Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through distinct mechanisms

G. R.Scott Budinger, Joanne L. McKell, Daniela Urich, Nancy Foiles, Ivy Weiss, Sergio E. Chiarella, Angel Gonzalez, Saul Soberanes, Andrew J. Ghio, Recep Nigdelioglu, Ece A. Mutlu, Kathryn A. Radigan, David Green, Hau C. Kwaan, Gökhan M. Mutlu

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69 Scopus citations

Abstract

Background: Exposure of human populations to ambient particulate matter (PM) air pollution significantly contributes to the mortality attributable to ischemic cardiovascular events. We reported that mice treated with intratracheally instilled PM develop a prothrombotic state that requires the release of IL-6 by alveolar macrophages. We sought to determine whether exposure of mice to PM increases the levels of PAI-1, a major regulator of thrombolysis, via a similar or distinct mechanism. Methods and Principal Findings: Adult, male C57BL/6 and IL-6 knock out (IL-6-/-) mice were exposed to either concentrated ambient PM less than 2.5 μm (CAPs) or filtered air 8 hours daily for 3 days or were exposed to either urban particulate matter or PBS via intratracheal instillation and examined 24 hours later. Exposure to CAPs or urban PM resulted in the IL-6 dependent activation of coagulation in the lung and systemically. PAI-1 mRNA and protein levels were higher in the lung and adipose tissue of mice treated with CAPs or PM compared with filtered air or PBS controls. The increase in PAI-1 was similar in wild-type and IL-6-/- mice but was absent in mice treated with etanercept, a TNF-α inhibitor. Treatment with etanercept did not prevent the PM-induced tendency toward thrombus formation. Conclusions: Mice exposed to inhaled PM exhibited a TNF-α-dependent increase in PAI-1 and an IL-6-dependent activation of coagulation. These results suggest that multiple mechanisms link PM-induced lung inflammation with the development of a prothrombotic state.

Original languageEnglish (US)
Article numbere18525
JournalPloS one
Volume6
Issue number4
DOIs
StatePublished - 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Budinger, G. R. S., McKell, J. L., Urich, D., Foiles, N., Weiss, I., Chiarella, S. E., Gonzalez, A., Soberanes, S., Ghio, A. J., Nigdelioglu, R., Mutlu, E. A., Radigan, K. A., Green, D., Kwaan, H. C., & Mutlu, G. M. (2011). Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through distinct mechanisms. PloS one, 6(4), [e18525]. https://doi.org/10.1371/journal.pone.0018525