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Integrin discovery may lead to better lung treatments

Jan. 8, 2015, 8:21 AM

Roy Zent, M.D., Ph.D., left, Erin Plosa, M.D., Timothy Blackwell, M.D., and colleagues are studying an integrin’s role in alveolar formation, one of the last stages of lung development. (photo by John Russell)

Vanderbilt University researchers have made an important advance in understanding lung development, which one day could lead to improvements in treating lung disease in premature infants and adults.

In the Dec. 15 issue of the journal Development, Erin Plosa, M.D., and colleagues report that epithelial beta1 integrin is required in mice for the development of the epithelial lining of the alveoli, at the tips of the respiratory “tree,” where the exchange of oxygen and carbon dioxide takes place.

Integrins are transmembrane receptors that play a critical role in the development of the kidney and other organs. This is the first report of an integrin’s essential role in alveolar formation, one of the last stages of lung development.

Transgenic mice in which beta1 integrin was “knocked out” also exhibited defects in “branching morphogenesis,” the growth of the respiratory tree, and persistent inflammation driven by macrophages, a type of white blood cell, which can damage the developing lung.

“Learning all we can about how lungs develop is critical for developing new therapies to help preterm babies survive,” said Plosa, assistant professor of Pediatrics and first author on the paper.

The role of beta1 integrin in human lung development is not known, although other groups have reported lung diseases in a small group of patients with mutations in the gene for another integrin, alpha3.

Plosa’s paper “opens up a whole new area of investigation that could advance understanding of adult diseases like chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis,” said Timothy Blackwell, M.D., the Ralph and Lulu Owen Professor of Medicine and director of the Division of Allergy, Pulmonary and Critical Care Medicine.

Among people who have lung injury, “why do some develop severe fibrosis and others don’t? Integrins could be at the bottom of a lot of that kind of biology,” added Roy Zent, M.D., Ph.D., the Thomas F. Frist Sr. Professor of Medicine and an integrin expert.

Plosa began her investigations at Vanderbilt as a research fellow in the lab of Lawrence Prince, M.D., Ph.D., now division chief of Neonatology at the University of California, San Diego. Zent and Blackwell contributed to the study and are the paper’s senior authors.

The research was supported in part by National Institutes of Health grants DK069221, DK083187, HL092870, HL085317, HL097195, HL116358 and HL086324.

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