Recent evidence suggests that imbalance in the proteinase-antiproteinase defense system may be a factor in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease that occurs in neonates as a sequella of prolonged 02 and ventilator therapy for respiratory distress. The major proteinase inhibitor in the alveolar regions of the lung, Alpha1-proteinase inhibitor (Alpha1-PI), is inactivated in lungs of infants treated with inspired oxygen concentrations (FIO2) greater than 0.6 for 6 or more days. Furthermore, alveolar macrophages and polymorphonuclear leukocytes containing proteolytic enzymes, i.e. elastase, are found in increased numbers in lung secretions of infants with respiratory distress treated for several days with a high FIO2, and a 10-20 fold increase in elastase activity has been observed in these infants. Uninhibited proteolytic enzymes could initiate or exacerbate pathologic changes associated with BPD such as damage to ciliated cells, focal emphysema, and squamous metaplasia of bronchial/bronchiolar epithelium. These enzymes could also degrade structural proteins in the lung such as elastin, collagen, and proteoglycans. Because elastin plays a major role in the development of true alveoli from the immature saccules present at birth, proteolysis of elastin could alter the course of neonatal lung development. Our objectives are to quantitate, by amino acid analysis, the degradation products of elastin (desmosines) contained in the urine and lung secretions and to determine whether there is a correlation between 02/ventilatory therapy and degradation of lung elastin. Next we will attempt to correlate, in individual infants, the antiproteinase status of lung secretions (determined by cytological examination, proteinase inhibitory capacity and concentration of free elastase) with degradation of lung elastin. Data on antiproteinase status and degradation of lung elastin will then be correlated with appearance of clinical and pathological evidence of chronic lung disease. In addition, we plan to investigate in the neonatal rat lung the influence of chronic hyperoxia, a major etiologic factor BPD, on lung maturation and lung elastin content. We anticipate that these studies will help to clarify the pathogenetic mechanisms of BPD and facilitate early recognition of infants at risk for developing chronic lung disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031172-02
Application #
3342191
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1984-05-01
Project End
1987-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Srinivasan, Suseela; Strange, Jennifer; Awonusonu, Feyisola et al. (2002) Insulin-like growth factor I receptor is downregulated after alveolarization in an apoptotic fibroblast subset. Am J Physiol Lung Cell Mol Physiol 282:L457-67
Liebeskind, A; Srinivasan, S; Kaetzel, D et al. (2000) Retinoic acid stimulates immature lung fibroblast growth via a PDGF-mediated autocrine mechanism. Am J Physiol Lung Cell Mol Physiol 279:L81-90
Bruce, M C; Honaker, C E; Cross, R J (1999) Lung fibroblasts undergo apoptosis following alveolarization. Am J Respir Cell Mol Biol 20:228-36
Al-Jumaily, W; Bruce, M C (1999) The postnatal age of rat lung fibroblasts influences G1/S phase transition in vitro. In Vitro Cell Dev Biol Anim 35:410-6
Chabra, S; Cottrill, C; Rayens, M K et al. (1998) Lymphocyte subsets in cord blood of preterm infants: effect of antenatal steroids. Biol Neonate 74:200-7
Bruce, M C; Honaker, C E (1998) Transcriptional regulation of tropoelastin expression in rat lung fibroblasts: changes with age and hyperoxia. Am J Physiol 274:L940-50
Alnahhas, M H; Karathanasis, P; Kriss, V M et al. (1997) Elevated laminin concentrations in lung secretions of preterm infants supported by mechanical ventilation are correlated with radiographic abnormalities. J Pediatr 131:555-60
Bruce, M C; Honaker, C; Karathanasis, P (1996) Postnatal age at onset of hyperoxic exposure influences developmentally regulated tropoelastin gene expression in the neonatal rat lung. Am J Respir Cell Mol Biol 14:177-85
Watts, C L; Bruce, M C (1995) Comparison of secretory component for immunoglobulin A with albumin as reference proteins in tracheal aspirate from preterm infants. J Pediatr 127:113-22
Smith, P G; Janiga, K E; Bruce, M C (1994) Strain increases airway smooth muscle cell proliferation. Am J Respir Cell Mol Biol 10:85-90

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