly prolonged survival of mice with severe sepsis. Anti-inflammatory and anti-migratory effect of BI 1029539 was confirmed in peripheral blood leukocytes from healthy volunteers. Conclusions BI 1029539 ameliorates leukocyte infiltration and lung injury resulting from both endotoxin-induced and sepsis-induced lung injury.

Anti-inflammatory effects of N-Acetylcysteine and Elaeagnus angustifolia extract on acute lung injury induced by λ-carrageenan in rat

“…BAL was collected from anesthetized mice through a 20-gage angiocath as previously described (Gurusamy et al 2021 ). Briefly, 4 ml of sterile PBS was instilled into the rat lung and lavaged three times.…”

“…The lower lobes of the right lung were harvested in all animals to determine the edema index (wet/dry ratio) as previously described (Gurusamy et al 2021 ). In brief, The wet weight of the right lower lungs was measured at the time scarification.…”

“…Acute lung injury (ALI) and it’s more severe form, Acute respiratory distress syndrome (ARDS), are clinical complications with high mortality, increased permeability of the alveolar-capillary barrier impairs the function of pulmonary capillary endothelial cells, (Wu et al 2020 ; Gurusamy et al 2021 ) and contributes to high protein content and pulmonary edema (Laffey and Matthay 2017 ). ALI can result from infection, trauma, burns, or sepsis.…”

Effects of microsomal prostaglandin E synthase‐1 inhibition on resistance artery tone in patients with end stage kidney disease

“…Due to compound-specific liver toxicity this program was discontinued (Norman et al, 2018). In support, a phase I clinical study using the selective mPGES-1 inhibitor GS-248 (alternative name OX-MPI, BI 1029539) (Gurusamy et al, 2021;Soldner et al, 2019) at sub-nanomolar concentration demonstrated inhibition of LPS-induced PGE 2 biosynthesis in ex vivo blood from healthy volunteers. In addition, a significant and durable inhibition of urinary PGE 2 -M was observed, accompanied with an increase of urinary PGI 2 -M (Edenius et al, 2020).…”

Nonacidic thiophene‐based derivatives as potential analgesic and design, synthesis, biological evaluation, and metabolic stability study

“…A recent approach for finding safer anti‐inflammatory agents involves inhibiting the synthesis of PGE2. PGE2 is a principle inflammatory mediator biosynthesized through a series of reactions starting from arachidonic acid (AA) which is converted to prostaglandin H 2 (PGH 2 ) via a cyclooxygenase enzyme (COX), PGH 2 is subsequently converted to PGE2 via prostaglandin E synthases (PGES) (Gomez et al, 2013; Gurusamy et al, 2021; Meuillet & Meuillet, 2011). PGES involves three isoforms: two of them, namely, cytosolic PGES (cPGES) and microsomal (mPGES‐2) are constitutively expressed.…”