Lipoxin a(4) attenuates microvascular fluid leak during inflammation.
BACKGROUND
The release of proinflammatory cytokines during inflammation disturbs the endothelial barrier and can initiate significant intravascular volume loss. Proinflammatory cytokines also induce the expression of anti-inflammatory mediators, such as lipoxin, which promote the resolution of inflammation. Our hypothesis is that lipoxin A(4) (LXA(4)) reverses the increased microvascular fluid leak observed during inflammatory conditions.


METHODS
Microvascular fluid leak (L(p)) was measured in rat mesenteric venules using a micro-cannulation technique. L(p) was measured under the following conditions: (1) LXA(4) (100 nM) alone (n = 5), (2) LXA(4) (100 nM) administered after endothelial hyperpermeability induced by a continuous perfusion of 10 nM platelet activating factor (PAF) (n = 5), (3) LXA(4) (100 nM) perfused after inflammation induced by a systemic bolus of 10 mg/kg lipopolysaccharide (LPS) (n = 5), and (4) LXA(4) (100 nM) perfused after LPS-induced inflammation during inhibition of c-Jun N-terminal kinase (n = 4).


RESULTS
LXA(4) alone slightly increased L(p) from baseline (L(p)-baseline = 1.05 +/- 0.03, L(p)-LXA(4) = 1.55 +/- 0.04; P < 0.0001). PAF increased L(p) 4-fold (L(p)-baseline = 1.20 +/- 0.10, L(p)-PAF = 4.49 +/- 0.95; P < 0.0001). LXA(4) administration after PAF decreased L(p) 66% versus PAF alone (from 4.49 +/- 0.95 to 1.54 +/- 0.13; P = 0.0004). LPS-induced inflammation increased L(p) over 2-fold (L(p)-baseline = 1.05 +/- 0.03, L(p)-LPS = 2.27 +/- 0.13; P < 0.0001). LXA(4) administration after LPS decreased L(p) 42% versus LPS alone (from 2.27 +/- 0.13 to 1.31 +/- 0.05; P < 0.0001). The effect of c-Jun N-terminal kinase inhibition during LPS-induced inflammation attenuated the decrease in leak cause by LXA(4) by 51% (P = 0.0002).


CONCLUSIONS
After either LPS or PAF, LXA(4) attenuated the intravascular volume loss caused by these inflammatory mediators. The activity of LXA(4) may be partly mediated by the c-Jun N-terminal kinase signaling pathway. These data support an anti-inflammatory role for LXA(4) and suggests a potential pharmacologic role for LXA(4) during inflammation.
Ereso
Alexander Q
AQ
Department of Surgery, UCSF-East Bay, Alameda County Medical Center, Oakland, California 94602, USA.
Cureton
Elizabeth L
EL
Cripps
Michael W
MW
Sadjadi
Javid
J
Dua
Monica M
MM
Curran
Brian
B
Victorino
Gregory P
GP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001826:Body Fluids; D002199:Capillary Permeability / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D007249:Inflammation / Q000503:physiopathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D044045:Lipoxins / Q000494:pharmacology*; D008833:Microcirculation / Q000187:drug effects*; D023421:Models, Animal; D010972:Platelet Activating Factor / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D044045:Lipoxins; D010972:Platelet Activating Factor; C040527:lipoxin A4; D048031:JNK Mitogen-Activated Protein Kinases