Polymorphonuclear neutrophil (PMN) activation is pivotal in acute inflammat
ion and injury from reperfusion. To elucidate components controlling PMNs i
n vivo, we prepared novel transgenic mice with the human leukotriene (LT) B
-4 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-lipoxyge
nase (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 exuda
tes, demonstrating that receptor overexpression amplifies proinflammatory c
ircuits. Endogenous lipoxin (LX) A(4) was produced in ischemic lungs and el
evated by reperfusion. Because LXA(4) and aspirin-triggered 15-epimeric LXA
4 (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 B
LTR with positive feedback, involving BLTR and 5-LO signaling in controllin
g PMNs. Moreover, LXA(4) and ATL counter BLTR-amplified networks, revealing
a novel protective role for LX and ATL in stress responses that has applic
ations in perioperative medicine.