Sustained pulmonary hypertension leads to progressive remodeling of the pulmonary circulation and attendant structurally-based, irreversible increases in vascular resistance. Inasmuch as platelet deposition in small pulmonary arteries is frequently observed in pulmonary hypertension, platelet-derived mitogens may be important mediators of structural abnormalities in hypertensive pulmonary vascular disease. However, neither the identities of the platelet-derived mitogens nor the mechanism by which they contribute to structural remodeling have been delineated. The proposed research focuses on the role of epidermal growth factor (EGF), an important platelet-derived mitogen with effects in cell culture and on other vascular beds reminiscent of those occurring in pulmonary hypertension. EGF released from platelets trapped in small arteries could mediate structural changes in the entire pulmonary arterial system. Along with local effects at its site of release, EGF could access upstream vascular segments by way of the bronchial circulation and vasa vasorum. EGF also could promote reactive changes in upstream vascular segments which occur as a consequence of its effects on the structure of small arteries. The rat model of monocrotaline (MCT)-induced lung injury and pulmonary hypertension will be used to test the hypothesis that EGF released from platelets contributes to hypertensive pulmonary vascular disease by promoting muscularization of normally non-muscularized intra-acinar arteries and by causing reactive changes In upstream vascular segments. To resolve this hypothesis, we will: (1) Delineate time-dependent alterations in the distribution of EGF in the lungs of control and MCT-treated rats and define the relationship between localization of EGF and development of structural abnormalities in the vasculature and airways; (2) Determine if platelets sequestered in the MCT-treated rat lung are the source of EGF and whether MCT causes platelet-independent accumulation of EGF in the lung by inducing expression of preproEGF MRNA in resident lung cells, and; (3) Determine if inhibitors of EGF, including neutralizing antibodies to EGF and its receptor and inhibitors of the EGF receptor tyrosine kinase, suppress MCT-induced structural abnormalities in the pulmonary vasculature and airways and attendant pathophysiologic changes. These studies will provide detailed information on the role of EGF in a well-characterized animal model of pulmonary vascular disease. In addition, the proposed research will delineate mechanisms by which platelet-derived EGF affects vascular remodeling in both small and large pulmonary arteries.
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