The overall objective of this application is to use urinary desmosine and isodesmosine (DES and IDES), specific for mature elastin and biologic markers of effect, to understand the tissue origins of these crosslink amino acids under normal and pathologic conditions. DES and IDES are neither metabolized nor taken up from dietary sources, but are excreted intact into the urine, reflecting degradation of elastin. We have developed an assay that measures the amount of DES and IDES in the urine with specificity and precision. With this method we will test the hypothesis that under normal conditions, DES turns over at different rates depending on the tissue in which the elastin is found. We will do these studies in adult hamsters that had received a radiolabeled precursor amino acid (lysine) when pups. The amount and specific radioactivity of urinary DES will be compared with that of tissue specific DES pools from lung, large blood vessels and skin. Based upon our urinary DES data, there are likely pool(s) of DES that rapidly turn over; those DES pools will exhibit significantly lower specific radioactivity in older hamsters than more slowly metabolized pools. Our second hypothesis states that severe elastolytic injury of the lung will increase acute and chronic turnover of lung DES. A low level of injury, such as produced by instillation of a low dose of human neutrophil elastase (HNE) may produce a transient elevation of urinary DES. The lung-derived DES will exhibit higher specific radioactivity as compared with urinary DES from the unperturbed animal. This injury can be repaired by the lung. Infliction of a more severe injury with a higher dose of HNE will elevate urinary DES and produce permanent airspace enlargement (emphysema). Infliction of even greater elastolytic injury to the lungs with porcine pancreatic elastase results in progressive airspace enlargement with time. This progression may be accompanied by continuous elevation of urinary DES. Physiologic studies on this hamster model indicate that lung collagen is remodelled during the evolution of the emphysema lesion. The third hypothesis states that the turnover of the collagen crosslink pyridinoline (HP) in emphysema also increases.
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