Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion

J Clin Invest. 1999 Aug;104(3):309-16. doi: 10.1172/JCI7016.


Polymorphonuclear neutrophil (PMN) activation is pivotal in acute inflammation and injury from reperfusion. To elucidate components controlling PMNs in vivo, we prepared novel transgenic mice with the human leukotriene (LT) B4 receptor (BLTR) for functional characterization. Overexpression of BLTR in leukocytes dramatically increased PMN trafficking to skin microabscesses and lungs after ischemia-reperfusion, whereas mice deficient in 5-lipoxygenase (5-LO) showed diminished PMN accumulation in reperfused lungs. Hence, both BLTR expression and LT biosynthesis are critical for PMN infiltration in reperfusion-initiated second-organ injury. Also, in BLTR transgenic mice, 5-LO expression and product formation were selectively increased in exudates, demonstrating that receptor overexpression amplifies proinflammatory circuits. Endogenous lipoxin (LX) A4 was produced in ischemic lungs and elevated by reperfusion. Because LXA4 and aspirin-triggered 15-epimeric LXA4 (ATL) selectively regulate leukocyte responses, they were tested in BLTR transgenic mice. Despite excessive PMN recruitment in BLTR transgenic mice, intravenous injection of ATL sharply diminished reperfusion-initiated PMN trafficking to remote organs, and topical application of LX was protective in acute dermal inflammation. These results demonstrate a direct role for BLTR with positive feedback, involving BLTR and 5-LO signaling in controlling PMNs. Moreover, LXA4 and ATL counter BLTR-amplified networks, revealing a novel protective role for LX and ATL in stress responses that has applications in perioperative medicine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / deficiency
  • Arachidonate 5-Lipoxygenase / genetics
  • Aspirin / pharmacology*
  • Cell Line
  • Cell Movement
  • Crosses, Genetic
  • Ear, External
  • Exudates and Transudates
  • Female
  • HL-60 Cells
  • Hindlimb
  • Humans
  • Hydroxyeicosatetraenoic Acids / biosynthesis
  • Hydroxyeicosatetraenoic Acids / physiology*
  • Lipoxins*
  • Male
  • Mice
  • Mice, Transgenic
  • Neutrophils / pathology
  • Peritonitis / metabolism
  • Peritonitis / pathology
  • RNA, Messenger / biosynthesis
  • Receptors, Cell Surface / physiology*
  • Receptors, Formyl Peptide*
  • Receptors, Leukotriene B4 / biosynthesis
  • Receptors, Leukotriene B4 / genetics*
  • Receptors, Leukotriene B4 / physiology
  • Receptors, Lipoxin*
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology


  • FPR2 protein, human
  • Hydroxyeicosatetraenoic Acids
  • Lipoxins
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Formyl Peptide
  • Receptors, Leukotriene B4
  • Receptors, Lipoxin
  • lipoxin A4
  • Arachidonate 5-Lipoxygenase
  • Aspirin