Leukotriene B-4 receptor transgenic mice reveal novel protective roles forlipoxins and aspirin-triggered lipoxins in reperfusion

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.