title: Procoagulant alveolar microparticles in the lungs of patients with acute respiratory distress syndrome.
abstract: Coagulation and fibrinolysis abnormalities are observed in acute lung injury (ALI) in both human disease and animal models and may contribute to ongoing inflammation in the lung. Tissue factor (TF), the main initiator of the coagulation cascade, is upregulated in the lungs of patients with ALI/acute respiratory distress syndrome (ARDS) and likely contributes to fibrin deposition in the air space. The mechanisms that govern TF upregulation and activation in the lung are not well understood. In the vascular space, TF-bearing microparticles (MPs) are central to clot formation and propagation. We hypothesized that TF-bearing MPs in the lungs of patients with ARDS contribute to the procoagulant phenotype in the air space during acute injury and that the alveolar epithelium is one potential source of TF MPs. We studied pulmonary edema fluid collected from patients with ARDS compared with a control group of patients with hydrostatic pulmonary edema. Patients with ARDS have higher concentrations of MPs in the lung compared with patients with hydrostatic edema (25.5 IQR 21.3-46.9 vs. 7.8 IQR 2.3-27.5 micromol/l, P = 0.009 by Mann-Whitney U-test). These MPs are enriched for TF, have procoagulant activity, and likely originate from the alveolar epithelium [as measured by elevated levels of RAGE (receptor for advanced glycation end products) in ARDS MPs compared with hydrostatic MPs]. Furthermore, alveolar epithelial cells in culture release procoagulant TF MPs in response to a proinflammatory stimulus. These findings suggest that alveolar epithelial-derived MPs are one potential source of TF procoagulant activity in the air space in ARDS and that epithelial MP formation and release may represent a unique therapeutic target in ARDS.
authors.affiliation: Vanderbilt Univ. School of Medicine, Nashville, TN 37232-2650, USA. julie.bastarache@vanderbilt.edu
authors.forename: Julie A
authors.initials: JA
authors.lastname: Bastarache
authors.forename: Richard D
authors.initials: RD
authors.lastname: Fremont
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kropski
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Bossert
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
mesh_terms: D000328:Adult; D000368:Aged; D001779:Blood Coagulation Factors / Q000378:metabolism*; D001826:Body Fluids / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000378:metabolism* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D011014:Pneumonia / Q000150:complications / Q000473:pathology; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D011654:Pulmonary Edema / Q000150:complications / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000150:complications / Q000401:mortality / Q000473:pathology*; D013347:Subcellular Fractions / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D001779:Blood Coagulation Factors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013925:Thromboplastin
references.citation: Blood. 2004 Jun 15;103(12):4545-53
references.pmid: 14988149
references.citation: Chest. 2007 Aug;132(2):410-7
references.pmid: 17573487
references.citation: J Appl Physiol (1985). 1999 Oct;87(4):1301-12
references.pmid: 10517756
references.citation: Blood. 2005 Sep 1;106(5):1604-11
references.pmid: 15741221
references.citation: Anesthesiology. 2006 Oct;105(4):689-95
references.pmid: 17006066
references.citation: Am Rev Respir Dis. 1988 Sep;138(3):720-3
references.pmid: 3202424
references.citation: Thorax. 2007 Jul;62(7):608-16
references.pmid: 17356058
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Sep;291(3):L307-11
references.pmid: 16648240
references.citation: Crit Care Med. 1992 Jun;20(6):864-74
references.pmid: 1597042
references.citation: Mol Biol Cell. 1997 Dec;8(12):2631-45
references.pmid: 9398681
references.citation: J Exp Med. 1996 Mar 1;183(3):1161-72
references.pmid: 8642258
references.citation: JAMA. 1993 Dec 22-29;270(24):2957-63
references.pmid: 8254858
references.citation: Thromb Res. 2000 Jun 1;98(5):461-6
references.pmid: 10828486
references.citation: Atherosclerosis. 2001 Oct;158(2):277-87
references.pmid: 11583705
references.citation: J Thromb Haemost. 2003 Dec;1(12):2561-8
references.pmid: 14738565
references.citation: Semin Thromb Hemost. 2006 Feb;32(1):11-23
references.pmid: 16479458
references.citation: Thromb Res. 2008;122(5):604-9
references.pmid: 18262600
references.citation: Am Rev Respir Dis. 1990 Dec;142(6 Pt 1):1250-7
references.pmid: 2252240
references.citation: Thromb Haemost. 2001 Apr;85(4):639-46
references.pmid: 11341498
references.citation: J Thromb Haemost. 2003 Nov;1(11):2434-43
references.pmid: 14629480
references.citation: J Clin Invest. 1997 Apr 1;99(7):1546-54
references.pmid: 9119998
references.citation: Am Rev Respir Dis. 1987 Dec;136(6):1466-74
references.pmid: 3688650
references.citation: Am J Respir Crit Care Med. 2006 May 1;173(9):1008-15
references.pmid: 16456142
references.citation: Am J Respir Cell Mol Biol. 2007 Apr;36(4):497-503
references.pmid: 17099142
references.citation: Am J Pathol. 1994 Oct;145(4):930-40
references.pmid: 7943182
references.citation: Crit Care. 2008;12 Suppl 6:S3
references.pmid: 19105796