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Genetic code lung cells cracked in battle against IPF

Scientists from Cincinnati Children’s Hospital Medical Center, in collaboration with investigators at Cedars-Sinai Medical Center in Los Angeles, have cracked the complete genetic code of individual cells in healthy and diseased human lung tissues to find potential new molecular targets for diagnosing and treating the lethal lung disease Idiopathic Pulmonary Fibrosis (IPF). Theirfindings have been published in the Journal of Clinical Investigation Insight (JCI Insight).

According to Jeffrey Whitsett MD, lead investigator and co-director of the Perinatal Institute at Cincinnati Children’s, the research identifies a number of novel targets and molecular pathways for IPF, for which there are pharmaceutical approaches (http://www.newswise.com/articles/scientists-unlock-genetic-code-of-diseased-lung-cells-to-find-new-treatments-for-ipf).  “Airway cells can be obtained by brushing the airway or biopsy, and marker genes can be tested to make a diagnosis or monitor treatment.”

Lethal interstitial lung disease

IPF is a common and lethal interstitial lung disease in adults: it inflames, scars and reconfigures lung tissues. This causes loss of the air sacs, called alveoli, where oxygen and carbon dioxide are normally exchanged. Similar losses of lung function can occur earlier in life, especially in children with diseases caused by mutations in genes critical for surfactant and maintenance of the lung saccules.

Biological processes controlling the formation and function of the lung’s alveolar region require precisely orchestrated interactions between diverse epithelial, stromal and immune cells, explain the study authors.  But despite many years of extensive laboratory studies of whole tissue samples – trying to identify genetic, cellular and molecular processes that fuel lung ailments like IPF – the precise biology has remained elusive.

First-ever single-cell RNA sequence analysis

To overcome this problem, Whitsett and colleagues – including first author and bioinformatician Yan Xu, PhD of Cincinnati Children’s – conducted what they believe to be the first-ever single-cell RNA sequence analysis of normal and diseased human lung tissues (all donated with prior informed consent). This novel approach provided the authors with a detailed genetic blueprint of all the different epithelial cell types involved in IPF progression and a window to identify aberrant biological processes driving inflammation and fibrosis.

Gene patterns

Analysis of normal lung epithelial cells found gene patterns linked to fully formed alveolar type 2 lung cells (AT2 cells), which are important for the production of surfactant, a substance containing a complex of proteins critical to breathing.

More analysis of diseased IPF cells also found genetic markers for lung cells that were in indeterminate states of formation, the authors report. IPF cells had lost the normal genetic control systems needed to guide their functions. This study identifies abnormalities in gene expression that can be targeted for therapy of chronic lung diseases like IPF.

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