Avani Dave, Jai Hind College
Excessive inflammation and disruption of the alveolar-capillary barrier result in lung edema and decreased gas exchange in acute lung injury (ALI), a frequent consequence of sepsis. ALI continues to be a major cause of morbidity and death in critically sick patients, emphasizing the need for new treatment approaches.
Due to its affinity for four PGE2 receptor subtypes, PGE2 receptors 1–4, prostaglandin E2 (PGE2) is implicated in a variety of biological processes, including pain, fever, inflammation, angiogenesis, and cancer. The cyclooxygenase (COX) pathway produces PGE2 from arachidonic acid, with PGE synthases (PGES) catalyzing the final step.
PGES is divided into three types:
- cytosolic PGES (cPGES),
- microsomal PGES 1 (mPGES)-1, and
- microsomal PGES 2 (mPGES-2).
Proinflammatory stimuli such as interleukin-1β (IL-1β), lipopolysaccharide (LPS), and tissue damage substantially up-regulate mPGES-1 expression under normal physiological circumstances. cPGES and mPGES-2 are expressed constitutively. mPGES-1 was found to be responsible for increased PGE2 synthesis and therefore a major amplifier of acute inflammatory processes in mPGES-1 knockout mice.
COX-2 inhibition is how nonsteroidal anti-inflammatory medications (NSAIDs) reduce pain and inflammation. NSAIDs, on the other hand, have cardiovascular hazards because they block prostanoids that are important for normal physiologic activities, such as COX-2-derived prostacyclin (PGI2). Inhibition of mPGES-1, on the other hand, inhibits solely the mPGES-1-derived PGE2 production, making mPGES-1 a viable new therapeutic target with decreased cardiovascular risk.
A recent study conducted by Gurusamy, M., et al. investigated the implications of BI1029539 (GS-248), a novel selective inhibitor of mammalian microsomal prostaglandin E synthase-1, (mPGES-1).
The course of the study:
The results received from the study were further parted into 2 distinct series to enable relative understanding.
Series 1: BI1029539 or celecoxib has reduced LPS-induced lung injury in mice as compared to vehicle-treated mice, with the relatively low neutrophil influx, protein isolate, TNF-, IL-1, and PGE2 concentrations in bronchoalveolar lavage (BAL), myeloperoxidase stimulation, expression of mPGES-1, COX-2, and intracellular adhesion molecule in lung cells.
Series 2: Sepsis-induced BAL inflammatory cell recruitment, lung damage score, and lung expression of mPGES-1 and inducible nitric oxide synthase were all decreased by BI1029539. Treatment with BI1029539 extended the lives of mice suffering from severe sepsis. The anti-inflammatory and anti-migratory effects of BI1029539 were verified in healthy individuals’ peripheral blood leukocytes.
The future prospects of the study:
The findings established that mPGES-1 is a crucial enzyme that produces PGE2 downstream of COX-2, however, it is not involved in the production of PGI2. The researchers further demonstrated that inhibiting mPGES-1 with BI1029539 reduces endotoxin and sepsis-induced lung damage, as well as improving survival after severe polymicrobial sepsis. Without altering PGI2 levels, this protective effect was found. As a result, mPGES-1 inhibitors have a COX-2 inhibitor-like effectiveness profile while avoiding the unfavourable cardiovascular effects associated with COX-2 inhibitors.
The study delineated that mPGES-1 might be a promising therapeutic target for ALI and sepsis-related lung damage, with a possible therapeutic benefit over selective COX-2 inhibitors. However, more research in this avenue is needed for a complete comprehension of the underlying mechanism.
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References: Gurusamy, M., Nasseri, S., Rampa, D. R., Feng, H., Lee, D., Pekcec, A., Doods, H., & Wu, D. (2021). Inhibition of microsomal prostaglandin E synthase-1 ameliorates acute lung injury in mice. Journal of Translational Medicine, 19(1), 340. https://doi.org/10.1186/s12967-021-03016-9
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Author’s Info:
Avani Dave is currently in the final year of her bachelor’s degree, majoring in Life Sciences. Holding a good academic and extra-curricular record, she is on a constant journey of acquiring exposure in her field of interest while simultaneously not limiting herself to just that. Avani likes studying Diseases and Syndromes and everything under this umbrella! That being said, she is adept at working across departments and promises to deliver.
LinkedIn – https://www.linkedin.com/avani-dave/
Publications in BioXone:
- Dave, A. (2021). Hirschsprung disease patients show novel gene revelations! BioXone. https://bioxone.in/news/worldnews/hirschsprung-disease-patients-show-novel-gene-revelations/
- Dave, A. (2021). Are children of heavy drinkers more exposed to adversities? BioXone. https://bioxone.in/news/worldnews/are-children-of-heavy-drinkers-more-exposed-to-adversities/
- Dave, A. (2021). HEI10: How do sex cells receive the right genetic mix? BioXone. https://bioxone.in/news/worldnews/hei10-how-do-sex-cells-receive-the-right-genetic-mix/
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