The focus of this proposal is to characterize mechanisms controlling elastin synthesis and turnover during the development of bronchopulmonary dysplasia (BPD) resulting from ventilation of the premature lung. Elastin confers the requisite property of elastic recoil to such lung structures as alveoli and alveolar ducts, bronchioles, and blood vessels, and thus is essential for lung function. We have previously demonstrated abnormal elastic fiber deposition in an experimental model of BPD, and others have demonstrated increased elastolytic activity in the BPD lung. Still, the root causes of elastic fiber abnormalities in BPD are not known. We hypothesize that mesenchymal cells of the premature lung respond to the strain of mechanical ventilation by increasing the expression and deposition of elastic extracellular matrix components out of proportion to what is required for alveolarization. Exposure to hyperoxia may result in the production and release of elastases such as neutrophil elastase or matrix metalloproteinases that damage elastic fibers, as well as cytokines or growth factors that alter extracellular matrix gene expression by lung fibroblasts. These events result in the excess deposition of disordered elastic fibers at sites of failed development of new alveolar walls. The accumulation of disorganized elastic fibers at these sites may limit the ability to recover from injury. To determine the causes of abnormal elastic fiber deposition during the development of BPD, we propose to study the expression of elastin, fibrillins 1 and 2, and lysyl oxidase, all required for normal elastic fiber synthesis, and to characterize the elastases present in the injured lung. Our experimental approaches will include quantitative analysis of elastic fiber-related and elastase mRNA expression by RNAse protection assays, as well as localization of expression by in situ hybridization and immunohistochemical analyses. The molecular mechanisms regulating tropoelastin expression during normal baboon lung development and the development of BPD will be determined by assessing changes in tropoelastin gene transcription, steady-state mRNA levels, and protein synthesis, expression and activity of elastases in the BPD lung will be assessed by a combination of substrate zymography, immunohistochemistry, and in situ hybridization. Determining the effects of interventive treatments on the expression of elastic fiber-related genes and the elaboration of elastases will test the hypothesis that treatments which prevent BPD will also restore normal patterns of elastic fiber-related gene expression and elastic fiber deposition.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Barnes-Jewish Hospital
Saint Louis
United States
Zip Code
McGavigan, Anne K; Henseler, Zachariah M; Garibay, Darline et al. (2017) Vertical sleeve gastrectomy reduces blood pressure and hypothalamic endoplasmic reticulum stress in mice. Dis Model Mech 10:235-243
Lob, Heinrich E; Schultz, David; Marvar, Paul J et al. (2013) Role of the NADPH oxidases in the subfornical organ in angiotensin II-induced hypertension. Hypertension 61:382-7
Kompass, Kenneth S; Deslee, Gaetan; Moore, Carla et al. (2010) Highly conserved transcriptional responses to mechanical ventilation of the lung. Physiol Genomics 42:384-96
McCurnin, Donald C; Pierce, Richard A; Willis, Brigham C et al. (2009) Postnatal estradiol up-regulates lung nitric oxide synthases and improves lung function in bronchopulmonary dysplasia. Am J Respir Crit Care Med 179:492-500
Pierce, Richard A; Joyce, Belinda; Officer, Susan et al. (2007) Retinoids increase lung elastin expression but fail to alter morphology or angiogenesis genes in premature ventilated baboons. Pediatr Res 61:703-9
Altiok, Ozden; Yasumatsu, Ryuji; Bingol-Karakoc, Gulbin et al. (2006) Imbalance between cysteine proteases and inhibitors in a baboon model of bronchopulmonary dysplasia. Am J Respir Crit Care Med 173:318-26