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

N Chiang, K Gronert, CB Clish… - The Journal of …, 1999 - Am Soc Clin Investig
N Chiang, K Gronert, CB Clish, JA O'Brien, MW Freeman, CN Serhan
The Journal of clinical investigation, 1999Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation