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Increase in resting tension of left ventricular papillary muscle with age has been attributed to the amount of collagen present. We therefore studied the total amount and structure of myocardial collagen as a function of age in the hearts of male Fischer 344 rats. Using amino acid analysis and quantification of hydroxyproline, we showed that collagen accumulates in relation to ventricular protein after 3 months of age and continues in that mode with increased age of the animal, levelling off at 22 months. In this strain of rats, collagen increased in the left ventricle from 5.5% of total protein in a 1 month old animal to approximately 12% in 22 and 26 month old animals; in the right ventricle the increase was from 7% in the 1 month old animal to approximately 19.5% in 22-26 month old animals. The larger percentages of collagen in the right ventricle relative to the left agree with findings of others. Collagen accumulates in intrinsic collagenous structures where the pre-existing fibres are thickened and are more extensive. These structures were detected with light microscopy and scanning electron microscopy and include perimysial weaves, coiled perimysial fibres and struts. Regions of fibrosis were also increased in size and volume in older animals.

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A B S T R A C T Collagen synthesis was measured in liver slices obtained from mice with hepatosplenic schistosomiasis. Enlarged fibrotic livers from these mice contained 20 times more collagen than normal. This model of hepatic fibrosis results from an inflammatory granulomatous host response to Schistosoma mansoni ova in portal tracts, rather than from direct liver cell injury as with carbon tetrachloride-induced liver fibrosis. Collagen synthesis, as measured by the formation of labeled protein-bound hydroxyproline, occurred in granulomas isolated from fibrotic livers. Labeled collagen that cochromatographed with type I collagen was extracted with neutral salt solution from liver slices incubated with labeled proline. The free proline pool of the liver was doubled in infected mice; coordinately, liver slices from these animals showed maximal collagen production when the concentration of free proline in the medium was raised to 0.4 mM, the same level measured in the fibrotic livers. Under such conditions, collagen synthesis was at a rate equivalent to the formation of 5.4 nmol of protein-bound hydroxyproline per g liver in 6 h.In comparative incubations in medium containing 0.2 mM proline, fibrotic liver slices produced 16-fold more collagen than normal slices. The proline analogue, L-azetidine 2-carboxylic acid, effectively inhibited synthesis of labeled collagen by fibrotic liver slices. These studies show the synthesis of collagen in a reproducible animal model of the most prevalent form of human liver fibrosis. Definitition of the controlling factors in this system is of interest for the general problem of fibrosis produced by immunological responses.