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Alveolar Epithelial Regeneration Following Acute Lung Injury

Image of Lung Alveoli

A recent article from a team of investigators at the Perelman School of Medicine and elsewhere* casts new light on acute alveolar injury and proposes targets for lung regenerative therapies, an effort of interest in the wake of the known effects of COVID-19 on alveolar structure. The full report is available in Nature Cell Biology.

Collected at the distal branches of the bronchial trees, alveoli are surrounded by thin-walled epithelial cells of two kinds: flat squamous type 1 cells (AT1) involved in gas exchange between the alveoli and adjacent capillaries, and type 2 alveolar cells (AT2), which primarily function to secrete surfactant, a mixture of lipids and proteins that prevents alveolar collapse after exhalation.

AT1 cell death is a leading cause of morbidity and mortality in many respiratory diseases, including pneumonia, influenza and acute respiratory distress syndrome, as well as COVID-19 pneumonia. For each of these diseases, however, patients survive despite alveolar destruction, suggesting the potential for regenerative therapies.

Over a 50-year span, investigators searching for the regenerative potential in lung tissue have characterized every facet of the alveoli to determine that AT2 cells possess host defense, reparative, differentiative and regenerative functions.

The Morrisey Lab at the Perelman School of Medicine, led by Edward E. Morrisey, PhD, has been a leader in this research, and contributed to the current investigation. Dr. Morrisey is the Director of the Penn-CHOP Lung Biology Institute (LBI).

A Pathway for Alveolar Cell Regeneration

Previous research has shown that type II alveolar pneumocytes (AT2) contribute to alveolar epithelial regeneration, both through self-renewal and transdifferentiation into type I alveolar pneumocytes (AT1), which facilitate gas exchange between the alveoli and nearby capillaries.

Prior to this study, it was unknown what changes in gene accessibility occurred in AT2 cells following disease-related injury to promote repair and how regenerating AT2 cells influence interactions with nearby mesenchymal niche cells, which are also important in tissue repair.

Using genome-wide analyses, the research team assessed changes in AT2 chromatin accessibility after lung injury. The researchers then used single-cell analysis of AT2 cells and mesenchymal niche cells to better understand how the AT2 cells and niche cells interact during regeneration. The two approaches converged on a single pathway, in which a transcription factor known as STAT3 increased the expression of brain-derived neurotrophic factor (BDNF), which in turn increased lung tissue regeneration via signaling to adjacent mesenchymal niche cells.

In further analyzing this pathway, the researchers identified a naturally-occurring compound known as 7,8-Dihydroflavone (7,8-DHF), which targeted a receptor in the pathway, accelerating lung regeneration in multiple murine models of lung injury.

Thanks to Andrew J. Paris, MD, who reviewed and contributed to this article.

*Also participating in this study were members of the Division of Pulmonary, Allergy and Critical Care Medicine; the Divisions of Hematology, Cardiology and Neonatology of the Department of Pediatrics; the Department of Pathology and Laboratory Medicine; the Division of Cardiovascular Surgery; the Penn Cardiovascular Institute; the Penn Institute for Regenerative Medicine; and the Department of Cell and Developmental Biology, all of the Perelman School of Medicine, as well as Divisions and Departments from the Children’s Hospital of Philadelphia, the Fred Hutchinson Cancer Research Center, the University of Cincinnati College of Medicine and Children’s National, Washington, DC.

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