Cyclooxygenase Inhibition in Sepsis: Is There Life after Death?

Abstract

Prostaglandins are important mediators and modulators of the inflammatory response to infection. The prostaglandins participate in the pathogenesis of hemodynamic collapse, organ failure, and overwhelming inflammation that characterize severe sepsis and shock. In light of this, cyclooxygenase (COX) inhibiting pharmacological agents have been extensively studied for their capacity to ameliorate the aberrant physiological and immune responses during severe sepsis. Animal models of sepsis, using the systemic administration of pathogen-associated molecular patterns (PAMPs) or live pathogens, have been used to examine the effectiveness of COX inhibition as a treatment for severe sepsis. These studies have largely shown beneficial effects on mortality. However, human studies have failed to show clinical utility of COX inhibitor treatment in severely septic patients. Why this approach “worked” in animals but not in humans might reflect differences in the controlled nature of animal investigations compared to human studies. This paper contrasts the impact of COX inhibitors on mortality in animal models of sepsis and human studies of sepsis and examines potential reasons for differences between these two settings.

Proresolving Lipid Mediators and Mechanisms in the Resolution of Acute Inflammation

“…Abandoned for over 15 years primarily due to one null randomized-controlled trial (Bernard et al, 1997), the concept of COX-inhibition and hence lipid mediator manipulation in severe inflammatory states is re-gaining traction (Aronoff, 2012; Eisen, 2012). A key factor in this has been the recent publication of multiple observational data sets relating predominantly aspirin and statin administration, but also non-steroidal anti-inflammatory agents (NSAIDs), to clinical benefit.…”

PGE2 suppression of innate immunity during mucosal bacterial infection

“…The phagocytic properties of alveolar macrophages are inhibited in an EP2-dependent manner during infection with Klebsiella pneumoniae and S. pneumoniae in the rat and mouse models, respectively. Phagocytosis is restored through the inhibition of PGE 2 synthesis with non-selective COX inhibitors such as indomethacin (Aronoff et al, 2004; Aronoff, 2012). The phagocytic properties of macrophages are dampened by PGE 2 through the induction of immunosuppressive IL-1R-associated kinase-M (IRAK-M), impairing bacterial clearance of P. aeruginosa (Hubbard et al, 2010).…”

Prostaglandin E 2 constrains systemic inflammation through an innate lymphoid cell–IL-22 axis

“…NSAID therapy is also thought to confer similar beneficial effects in treating severe inflammation, but large randomized controlled clinical trials have found that NSAIDs failed to reduce mortality in severe systemic inflammation (7,8). More importantly, NSAIDs use during evolving bacterial infection is associated with more severe critical illness (9–13). Therefore there is an imperative to define the paradoxical regulatory role of PGs in systemic inflammation (14).…”