MATRIX: BIOLOGY & PATHOBIOLOGY OF PRE & POST NATAL ELASTIC TISSUES

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The objective of this proposal is to test the hypotheses that transgenic mice with gene mutations specifically affecting lung elastin will have altered airway smooth muscle contractile properties and be more susceptible to hyperoxia- and nitric oxide-induced airway dysfunction. Phenotypes of four tropoprom (TP) minigene constructs reveal disorders of elastic tissue which appear developmentally regulated and tissue-specific. Progeny from founder lines TP-2 die at 5-7 weeks of age associated with respiratory distress and emphysema. TP-4 constructs die between 7-9 months of age with hemorrhage and histopathology demonstrating abnormal medial elastic fibers in the ascending aorta,. consistent with predisposition to ascending aortic aneurysm. Th-l and TP-3 constructs do not develop abnormal elastic tissue phenotypes. Studies will be divided into three specific aims: #1: Determine the developmental regulation of vascular and airway smooth muscle function in transgenic mice with elastin gene mutations; #2: Determine the airway functional effect and lung elastin damage of hyperoxic exposure during the newborn period; and #3: Determine the airway functional effect and lung elastin damage of inhaled NO during the newborn period. Isometric force measurements of airway and vascular smooth muscle will be employed. Lung function will be determined by pressure-volume curves and elastin integrity measured by light microscopy, scannmg EM histology, and measurement of total elastin synthesis. Indices of lung inflammation will be assessed by histology, tracheal aspirate fluid white cell composition and inflammatory cell proteinase activity.