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The aminoterminal propeptide of type III procollagen. Studies on physiology and pathophysiology

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The aim of the present study was to examine the physiological basis for the clinical use of serum PIIINP as a marker of the deposition rate of type III collagen. The assumption was that the serum concentration of PIIINP would reflect the turnover of type III collagen and thus directly reflect the inflammatory response. For the study we assessed commercially available RIAs and optimised one of them. Porcine PIIINP was purified and compared with human PIIINP. The application of a gentle iodination procedure made it possible to perform tracer studies. An experimental model consisting of a thoracic duct-venous shunt in conscious pigs was developed. Double and triple isotope tracer techniques were used for kinetic studies in the animal model and in cultures of tubule cells. The rat model with the induction of granulation tissue was used to investigate catabolic states. The anabolic state was studied in humans receiving growth hormone therapy. We conclude: 1) That, for our purpose, the best method of determining PIIINP is the PIIINP RIA, owing to the profile of the substances determined. It was possible to improve the quality of the tracer and to increase sensitivity by changing the assay procedure. 2) That porcine PIIINP is similar to human PIIINP, therefore the human assay is suitable for studies in pigs. 3) That PIIINP most likely escapes from the extracellular space by bulk flow, similar to that of albumin. That the major part of the PIIINP synthesised is drained via the lymphatics. That intact PIIINP is not, or only to a minor extent, degraded through the lymphatics. Consequently, peak B is not a product of processes of the lymph system. 4) That in pigs intact PIIINP has a circulatory half-life of about 1 hour, and that it is degraded by at least two intermediary steps. The first step gives rises to peak B, which is found in an almost constant ratio to intact PIIINP. Peak B has a half-life of about 4 hours. Given steady state conditions peaks B and C (intact PIIINP) thus reflect the same process. In three different studies a fraction with an MW lower than that of PIIINP but higher than the col 1 domain, appeared during the degradation of intact PIIINP. This fraction (peak E) has not been described before. Furthermore, we did not observe the formation of peak D (proposed to be the col 1 domain of PIIINP) which indicates that this fraction does not originate from the metabolism of PIIINP. 5) That PIIINP rapidly distributed from the circulation to tissues, and that the liver and the kidneys are the organs mainly responsible for the degradation of PIIINP. The high hepatic clearance described previously is in part due to shunting of PIIINP directly to the lymph, but most of it is extracted by the liver for subsequent degradation or release of the intact molecule to the hepatic vein. Only a small part is irreversibly cleared and metabolised (about 5%). 6) That, given steady state conditions, the turnover of PIIINP is well reflected by changes in serum PIIINP, but also that this relation disappears when the body is in a catabolic state. Anabolic states give rise to increased serum concentrations of PIIINP as compared with normals states. The general conclusion is that serum PIIINP is a marker of type III collagen turnover under well-defined conditions. Serum PIIINP, mainly consisting of peaks B and C (intact PIIINP) may, owing to the disposal rate, reflect changes in type III collagen turnover over one day (6 half-lives). The liver and kidneys actively take part in the degradation of circulating PIIINP. Serum concentrations of PIIINP in the presence of changing body composition (weight loss) or during treatment with cytostatic drugs (cyclophosphamide) should be interpreted with caution.

OriginalsprogEngelsk
TidsskriftDanish Medical Bulletin (Print)
Vol/bind44
Udgave nummer1
Sider (fra-til)70-8
Antal sider9
ISSN0907-8916
StatusUdgivet - feb. 1997

ID: 168532706