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Intra-Alveolar Tissue Factor Pathway Inhibitor Is Not Sufficient to Block Tissue Factor Procoagulant Activity

¹ Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee; ² Department of Pediatrics, University of Utah, Salt Lake City, Utah; and ³ Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Julie A. Bastarache, M.D., Division of Allergy, Pulmonary and Critical Care, Vanderbilt University, 1611 21st Avenue South, Suite T-1217 MCN, Nashville, TN 37232. E-mail: julie.bastarache{at}vanderbilt.edu

The alveolar compartment in acute lung injury (ALI) contains high levels of tissue factor (TF) procoagulant activity favoring fibrin deposition. We previously reported that the alveolar epithelium can release TF procoagulant activity in response to a pro-inflammatory stimulus (1). We hypothesized that the alveolar epithelium further modulates intra-alveolar fibrin deposition through secretion of an endogenous inhibitor of TF, tissue factor pathway inhibitor (TFPI). To determine whether the alveolar epithelium can release TFPI, TFPI was measured (by enzyme-linked immunosorbent assay) in the conditioned media (CM) and cell lysates (CL) from human alveolar epithelial cells (A549) after exposure to cytomix (TNF-, IL-1β, IFN-). TFPI protein was decreased in CL and increased in CM over the 24-hour cytomix treatment. TFPI mRNA levels (RT-PCR) did not change over the same time period. Lung immunohistochemistry on patients with ALI showed that alveolar epithelial TFPI staining is decreased in patients with ALI compared with control subjects. Taken together, these findings suggest that the alveolar epithelium releases TFPI in response to inflammatory stimuli. We then measured levels of TF and TFPI antigen in undiluted pulmonary edema fluid (EF) from patients with ALI. Although levels of TFPI were high in the EF from patients with ALI (265 ± 161 ng/ml), TF levels were significantly higher (1,559 ± 1,163 ng/ml). Furthermore, despite the presence of high levels of TFPI, both the EF and CM retained significant TF procoagulant activity as measured by plasma recalcification time. We conclude that the alveolar epithelium releases TFPI in response to an inflammatory stimulus, but does not increase TFPI gene transcription or protein production. However, levels of intra-alveolar TFPI in clinical ALI are not sufficient to block intra-alveolar TF procoagulant activity in patients with ALI.

FOOTNOTES

Supported by Vanderbilt Physician Scientist Development Award to J.A.B., and HL081332 and HL70521 to L.B.W.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form August 29, 2007; accepted in final form October 16, 2007)

REFERENCES

1. Bastarache JA, Wang L, Geiser T, Wang Z, Albertine KH, Matthay MA, Ware LB. The alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor. Thorax 2007;62:608–616.

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bastarache, J. A. Articles by Ware, L. B. PubMed Articles by Bastarache, J. A. Articles by Ware, L. B.