Inhaled NO as a viable antiadhesive therapy for ischemia/reperfusion injury of distal microvascular beds.
Open accessAbstract
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.
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Complex I inhibition appears to occur through S-nitrosylation of cysteine thiol residues.
“Complex I inhibition appears to occur through S-nitrosylation of cysteine thiol residues, although the exact details still need to be elucidated.152,153”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [153]
The Introduction and Discussion describe nitric oxide binding to protein thiols, including a cysteine residue in hemoglobin, as a possible way to transport NO to peripheral tissues. Searches for Complex I inhibition and mitochondrial respiratory Complex I found no passage connecting that process to S-nitrosylation. The copy therefore does not address the claim’s central point. (LLM, conf=0.76)
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Research works printed but not linked: 3
- Kubes, P., M. Suzuki, and D.N. Granger. 1991. Nitric oxide: an endoge- nous modulator of leukocyte adhesion. Proc. Natl. Acad. Sci. USA. 88:4651- 4655.
- Stamler, J.S., D.I. Simon, J.A. Osborne, M.E. Mullins, O. Jaraki, D.J. Singel, and J. Loscalzo. 1992. S-nitrosylation of proteins by nitric oxide: synthe- sis and characterization of novel biologically active compounds. Proc. Natl. Acad. Sci. USA. 89:444-448.
- Weber, C., and T.A. Springer. 1997. Neutrophil accumulation on acti- vated, surface-adherent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound to alphaIIbbeta3 and stimulated by platelet-activating factor. J. Clin. Invest. 100:2085-2093.
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- Authors
- Fox-Robichaud, A., Payne, D., Hasan, S. U., Ostrovsky, L., Fairhead, T., Reinhardt, P., & Kubes, P.
- Affiliations
- University of Calgary (CA)
- Corresponding author
- Kubes, P
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 1998-06-01
- Volume
- 101
- Issue
- 11
- Pages
- 2497-2505
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508839
- OpenAlex
- W1986005376
- Cited by
- 227
- References
- 0
- Citations by year
- 2026: 1 · 2024: 8 · 2023: 2 · 2022: 7 · 2021: 2 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 9 · 2014: 9 · 2013: 5 · 2012: 11
- FWCI
- 10.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Fondation pour la Recherche Médicale
- Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Keywords
- inhaled nitric oxide, ischemia-reperfusion injury, leukocyte adhesion, leukocyte rolling, endothelial dysfunction, microvascular blood flow, P-selectin, CD18, endotoxemia, mesentery, leukocyte recruitment, vasoconstriction, nitric oxide synthase inhibition
- MeSH terms
- Administration, Inhalation, Animals, Cats, Cell Adhesion, Cell Communication, Endothelium, Vascular, Hemodynamics, Ischemia, Leukocytes, Microcirculation, Nitric Oxide, Reperfusion Injury
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