Lipid mediator class switching during acute inflammation: signals in resolution

Abstract

Leukotrienes (LTs) and prostaglandins (PGs) amplify acute inflammation, whereas lipoxins (LXs) have unique anti-inflammatory actions. Temporal analyses of these eicosanoids in clinical and experimental exudates showed early coordinate appearance of LT and PG with polymorphonuclear neutrophil (PMN) recruitment. This was followed by LX biosynthesis, which was concurrent with spontaneous resolution. Human peripheral blood PMNs exposed to PGE2 (as in exudates) switched eicosanoid biosynthesis from predominantly LTB4 and 5-lipoxygenase (5-LO)-initiated pathways to LXA4, a 15-LO product that "stopped" PMN infiltration. These results indicate that first-phase eicosanoids promote a shift to anti-inflammatory lipids: functionally distinct lipid-mediator profiles switch during acute exudate formation to "reprogram" the exudate PMNs to promote resolution.

Conditional Expression of 15-Lipoxygenase-1 Inhibits the Selenoenzyme Thioredoxin Reductase

“…One prevalent hypothesis asserts that autocoids from the 15-LOX-1 pathway antagonize the actions of pro-inflammatory autocoids from the 5-LOX pathway, and thereby facilitate the resolution of inflammation (19). Our results provide another molecular mechanism consistent with this hypothesis.…”

“…In contrast to 15-LOX-1, expression of 5-LOX enzyme did not inhibit TrxR. These findings support the concept that molecular interactions between 15-LOX-1 and TrxR, a vital selenoenzyme, might be relevant to carcinogenesis (17,18) and inflammation (19,20).…”

“…15-LOX-1 also has anti-inflammatory effects (19,51,52). One prevalent hypothesis asserts that autocoids from the 15-LOX-1 pathway antagonize the actions of pro-inflammatory autocoids from the 5-LOX pathway, and thereby facilitate the resolution of inflammation (19).…”

Success of prostaglandin E 2 in structure–function is a challenge for structure-based therapeutics

“…15-epi-lipoxins, and resolvins (29)(30)(31). In the absence of mPGES-1, paw edema formation and leukocyte accumulation are reduced in delayed-type hypersensitivity.…”

“…Antibodies against type II collagen were detected in both control and the mPGES1-deficient mice, but the titers were decreased in mPGES1-deficient animals. Although profound immunosuppression was not present, PGE 2 displays pivotal regulatory actions on innate and adaptive immune effector cells (9,30). Toll 4 activation regulates PGE 2 formation by mPGES1 (25), and, hence, further study is needed to determine whether decrements in its formation in mPGES1-deficient mice may ultimately lead to adverse effects in the host's capacity to resolve acute inflammation or respond to infectious agents.…”