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

  • J Transl Med. 2021 Aug 9;19(1):340. doi: 10.1186/s12967-021-03016-9.
Malarvizhi Gurusamy  1 ,  Saeed Nasseri  1  2 ,  Dileep Reddy Rampa  1 ,  Huiying Feng  1 ,  Dongwon Lee  3 ,  Anton Pekcec  4 ,  Henri Doods  4 ,  Dongmei Wu  5  6
Affiliations
  • 1. Department of BIN Convergence Technology, Chonbuk National University, Jeonju, South Korea.
  • 2. Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
  • 3. Department of BIN Convergence Technology, Chonbuk National University, Jeonju, South Korea. [email protected].
  • 4. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
  • 5. Department of BIN Convergence Technology, Chonbuk National University, Jeonju, South Korea. [email protected].
  • 6. Department of Research, Mount Sinai Medical Center, Miami Beach, FL, USA. [email protected].
PMID: 34372885 DOI: 10.1186/s12967-021-03016-9
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.

Keywords
BI 1029539; Celecoxib; GS-248; Leukocyte infiltration; Lung injury; Sepsis; Vascular permeability; mPGES-1.
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