heparitin-sulfate and Emphysema

The burden of proteinases from inflammatory cells in the lung of subjects with type Pi ZZ of alpha-1-antitrypsin deficiency is higher than in those without the deficiency. Cross-sectional studies have shown increased levels of biomarkers of extracellular matrix degradation in vivo. Longitudinal variability of these biomarkers is unknown but desirable for clinical studies with proteinase inhibitors.. We measured three different types of biomarkers, including desmosines, elastase-formed fibrinogen fragments and heparan sulfate epitope JM403, in plasma and urine for a period of 7 weeks in a group of 12 patients who participated in a placebo-controlled study to assess the safety of a single inhalation of hyaluronic acid.. Effect of study medication on any of the biomarkers was not seen. Baseline desmosines in plasma and urine correlated with baseline CO diffusion capacity (R = 0.81, p = 0.01 and R = 0.65, p = 0.05). Mean coefficient of variation within patients (CVi) for plasma and urine desmosines was 18.7 to 13.5%, respectively. Change in urinary desmosine levels correlated significantly with change in plasma desmosine levels (R = 0.84, p < 0.01). Mean CVi for fibrinogen fragments in plasma was 20.5% and for JM403 in urine was 27.8%. No correlations were found between fibrinogen fragments or JM403 epitope and desmosines.. We found acceptable variability in our study parameters, indicating the feasibility of their use in an evaluation of biochemical efficacy of alpha-1-antitrypsin augmentation therapy in Pi Z subjects.

Topics: Adult; alpha 1-Antitrypsin Deficiency; Biomarkers; Desmosine; Double-Blind Method; Emphysema; Female; Heparitin Sulfate; Humans; Hyaluronic Acid; Male; Peptide Hydrolases; Placebo Effect; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome

Hyaluronic acid (HA), heparan sulfate (HS) and structural glycoproteins (SGP) were investigated in explant cultures of hamster lungs by studying incorporation of 14C-glucosamine (14C GlcN) on the first and on the 24th day after intratracheal administration of pancreatic elastase. The different 14C radiolabeled macromolecules were extracted sequentially by 0.4 M guanidinium chloride (0.4 M GUA), 4 M GUA and collagenase digestion. At one day following elastase injury, a 4.2 fold increase of 14C GlcN incorporation into HA released in 0.4 M GUA extract and a 2.6 fold increase into HS released in the collagenase digests were observed compared to control tissues; at 24 days, the increased 14C GlcN incorporation into HA and HS persist but to a lesser extent. Polyacrylamide gel electrophoresis and isoelectric focusing carried out on 4 M GUA extracts, demonstrated identical quantitative and qualitative distribution of 14C GlcN between the major SGP (140 and 110 K with pI 7.8 and 4.5 respectively) in the normal and the experimental groups. These results indicate that pulmonary SGP biosynthesis is not modified at one and 24 days after elastase injury, whereas HA and HS biosynthesis are consistently increased. These results suggest a specific role of these macromolecules in emphysematous injury of the lung.

Topics: Animals; Cricetinae; Emphysema; Glucosamine; Glycoproteins; Glycosaminoglycans; Heparitin Sulfate; Hyaluronic Acid; Isoelectric Focusing; Lung; Male; Mesocricetus; Pancreatic Elastase