Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10.
Interleukin (IL)-10 is an anti-inflammatory cytokine implicated in the regulation of airway inflammation in asthma. Among other activities, IL-10 suppresses production of nitric oxide (NO); consequently, its absence may permit increased NO production, which can affect airway smooth muscle contractility. Therefore, we investigated airway reactivity (AR) in response to methacholine (MCh) in IL-10 knockout (-/-) mice compared with wild-type C57BL/6 (C57) mice, in which airway NO production was measured as exhaled NO (E(NO)), and NO production was altered with administration of either NO synthase (NOS)-specific inhibitors or recombinant murine (rm)IL-10. AR, measured as enhanced pause in vivo, and tracheal ring tension in vitro were lower in IL-10(-/-) mice by 25-50%, which was associated with elevated E(NO) levels (13 vs. 7 ppb). Administration of NOS inhibitors N(G)-nitro-L-arginine methyl ester (8 mg/kg ip) or L-N(6)-(1-iminoethyl)-lysine (3 mg/kg ip) to IL-10(-/-) mice decreased E(NO) by an average of 50%, which was associated with increased AR, to levels similar to C57 mice. E(NO) in IL-10(-/-) mice decreased in a dose-dependent fashion in response to administered rmIL-10, to levels similar to C57 mice (7 ppb), which was associated with a 30% increment in AR. Thus increased NO production in the absence of IL-10, decreased AR, which was reversed with inhibition of NO, either by inhibition of NOS, or with reconstitution of IL-10. These findings suggest that airway NO production can modulate airway smooth muscle contractility, resulting in airway hyporesponsiveness when IL-10 is absent.
Ameredes
Bill T
BT
Asthma, Allergy, and Airway Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. ameredesbt@upmc.edu
Sethi
Jigme M
JM
Liu
He-Liang
HL
Choi
Augustine M K
AM
Calhoun
William J
WJ
D000818:Animals; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics* / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors
D016085:Bronchoconstrictor Agents; D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D016210:Methacholine Chloride; D016753:Interleukin-10; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D008239:Lysine