Experimental models exploring metabolic processes in skin and whole body In Vivo

The knowledge of energy and substrate metabolism in skin in vivo and its relationship to altered whole body metabolic status in health and disease has not been fully elucidated due to the lack of an appropriate experimental approach in obtaining simultaneous measurements of metabolic processes in both sites in a living animal. The development of in vivo experimental models using a stable isotope technique has significantly expanded our knowledge of the functional metabolism of proteins and DNA in the skin and its relationship with the whole body status of protein metabolism. Therefore, it is worthwhile to briefly review some of the major in vivo metabolism models used for this purpose.

In Vivo Quantitative Estimate of Collagen Turnover as an Indicator of the Dynamic Metabolic Process of Wound Healing

The first series of investigations was focused on quantitative evaluation of the collagen turnover rate in vivo. Early investigations defining the model concentrated on the evaluation of skin, because 70 to 90% of the protein of skin is collagen, it is readily available for sampling with minimal harm to the animal, and skin is the largest organ of the body and represents approximately 10 to 12% of the body weight of the animal.1-3 Finally, collagen is the major protein of the healing wound and alteration of collagen synthesis rate reflects the process of wound healing. In order to measure how fast the collagen was formed and degraded, the collagen would first be labeled with stable isotopes, and then observed to see how fast the labeled collagen is replaced by the newly synthesized collagen in subsequent hours or days (decay kinetic model). In a series studies by Molnar et al.,26-28 rats were exposed to pure 18O2 in a chamber for 36 h. The major peptide structure of a collagen molecule is mostly the repeated units of glycine-X-Y; where X may be any amino acid, and Y is approximately 25% proline or hydroxyproline4 (see Chapter 1). As there is no transfer RNA for hydroxyproline, the only source of this amino acid is from the posttranslational hydroxylation of the peptide-bound proline. After the animals constantly inhale 18O2-containing air, the proline residue of the newly synthesized collagen would become 18O labeled hydroxyproline from the incorporation of free molecular oxygen into the hydroxyl group. After 36 h, about 7 to 10% of the protein-bound proline became 18OH-hydroxyproline. By sequential biopsy of the skin at different time points, the turnover rate of collagen protein can be accurately measured based on the fractional change in the abundance of the protein-bound 18O-hydroxyproline. The results revealed that in a healthy rat, soluble collagen synthesis is about 95 mg/d, about 55% of the newly synthesized soluble collagen per day is subsequently matured into insoluble collagen, and 45% of the soluble collagen is degraded into amino acids, which is equivalent to less than 30 mg/d. Using this method, further studies revealed that in protein malnourished rats (where the animals received only 1/6 of the adequate amount of total protein intake for 180 d), the rates of collagen synthesis, degradation, and maturation were reduced to only 11, 16, and 16%, respectively, of those seen in well-nourished healthy controls.3

These studies provided strong evidence that whole body nutritional status has significant impact on skin collagen metabolism and, hence, the healing process of the wound. They support the clinical observations that improving whole body protein nutritional status accelerates the wound healing process in severely burned patients and other surgical patients. It should be noted that, because 18OH-hydroxyproline does not reincorporate into collagen after this amino acid is released from collagen degradation, scientifically, the 18O inhalation method has provided the most accurate estimate of collagen metabolism. Other approaches to label collagen using either [2H]-or [13C]proline as probes always underestimated the rate of collagen metabolism due to the fact that proline can be released and reincorporated into collagen proteins. In Molnar's study, the simultaneous use of 18O2 and [2H2]proline tracers revealed that the underestimate could be 44%.! So far, the 18O2 method is the most accurate and least harmful approach with which to determine collagen metabolic rate. It could potentially be applied to investigations in human subjects and burn patients.

Experimental Models for Assessing the Dynamics of Skin dna and Protein Metabolism

Zhang et al.,5-9 from the Metabolic Unit of Shriners Hospital in Galveston, Texas, established a unique animal model with which to estimate the in vivo pathways of skin DNA metabolism and protein metabolism by using stable isotope labeled glucose, glycine, and phenylalanine tracers. Their work provided the opportunity to quantify whole body protein metabolism, skin protein metabolism, and skin DNA metabolism simultaneously in a living animal. This has been a major contribution to the knowledge of the in vivo aspects of skin protein and cellular turnover, their impact on the wound healing process, and their relationship to whole body nutritional status.

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