Malarvizhi Gurusamy1, Saeed Nasseri1,2, Dileep Reddy Rampa1, Huiying Feng1, Dongwon Lee3, Anton Pekcec4, Henri Doods4, Dongmei Wu5,6. 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. dlee@jbnu.ac.kr. 4. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany. 5. Department of BIN Convergence Technology, Chonbuk National University, Jeonju, South Korea. dongmeiwu18@gmail.com. 6. Department of Research, Mount Sinai Medical Center, Miami Beach, FL, USA. dongmeiwu18@gmail.com.
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.
BACKGROUND: To examine the effects of BI 1029539 (GS-248), a novel selective humanmicrosomal 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.
Authors: Stephanie Nonas; Ian Miller; Kamon Kawkitinarong; Santipongse Chatchavalvanich; Irina Gorshkova; Valery N Bochkov; Norbert Leitinger; Viswanathan Natarajan; Joe G N Garcia; Konstantin G Birukov Journal: Am J Respir Crit Care Med Date: 2006-03-02 Impact factor: 21.405
Authors: Annika O Hofstetter; Sipra Saha; Veronica Siljehav; Per-Johan Jakobsson; Eric Herlenius Journal: Proc Natl Acad Sci U S A Date: 2007-05-29 Impact factor: 11.205