| Systemic Microvascular Dysfunction and Inflammation after Pulmonary Particulate Matter Exposure Timothy R. Nurkiewicz,1,2 Dale W. Porter,1,3 Mark Barger,3 Lyndell Millecchia,3 K. Murali K. Rao,3 Paul J. Marvar,1,2 Ann F. Hubbs,3 Vincent Castranova,1,3 and Matthew A. Boegehold1,2 1Department of Physiology and Pharmacology, and 2Center for Interdisciplinary Research in Cardiovascular Sciences, West Virginia University School of Medicine, Morgantown, West Virginia, USA; 3Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA Abstract
The epidemiologic association between pulmonary exposure to ambient particulate matter (PM) and cardiovascular dysfunction is well known, but the systemic mechanisms that drive this effect remain unclear. We have previously shown that acute pulmonary exposure to PM impairs or abolishes endothelium-dependent arteriolar dilation in the rat spinotrapezius muscle. The purpose of this study was to further characterize the effect of pulmonary PM exposure on systemic microvascular function and to identify local inflammatory events that may contribute to these effects. Rats were intratracheally instilled with residual oil fly ash (ROFA) or titanium dioxide at 0.1 or 0.25 mg/rat 24 hr before measurement of pulmonary and systemic microvascular responses. In vivo microscopy of the spinotrapezius muscle was used to study systemic arteriolar responses to intraluminal infusion of the Ca2+ ionophore A23187 or iontophoretic abluminal application of the adrenergic agonist phenylephrine (PHE) . Leukocyte rolling and adhesion were quantified in venules paired with the studied arterioles. Histologic techniques were used to assess pulmonary inflammation, characterize the adherence of leukocytes to systemic venules, verify the presence of myeloperoxidase (MPO) in the systemic microvascular wall, and quantify systemic microvascular oxidative stress. In the lungs of rats exposed to ROFA or TiO2, changes in some bronchoalveolar lavage markers of inflammation were noted, but an indication of cellular damage was not found. In rats exposed to 0.1 mg ROFA, focal alveolitis was evident, particularly at sites of particle deposition. Exposure to either ROFA or TiO2 caused a dose-dependent impairment of endothelium-dependent arteriolar dilation. However, exposure to these particles did not affect microvascular constriction in response to PHE. ROFA and TiO2 exposure significantly increased leukocyte rolling and adhesion in paired venules, and these cells were positively identified as polymorphonuclear leukocytes (PMNLs) . In ROFA- and TiO2-exposed rats, MPO was found in PMNLs adhering to the systemic microvascular wall. Evidence suggests that some of this MPO had been deposited in the microvascular wall. There was also evidence for oxidative stress in the microvascular wall. These results indicate that after PM exposure, the impairment of endothelium-dependent dilation in the systemic microcirculation coincides with PMNL adhesion, MPO deposition, and local oxidative stress. Collectively, these microvascular observations are consistent with events that contribute to the disruption of the control of peripheral resistance and/or cardiac dysfunction associated with PM exposure. Key words: arteriole, endothelium, microcirculation, myeloperoxidase, oxidative stress, particulate matter, polymorphonuclear leukocyte, systemic, venule. Environ Health Perspect 114:412-419 (2006) . doi:10.1289/ehp.8413 available via http://dx.doi.org/ [Online 13 October 2005]
Address correspondence to T.R. Nurkiewicz, Department of Physiology and Pharmacology, Box 9229, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506-9229 USA. Telephone: (304) 293-7328. Fax: (304) 293-5513. E-mail: tnurkiewicz@hsc.wvu.edu We thank K. Wix for her expert technical assistance in this study. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health. This work was supported by the National Institutes of Health (Research Service Award HL-67562 to T.R.N. and RO1 HL-44012 to M.A.B.) . The authors declare they have no competing financial interests. Received 20 June 2005 ; accepted 12 October 2005.
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