POTENTIAL OF NOVEL ANTI-INFLAMMATORY AGENTS TO SUPPRESS CHRONIC INFLAMMATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fibrin(ogen) induces proliferative signals, but some of its proteolytic fragments induce endothelial cell injury. Integrins are known to play a critical role in signal transduction from fibrin(ogen). The fibrinogen gamma chain has a C-terminal globular domain (gamma C, residues 151-411 of gamma chain, 30 Kd) to which several integrin cell adhesion receptors (e.g., platelet alpha IIb beta 3, endothelial alpha v beta 3, and leukocyte alpha M beta 2) bind. We found that the isolated gamma C fragment and its truncation mutant (gamma C399tr, 12 residue truncation) induced apoptosis of endothelial cells in vitro, while native fibrinogen or fragment D did not. gamma C or gamma C399tr did not affect proliferation of several other cell types tested including keratinocytes and cancer cells. We found that the binding site for alpha v beta 3 is cryptic in native fibrinogen and proteolytic fragment D, but is exposed in gamma C and gamma C399tr. These results suggest that gamma C and gamma C399tr are potential anti-angiogenic agents, that determinants in gamma C and gamma C399tr (which are cryptic in fibrinogen and fragment D) are involved in endothelial cell apoptosis, and that integrins are potentially involved in this process. Also we showed that gamma C399tr suppressed tumor growth in tumor xenograft models. These results were recently published [1]. Furthermore we found that gamma C399tr reduced the level of circulating endothelial cells (CEC), a marker of angiogenesis, in tumor-bearing mice (our unpublished results) and we hypothesize that this is a potential mechanism of anti-angiogenic action by gamma C399tr. It has been recently recognized that angiogenesis plays a role in chronic inflammation. We recently found that gamma C399tr markedly suppressed the onset of experimental allergic encephalomyelitis (EAE), a multiple sclerosis (MS)-like disease in mice (our unpublished results). We hypothesize that gamma C399tr may have potential as an anti-inflammatory agent as well, and suppress angiogenesis and chronic inflammation in primate. We propose to test whether gamma C399tr may have potential as anti-angiogenic and anti-inflammatory agent in primate inflammation models. We will use the well-established primate asthma model for this purpose. We expect that gamma C399tr will show anti-angiogenic and inflammatory effects and thus improve asthma symptoms in this model.