title: Inhaled NO as a viable antiadhesive therapy for ischemia/reperfusion injury of distal microvascular beds.
abstract: Inhaled nitric oxide (NO) is being used more and more in intensive care units as a modality to improve the outcome of patients with pulmonary complications. Our objective was to demonstrate that inhaled NO could impact upon a distally inflamed microvasculature-improving perfusion, leukocyte adhesive interactions, and endothelial dysfunction. Using intravital microscopy to visualize ischemia/reperfusion of postcapillary venules, we were able to demonstrate that the reduction in perfusion, the dramatic increase in leukocyte rolling, adhesion, and emigration, and the endothelial dysfunction could all be significantly abrogated with 80 ppm, but not 20 ppm inhaled NO. Perfusing whole blood directly over an inert P-selectin and CD18 ligand substratum incorporated in a flow chamber recruited the same number of rolling and adhering leukocytes from NO-ventilated and non-NO-ventilated animals, suggesting that inhaled NO was not directly affecting leukocytes. To demonstrate that inhaled NO was actually reaching the peripheral microvasculature in vivo, we applied a NO synthase inhibitor locally to the feline mesentery and demonstrated that the vasoconstriction, as well as leukocyte recruitment, were essentially abolished by inhaled NO, suggesting that a NO-depleted peripheral microvasculature could be replenished with inhaled NO in vivo. Finally, inhaled NO at the same concentration that was effective in ischemia/reperfusion did not affect vascular alterations, leukocyte recruitment, and endothelial dysfunction associated with endotoxemia in the feline mesentery. In conclusion, our data for the first time demonstrate a role for inhaled NO as a therapeutic delivery system to the peripheral microvasculature, showing tremendous efficacy as an antiadhesive, antivasoconstrictive, and antipermeabilizing molecule in NO-depleted tissues, but not normal microvessels or vessels that have an abundance of NO (LPS-treated). The notion that blood borne molecules have NO carrying capacity is conceptually consistent with our observations.
authors.affiliation: Immunology Research Group, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Fox-Robichaud
authors.forename: D
authors.initials: D
authors.lastname: Payne
authors.forename: S U
authors.initials: SU
authors.lastname: Hasan
authors.forename: L
authors.initials: L
authors.lastname: Ostrovsky
authors.forename: T
authors.initials: T
authors.lastname: Fairhead
authors.forename: P
authors.initials: P
authors.lastname: Reinhardt
authors.forename: P
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007511:Ischemia / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects*; D008833:Microcirculation / Q000187:drug effects*; D009569:Nitric Oxide / Q000008:administration & dosage*; D015427:Reperfusion Injury / Q000188:drug therapy*
chemical_list: D009569:Nitric Oxide