Potential angiogenic activity and biochemical mechanisms of neutrophil activating protein-2 / John A. Powell, Jr.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Powell, John A., Jr.

Contributor:

FitzGerald, Garret, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

Pharmacological Sciences.

Academic Dissertations as Topic.

Medical Subjects:

Pharmacological Sciences.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

Physical Description:

x, 133 pages : illustrations (some color) ; 29 cm

Production:

2001.

Summary:

The ELR motif-containing alpha-chemokines, IL-8 (interleukin-8) and MGSA (melanoma growth stimulating activity) show angiogenic activity in vivo along with chemotaxis and mitogenicity in vitro. However, the in vivo angiogenic response of a related family member, NAP-2 (neutrophil activating factor-2) has not been fully elucidated. NAP-2 is a first line mediator of neutrophil chemotaxis as a part of the inflammatory response. Although NAP-2 and IL-8 signal through chemokine receptors CXCR1 and CXCR2, they differ in their ability to activate neutrophils. IL-8 is more potent than NAP-2 at stimulating degranulation, phospholipase D activation and MAC1 integrin expression. Activated platelets provide the protein precursor that is cleaved to form NAP-2. This may be an important contributing factor in tumor-mediated angiogenesis because activated platelets are found within the tumor stroma. We tested the hypothesis that NAP-2 functions as an endothelial cell mitogen and as a stimulator of angiogenesis in vivo and in vitro. These studies revealed that NAP-2 is angiogenic in vivo, but not in vitro. In vitro studies revealed that NAP-2 and IL-8 failed to stimulate proliferation or induce differentiation in cultured endothelial cells. In contrast, both agents enhanced endothelial cell differentiation in the presence of neutrophils. A correlation between neutrophil number and the level of matrix metalloproteinase-9 was discovered. Inhibitors of matrix metalloproteinase-9, as well as neutralizing antibodies to CXCR1 and CXCR2, abrogated tube formation in co-culture and this was associated with decreases in VEGF levels. This suggests that the dichotomy between the in vivo and in vitro effects of NAP-2 on endothelial cells may be due to the absence of neutrophils. In additional studies, NO donors and an antagonist of the alphavbeta3 integrin were shown to inhibit NAP-2- and FGF2-mediated angiogenesis. These findings indicate that NAP-2 angiogenic activity is indirect and occurs through neutrophil recruitment and release of VEGF and matrix metalloproteinases.

Notes:

Adviser: Garret Fitzgerald.

Thesis (Ph.D. in Pharmacological Sciences) -- University of Pennsylvania, 2001.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3003683.

OCLC:

244971850