Glycosaminoglycan and Collagen Synthesis in N-Nitroso-N-Methylurethane Induced Pulmonary Fibrosis

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Abstract
Glycosaminoglycan and collagen synthesis were studied in a hamster model of interstitial pulmonary fibrosis, induced by weekly subcutaneous injections of N-nitroso-N-methylurethane (NNNMU) for up to 16 weeks. Experimental and control animals were injected intraperitoneally with 35S or [3H]proline to label glycos-aminoglycans and collagen, respectively. The labeling studies were performed at 1 and at 3 months following completion of NNNMU treatment. Uptake of 35S into lung glycosaminoglycans was higher in diseased animals than in controls at both 1 and 3 months post-NNNMU. The experimental lungs had a significantly increased percentage of labeled dermatan sulfate and/or chondroitin 4-sulfate compared to controls at both time intervals. Additional studies performed only on the 1-month samples showed that this increase in percentage labeling was primarily in dermatan sulfate. NNNMU-treated lungs also had a significantly lower percentage of labeled heparin and/or heparan sulfate than did controls at 1 and 3 months post-NNNMU. Regarding collagen synthesis, both 3H-labeled and total collagenase-digestible collagen was lower in diseased lungs than in controls at 1 and 3 months post-NNNMU. The differences at 1 month post-NNNMU were statistically significant. These results suggest that, in this model, changes from normal in glycosaminoglycans occur during the repair process. However, the histologically apparent increase in lung collagen is not corroborated by biochemical analysis.

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