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Brian M Varisco MDDivision of Critical Care MedicineCincinnati Children's Hospital Medical Center3333 Burnet AvenueCincinnati, OH 45229-3039
513-803-2485 Office513-803-3311 Faxbrian.email@example.com
The principal function of the lung is to facilitate the absorption of oxygen and elimination of carbon dioxide necessary for lung development. This exchange occurs principally at the level of the alveolus. Premature birth often impairs alveolar formation and lung injury can reduce the number of alveoli. Postnatally, a host of pathologic conditions can lead to alveolar destruction and reduced lung function. Our laboratory is focused on understanding the mechanisms which govern alveolar growth and regeneration and how alveolar and pulmonary microvascular growth are coordinated to maximize ventilation/perfusion matching.
Specifically, our laboratory is focused on how lung matrix remodeling may coordinate alveologenesis and pulmonary vascular morphogenesis. Elastin is critical for normal lung function and elastin remodeling is also important in angiogenesis in during repair of other organs and in some cancers. We have demonstrated that lung elastin remodeling is dynamically regulated in both lung development and lung regeneration, that this remodeling localizes to suspected areas of alveolar growth, and that the remodeling is associated pulmonary angiogenesis. A novel protease, chymotrypsin-like elastase 1 (CELA1) was highly associated with this remodeling with expression profiles paralleling changes in lung elastin remodeling. We have demonstrated a role for both elastin remodeling and CELA1 in angiogenesis in vitro. We have also shown that by preventing stretch in our lung regeneration model, we prevent induction of elastin remodeling.
We have also demonstrated that elastin remodeling is increased in the pulmonary artery on postnatal day 1 in the mouse and that doubling of pulmonary artery blood flow changes pulmonary artery elastin architecture. In the pneumonectomy model, right pulmonary artery CELA1 RNA levels increase 5-fold after doubling of pulmonary blood flow. We are currently investigating a role for CELA1 in stretch-regulated elastin remodeling of the pulmonary artery.
The schematic to the left outlines our research. (A) Tropoelastin monomers contain two evolutionarily conserved hydrophobic domains which align and are responsible for the multimer’s elastic properties. One of these conserved domains, exon-14, is a preferred cleavage site for chymotrypsin-like elastase family. Other groups have demonstrated that this family of elastases binds lung elastin fibers only in the direction of stretch and proportionate to the vector of stretch. We propose that under un-stretched conditions, exon-14 is hidden but that once a critical stretch threshold is exceeded, the CELA1 binding site is exposed leading to elastin remodeling. One research focus of our lab is defining the stretch-dependent binding kinetics of CELA1 and target specificity. (B) Closure of the ductus arteriosus after birth and ligature of the pulmonary artery after pneumonectomy leads to increased pulmonary blood flow and increased pulmonary arterial stretch. This stretch permits CELA1-regulated elastin remodeling. A second research focus of our lab is defining the role of stretch in pulmonary arterial elastin remodeling and whether this remodeling is CELA1-dependent. (C) The alveolus is subjected to the cyclic stretch of the respiratory cycle which is increased by both increased thoracic dimensions during development or expansion following pneumonectomy. Alveolar septal tips have a low compliance elastin band at the tip of the alveolar septum and higher compliance elastin fibers in the alveolar walls that allow for passive exhalation. Once a critical stretch threshold is exceeded in the alveolar walls, alveolar growth ensues and since elastin remodeling is angiogenic, there is also capillary growth leading to matching of ventilation and perfusion. A third research focus of our lab is defining the importance of elastin remodeling and CELA1 in alveolar growth and a fourth is understanding the operative angiogenic mechanism or mechanisms.
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