Targeting eicosanoid pathways in the development of novel anti-influenza drugs

Abstract

The constant new emergence of life-threatening human respiratory viral pathogens presents new challenges to clinicians who are left with no available therapeutic interventions. Highly pathogenic strains of influenza A virus (IAV) share an enhanced capacity to propagate to the lower airways and paralyze alveolar macrophage antiviral capacity in order to replicate efficiently and cause pathologic inflammation. Following a century of using NSAIDs for the management of influenza symptoms, a number of studies have interrogated their function in the host response to IAV infection. We herein provide an overview of these studies as well as further insight of how pathogenic IAV hijacks the microsomal prostaglandin E synthase-1-dependent prostaglandin E2 pathway in order to evade host type I interferon-mediated antiviral immunity. We also reflect on the potential beneficial action of microsomal prostaglandin E synthase-1 inhibitory compounds in the treatment of IAV infections and potentially other RNA viruses.

Monocytic Myeloid-Derived Suppressor Cells in Chronic Infections

“…In addition, PGE2 positively regulates enzymatic pathways critical for the suppressive function of the MDSC, including iNOS, IDO1, and IL-10. COX2 crosstalks with the IL-1/IL-1R pathway, as well as with IFN I pathway, which has been revealed in TB and flu ( 82 , 83 ). The positive cross-regulation between COX2 and IL-1 may affect M-MDSC genesis.…”

Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE

“…ALOX15 generates 12-HETE, 15-HETE and specialized pro-resolving mediators such as lipoxin A 4 , while the cyclooxygenase pathway produces prostaglandins, including PGE 2 12 . While eicosanoid metabolites are produced in the lung at homeostasis 18 and control macrophage-mediated host defense against pathogens 13,19,20 , little is known about their contribution to lung alveolarization. In the current study, we demonstrated the critical role of the ALOX15 pathway in neutrophil-dependent AM programming in the developing lung.…”

COVID-19: Integrating the Complexity of Systemic and Pulmonary Immunopathology to Identify Biomarkers for Different Outcomes

“…In this context, the role of PGE 2 in viral infection has been documented (163). In influenza A virus infection, it was described that the augment of PGE 2 secretion inhibits type I interferon release, macrophage apoptosis, antigen presentation and T cell mediated immunity, with consequent increase in virus burden (164). Using genetic and pharmacological tools to inhibit PGE 2 production, it was shown an increase in the survival of lethally virus-infected mice, and PGE 2 inhibition was suggested as a treatment for influenza A infection (164).…”

“…In influenza A virus infection, it was described that the augment of PGE 2 secretion inhibits type I interferon release, macrophage apoptosis, antigen presentation and T cell mediated immunity, with consequent increase in virus burden (164). Using genetic and pharmacological tools to inhibit PGE 2 production, it was shown an increase in the survival of lethally virus-infected mice, and PGE 2 inhibition was suggested as a treatment for influenza A infection (164). More recently, in H1N1 infected obese mice, an immune suppressive role of PGE 2 was also reported, and the investigators suggested the treatment with paracetamol to restore cytokine production and to rescue lethally H1N1 infected mice from death (165).…”