Leukotriene D4 and prostaglandin E2 synergism in inflammation and asthma

Abstract

Mast cells (MCs) are effector cells in asthma and their activation causes secretion of cysteinyl leukotrienes (cys‐LTs) and prostaglandins (PGs). MCs not only secrete these mediators, but they also possess receptors for them, to perceive their signals. Cys‐LTs are potent bronchoconstrictors, powerful inducers of vascular leakage, potentiators of airway hyper‐responsiveness and play an important role in asthma and other inflammatory disorders. On the other hand, Prostaglandin E2 (PGE2) function in the field of asthma is controversial acting both as pro and anti‐inflammatory, depending mainly on the receptor/s through which PGE2 exerts its effect. Our results indicate that cys‐LTs together with PGE2 synergistically potentiated vascular inflammation through their action on MCs (enhanced calcium flux, c‐Fos, COX‐2, PGD2 and Macrophage Inflammatory Protein‐1b (MIP‐1b; CCL4) generation). Interestingly, LTD4‐PGE2 synergism is blocked only by combined treatment of CysLT1R antagonist (MK571/singulair) and EP3 antagonist (L‐798), suggesting the need for a combination of CysLT1R antagonists and EP3 blockers to treat inflammation in asthma. Furthermore, LTD4+PGE2 synergism also potentiates pulmonary inflammation in D. farinae‐induced airway remodeling during asthma in vivo (recruitment of immune cells, goblet cell metaplasia, up‐regulation of inflammatory transcripts). Our data suggests that LTD4 has a potential to switch PGE2 signals from EP2/Gs/cAMP/PKA pathway to EP3/Gi/cGMP/PKG axis, generating pro‐inflammatory signals and MC activation via PPARƔ, COX‐2 and PGD2. Our studies carry substantial pathogenic and therapeutic implications for asthma and allergic diseases, and provide the basis for development and translation of future therapeutic molecules to target inflammation.Support or Funding InformationThis work is supported by NIH R15 grant (1R15HL133918), and James Foght Assistant Professor support.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.