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.
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