Lactoferrin is a prominent component of neutrophil secondary granules and can be released when neutrophils are activated. The concentration of lactoferrin in blood has been demonstrated to be increased in certain inflammatory diseases. In contrast to a well described biochemical characterization of lactoferrin as an iron-binding protein, its physiological role in the regulation of inflammation and other host defense mechanisms is unclear. The current proposed study will test three hypotheses: (i) lactoferrin derived from neutrophils is an important physiological mediator in the down-regulation of blood anticoagulation; (ii) the significant elevation of lactoferrin in blood, or at sites of inflammation can contribute significantly to the development of prothrombotic sequelae as seen in the disseminated intravascular coagulation (DIC) associated with bacterial infections; and (iii) the structural determinant(s) of lactoferrin involved in heparin binding is located within a specific sequence (residues 25-31) of the N-terminus. Thus, specific aims of this proposal are: (1) to determine the relationship between the elevation of plasma lactoferrin and the development of prothrombotic complications in patients with bacterial infections. The plasma lactoferrin concentration in patients with DIC resulting from different underlying diseases or with different inflammatory diseases will be examined; (2) to define the structural determinant(s) of lactoferrin involved in heparin binding. Both site- specific and domain-replacement mutagenesis will be used to determine the contribution of N-terminal basic residues (25 to 31) in heparin binding; (3) to study the activity of lactoferrin in the regulation of protein C anticoagulant pathway. Both the effect of lactoferrin on the generation of activated protein C and the specific binding of lactoferrin to chondroitin sulfate moiety of thrombomodulin will be examined. The completion of these studies will enable us to understand the biological role of lactoferrin in the regulation of inflammation and blood coagulation, and will provide new scientific background for the clinical evaluation and management of infectious diseases with thrombotic complications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003279-03
Application #
2392540
Study Section
Special Emphasis Panel (ZHL1-CCT-L (O1))
Project Start
1995-04-01
Project End
2001-03-31
Budget Start
1997-04-01
Budget End
2001-03-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Cataland, Spero R; Jin, Ming; Ferketich, Amy K et al. (2007) An evaluation of cyclosporin and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura. Br J Haematol 136:146-9
Cataland, S R; Jin, M; Smith, E et al. (2006) Full evaluation of an acquired case of thrombotic thrombocytopenic purpura following the surgical resection of glioblastoma multiforme. J Thromb Haemost 4:2733-7

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