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Blood, 15 May 2008, Vol. 111, No. 10, pp. 5187-5194.
Prepublished online as a Blood First Edition Paper on February 15, 2008; DOI 10.1182/blood-2007-10-117283.
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PHAGOCYTES
Circulating neutrophils maintain physiological blood pressure by suppressing bacteria and IFN -dependent iNOS expression in the vasculature of healthy mice
Jonathan Morton1,
Barbara Coles1,
Kate Wright1,
Awen Gallimore1,
Jason D. Morrow2,
Erin S. Terry2,
Peter B. Anning1,
B. Paul Morgan1,
Vincent Dioszeghy1,
Hartmut Kühn3,
Pavlos Chaitidis3,
Adrian J. Hobbs4,
Simon A. Jones1, and
Valerie B. O'Donnell1
1 Department of Medical Biochemistry & Immunology, Cardiff University, Cardiff, United Kingdom;
2 Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN;
3 Institute of Biochemistry, University Medicine Berlin-Charité, Berlin, Germany; and
4 Wolfson Institute for Biomedical Research, University College London, London, United Kingdom
Whether leukocytes exert an influence on vascular function in vivo is not known. Here, genetic and pharmacologic approaches show that the absence of neutrophils leads to acute blood pressure dysregulation. Following neutrophil depletion, systolic blood pressure falls significantly over 3 days (88.0 ± 3.5 vs 104.0 ± 2.8 mm Hg, day 3 vs day 0, mean ± SEM, P < .001), and aortic rings from neutropenic mice do not constrict properly. The constriction defect is corrected using L-nitroarginine-methyl ester (L-NAME) or the specific inducible nitric oxide synthase (iNOS) inhibitor 1400W, while acetylcholine relaxation is normal. iNOS- or IFN -deficient mice are protected from neutropenia-induced hypotension, indicating that iNOS-derived nitric oxide (NO) is responsible and that its induction involves IFN. Oral enrofloxacin partially inhibited hypotension, implicating bacterial products. Roles for cyclooxygenase, complement C5, or endotoxin were excluded, although urinary prostacyclin metabolites were elevated. Neutrophil depletion required complement opsinization, with no evidence for intravascular degranulation. In summary, circulating neutrophils contribute to maintaining physiological tone in the vasculature, at least in part through suppressing early proinflammatory effects of infection. The speed with which hypotension developed provides insight into early changes that occur in the absence of neutrophils and illustrates the importance of constant surveillance of mucosal sites by granulocytes in healthy mice.
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Related Article in Blood Online:
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Blood pressure regulation: role for neutrophils?
- Volker Rudolph, Tanja K. Rudolph, and Bruce A. Freeman
Blood 2008 111: 4840.
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