Abstract
BackgroundTo 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.MethodsSeries 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.ResultsSeries 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.ConclusionsBI 1029539 ameliorates leukocyte infiltration and lung injury resulting from both endotoxin-induced and sepsis-induced lung injury.
Highlights
Acute lung injury (ALI), a common complication of sepsis, involves excessive inflammation and disruption of the alveolar-capillary barrier resulting in lung edema and impaired gas exchange [1,2,3]
Using knock-in mice that express human microsomal prostaglandin E synthase-1 (mPGES-1), this study examined the effect of BI 1029539 on endotoxin-induced direct lung injury and sepsis-induced indirect lung injury
COX-2, cyclooxygenase-2; histological lung damage (H&E), hematoxylin and eosin; ICAM, intracellular adhesion molecule; LPS, lipopolysaccharide; microsomal PGES 1 (mPGES)-1, microsomal prostaglandin-E synthase; MPO, myeloperoxidase by LPS were significantly attenuated after treatment with BI1029539 and celecoxib, respectively (Fig. 2A, 3C)
Summary
Acute lung injury (ALI), a common complication of sepsis, involves excessive inflammation and disruption of the alveolar-capillary barrier resulting in lung edema and impaired gas exchange [1,2,3]. MPGES-1 derived PGE2 plays an important role in various inflammatory responses commonly displayed in sepsis including swelling, fever, inflammatory pain, and apnea [9,10,11,12, 14,15,16,17]. NSAIDs exhibit cardiovascular risks due to the inhibition of prostanoids critical for normal physiologic functions, such as COX-2-derived prostacyclin (PGI2) [18, 19]. 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
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