Endogenous antimicrobial peptide LL-37 induces human vasodilatation.
BACKGROUND
Septic shock includes blood vessel dilatation and activation of innate immunity, which in turn causes release of antimicrobial peptides such as LL-37. It has been shown that LL-37 can attract leucocytes via the lipoxin A(4) receptor (ALX, FPRL1). ALX is also present in vascular endothelial cells. To explore possible ways of pharmacological intervention in septic shock, we investigated if LL-37 can affect vascular tone.


METHODS
Human omental arteries and veins were obtained during abdominal surgery, and circular smooth muscle activity was studied in organ baths. Gene expression was studied using reverse transcriptase-polymerase chain reaction.


RESULTS
LL-37, at micromolar concentrations, induced a concentration- and endothelium-dependent relaxation in vein but not in artery segments precontracted by endothelin-1. The relaxation was profoundly reduced by potassium chloride (30 mM) to inhibit endothelium-derived hyperpolarizing factor (EDHF), whereas it was less affected by the NOS inhibitor, l-N(G)-nitroarginine methyl ester, and not at all by indomethacin. The ALX agonist, WKYMVm, also induced a relaxation and both the relaxations induced by LL-37 and WKYMVm were inhibited by the ALX antagonist, WRWWWW. ALX was expressed in the vein endothelium.


CONCLUSIONS
We demonstrate, for the first time, that the human antimicrobial peptide, LL-37, induces endothelium-dependent relaxation in human omental veins mediated via an effect on endothelial ALX. The relaxation involves the release of nitric oxide and EDHF but not prostanoids. LL-37 released from white blood cells could contribute to blood vessel dilatation during sepsis and treatment with ALX antagonists might be successful.
Berkestedt
I
I
Section of Anaesthesiology and Intensive Care, Department of Clinical Sciences, Lund University, SE-221 85 Lund, Sweden.
Nelson
A
A
Bodelsson
M
M
D048868:Adaptor Proteins, Signal Transducing / Q000819:agonists / Q000378:metabolism / Q000502:physiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology* / Q000502:physiology; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D054804:Cathelicidins; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014680:Veins / Q000187:drug effects / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D019332:Endothelin-1; C442142:HSH2D protein, human; D014662:Vasoconstrictor Agents