desmosine and Bronchopulmonary-Dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that adversely affects long-term pulmonary function as well as neurodevelopmental outcomes of preterm infants. Elastolytic proteases have been implicated in the pathogenesis of BPD. Cathepsin S (cat S) is a cysteine protease with potent elastolytic activity. Increased levels and activity of cat S have been detected in a baboon model of BPD.. To investigate whether deficiency of cat S alters the course of hyperoxia-induced neonatal lung injury in mice.. Newborn wild-type and cat S-deficient mice were exposed to 80% oxygen for 14 days. Histologic and morphometric analysis were performed and bronchoalveolar lavage protein and cells were analyzed. Lung elastin was assessed by real-time polymerase chain reaction, in situ hybridization, desmosine analysis, and Hart's stain. Distribution of myofibroblasts was analyzed by immunofluorescence. Hydroxyproline content of lung tissues was measured.. Hyperoxia-exposed cat S-deficient mice were protected from growth restriction and had improved alveolarization, decreased septal wall thickness, lower number of macrophages, and lower protein concentration in bronchoalveolar lavage fluid. alpha-Smooth muscle actin-expressing myofibroblasts accounted for at least some of the increased interstitial cellularity in hyperoxia-exposed mouse lungs and were significantly less in cat S-deficient lungs. Lung hydroxyproline content was increased in hyperoxia-exposed wild-type, but not in cat S-deficient lungs. Desmosine content was significantly reduced in both genotypes with hyperoxia.. Cathepsin S deficiency improves alveolarization, and attenuates macrophage influx and fibroproliferative changes in hyperoxia-induced neonatal mouse lung injury.

Topics: Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Cathepsins; Collagen; Desmosine; Disease Models, Animal; Elastin; Humans; Hydroxyproline; Hyperoxia; Infant, Newborn; Lung; Lung Injury; Macrophages, Alveolar; Mice; Proteins; Pulmonary Alveoli; RNA, Messenger

We correlated clinical, biochemical, and morphologic findings in the lungs of 48 infants dying of either bronchopulmonary dysplasia (BPD) or hyaline membrane disease (HMD) to obtain a better idea of the disease process. The infants ranged from 24 weeks of gestation to 1 1/2 postnatal years. The lungs of BPD and HMD infants had higher contents of DNA, alkalisoluble protein, hydroxyproline, and desmosine, as well as increased concentrations of DNA, hydroxyproline, and desmosine when compared with the lungs of 72 control infants. BPD was classified histologically into 4 groups: Group I was a phase of acute lung injury, Group II the proliferative phase; Group III the phase of early repair, and Group IV the phase of late repair. We saw a significant increase in hydroxyproline concentration in Groups II and III. The ratio of type I/III collagen decreased in BPD Groups II to IV. Desmosine was significantly higher only in Group III than in controls. When the pathological classification was related to biochemical and clinical features of BPD, the classification showed dependence on the number of days the infant survived postnatally and not on the gestational age of the infant. The number of days on assisted ventilation was a slightly better predictor of the disease classification than days on > 60% oxygen. A statistical model correctly predicted the pathologic classification 83% of the time.

Topics: Bronchopulmonary Dysplasia; Case-Control Studies; Collagen; Desmosine; DNA; Humans; Hyaline Membrane Disease; Hydroxyproline; Infant; Infant, Newborn; Lung

In order to evaluate the risk for proteolytic destruction of lung parenchymal elastic fibers in ventilated premature infants, the concentrations of elastase were determined in tracheal aspirates of 65 infants from whom we obtained a total of 327 sequential samples. Elastase was detected at least once in 39 of the 65 infants studied. Eleven of these infants were ventilated with greater than 60% oxygen for greater than 5 days. In 19 infants, the presence of elastase was associated with positive bacterial and/or viral cultures and/or elevated ratios (greater than 0.22) of immature neutrophils to total neutrophils. Elastase was not detected in the lung secretions of 26 infants ventilated with greater than 60% oxygen for less than 3 days, suggesting minimal risk for elastic fiber destruction in the intubated infant who neither has pneumonia nor requires prolonged hyperoxic ventilation. The risk for elastic fiber destruction was further evaluated by analyzing sequential urine and tracheal aspirate samples for the presence of an elastolytic degradation product of elastin (desmosine). The biochemical data indicated a potential risk for proteolytic destruction of elastic fibers in association with infection and/or prolonged hyperoxic exposure. In addition, autopsy specimens obtained from three of the infants revealed structurally abnormal lung parenchymal elastic fibers. Because elastic fibers are believed to provide the structural support for alveolar septal development, proteolytic degradation of these fibers may be a significant factor in the impaired lung development that occurs in infants with bronchopulmonary dysplasia.

Topics: Bronchopulmonary Dysplasia; Desmosine; Elastic Tissue; Female; Humans; Infant, Newborn; Lung; Male; Pancreatic Elastase; Respiration, Artificial; Risk Factors; Trachea

In order to determine whether elastin degradation is increased in infants whose respiratory insufficiency requires ventilation with high concentrations of O2, we quantitated, by amino acid analysis, the elastin degradation products (desmosines) excreted in the urine of 14 premature male infants during the first 3 wk of life. Eight of these infants, the "low-O2" infants, did not have severe lung disease and did not require more than 40% O2 beyond the first 8 h of life. The other 6 infants, selected retrospectively because they developed bronchopulmonary dysplasia (BPD), were ventilated with more than 60% O2 for at least the first 72 h of life. The pattern of desmosine excretion observed in infants who developed BPD differed significantly (p less than 0.05) from the excretion pattern seen in "low-O2" infants during the first 3 wk of life. At the end of the first week of life, desmosine excretion was significantly greater (p less than 0.05) in the infants who later developed BPD than in the "low-O2" infants without severe lung disease. From Days 7-9 to 20-22, desmosine excretion increased in the "low-O2" infants from 6.9 +/- 1.7 micrograms/kg to 9.0 +/- 3.5 micrograms/kg. In contrast, desmosine excretion did not remain elevated in the BPD infants, decreasing from 10.6 +/- 2.2 micrograms/kg to 6.1 +/- 2.9 micrograms/kg during the same period. In the BPD infants, elevated desmosine excretion through Day 9 is likely to reflect lung injury, whereas decreased desmosine excretion beyond Day 9 suggests that elastin synthesis and turnover is impaired, possibly as a result of nutritional deficiencies.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Age Factors; Bronchopulmonary Dysplasia; Desmosine; Elastin; Humans; Infant, Newborn; Infant, Premature, Diseases; Isodesmosine; Male; Oxygen Inhalation Therapy