Fibrin deposition commonly accompanies inflammation and may be involved in tissue repair. Coagulation abnormalities, intravascular and extravascular pulmonary fibrin deposition and the early development of pulmonary fibrosis are commonly found in the Adult Respiratory Distress Syndrome (ARDS). ARDS affects 150,000 patients annually and is lethal in half these cases. The participation of coagulation mechanisms in the pathogenesis of ARDS particularly with respect to lung repair and fibrosis is not well defined. A factor X activating procoagulant activity has been found in bronchoalveolar lavage (BAL) from the lungs of patients with ARDS. Similar activity has been found in BAL of marmosets following treatment with bleomycin, an agent which causes acute lung injury followed by pulmonary fibrosis. The purpose of this study is to characterize the origins and properties of BAL procoagulant activity and to define the relationship of BAL procoagulants to acute lung injury. This will be studied in humans and a well characterized animal model of lung injury. Further, we will examine the role of these procoagulants in the development of pulmonary fibrosis following acute lung injury. This proposal addresses the following questions: 1. What are the mechanisms of the activation of factor X in BAL in inflammatory lung disease? 2. Is the factor X activation the major procoagulant activity in ARDS BAL and in other forms of pulmonary inflammation? 3. Is the generation of BAL procoagulant correlated in vivo with physiologic impairment or pulmonary fibrosis in ARDS and bleomycin induced lung injury? 4. Which cells produce the procoagulants in BAL? Immunochemical and functional assays of procoagulant activators of factor X; in particular factor VII and tissue factor, will be used to investigate the mechanism of activation of factor X. Serial studies of patients and experimental animals will help to determine the physiologic importance of the procoagulant factor X activator. Lung cells in culture will be used to study the origins and mechanisms of expression of BAL procoagulants. Information from these studies will contribute to an understanding of the role of coagulation mechanisms in acute lung injury and repair.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001603-05
Application #
3081995
Study Section
Special Emphasis Panel (SRC)
Project Start
1986-09-01
Project End
1991-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas Health Center at Tyler
Department
Type
Other Domestic Higher Education
DUNS #
City
Tyler
State
TX
Country
United States
Zip Code
75708
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Idell, S; Girard, W; Koenig, K B et al. (1991) Abnormalities of pathways of fibrin turnover in the human pleural space. Am Rev Respir Dis 144:187-94
Idell, S; Garcia, J G; Gonzalez, K et al. (1989) Fibrinopeptide A reactive peptides and procoagulant activity in bronchoalveolar lavage: relationship to rheumatoid interstitial lung disease. J Rheumatol 16:592-8
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Idell, S; James, K K; Gillies, C et al. (1989) Abnormalities of pathways of fibrin turnover in lung lavage of rats with oleic acid and bleomycin-induced lung injury support alveolar fibrin deposition. Am J Pathol 135:387-99
Idell, S; Peters, J; James, K K et al. (1989) Local abnormalities of coagulation and fibrinolytic pathways that promote alveolar fibrin deposition in the lungs of baboons with diffuse alveolar damage. J Clin Invest 84:181-93
Idell, S; James, K K; Levin, E G et al. (1989) Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 84:695-705
Idell, S; Thrall, R S; Maunder, R et al. (1989) Bronchoalveolar lavage desmosine in bleomycin-induced lung injury in marmosets and patients with adult respiratory distress syndrome. Exp Lung Res 15:739-53

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