Researchers at Weill Cornell Medicine and New York-Presbyterian in New York have discovered that injecting mice with healthy pulmonary endothelial cells (ECs)—the cells that line the walls of blood vessels in the lung—can reverse the symptoms of emphysema. Their studies also implicated a gene called LRG1 as a driver of emphysema, and showed that deleting the gene from endothelial cells held back disease progression. The team suggested the findings may lead to new treatments for chronic obstructive pulmonary disease (COPD), an inflammatory lung disease associated with smoking that is estimated to be the third leading cause of death worldwide.

“Taken together, our data strongly suggest the critical role of endothelial cell function in mediating the pathogenesis of COPD/emphysema,” said Alexandra Racanelli, MD, PhD, an instructor in medicine at Weill Cornell Medicine. “Targeting endothelial cell biology by administering healthy lung endothelial cells and/or inhibiting the LRG1 pathway may therefore represent strategies of immense potential for the treatment of patients with advanced COPD or emphysema.”

Racanelli is co-first author of the team’s published paper in the Journal of Experimental Medicine (JEM), which is titled, “Reversal of emphysema by restoration of pulmonary endothelial cells.”

Emphysema is one of the characteristic features of COPD in which the tiny air sacs—alveoli—within the lungs are gradually destroyed, leading to breathing difficulties and, eventually, respiratory failure. The loss of alveoli is accompanied by a remodeling of the lung’s blood vessels that could indicate changes in the endothelial cells that form the blood vessel walls. Under normal circumstances, endothelial cells secrete molecules that help surrounding tissues maintain and repair themselves, but dysfunctional endothelial cells can drive various diseases, including tissue fibrosis and cancer.

“The cellular and molecular determinants underpinning the pathogenesis of COPD remain to be fully understood, but the current thought is that long-term inflammation serves as a driver of remodeling and parenchymal destruction in the proximal airways and distal lung tissue leading to the disease states of chronic bronchitis and emphysema,” the authors wrote.

“… it is not clear whether endothelial dysfunction drives COPD pathophysiology or is simply the consequence of damaged alveolar surface area,” noted Augustine M.K. Choi, PhD, the Stephen and Suzanne Weiss dean of Weill Cornell Medicine and a co-senior author of the new JEM study.

Choi and colleagues found that various markers of healthy endothelial cells were reduced in the lungs of COPD patients, as well as in laboratory mice with an induced form of emphysema. Indeed, in the lung endothelial cells of mice with emphysema, numerous genes were associated with endothelial dysfunction, including genes that promote inflammation, cell death, and vascular remodeling. “We found a direct relationship between the loss of expression of several endothelial markers and a reduction in lung function,” the team noted. “Loss of the lung EC signature also reflected increased severity of radiographical evidence of advanced emphysematous changes, suggesting that endothelium dysfunction underscores the loss of competent lung parenchyma observed in cases of severe emphysema.”

“We took these features to denote a potentially dysfunctional state that could drive the development of emphysema,” said co-senior author Shahin Rafii, PhD, chief of the division of regenerative medicine, director of the Ansary Stem Cell Institute, and the Arthur B. Belfer professor in genetic medicine at Weill Cornell Medicine. “This could indicate that re-establishing a healthy vasculature—by either intravenous delivery of normal lung endothelial cells or reversing aberrant endothelial cell signaling—could encourage repair and regeneration of damaged lung tissue.”

To test their hypothesis, the team turned to an elastase-induced mouse model of COPD. Their experiments showed that, remarkably, injecting the mice with healthy lung endothelial cells reduced the alveolar destruction associated with emphysema, and restored lung function. Other cell types—even endothelial cells from other tissue—failed to have any beneficial effect. Reporting in their paper, the team stated, “We took these data to support the notion that delivery of healthy lung ECs appears to diminish emphysema and or promote repair and regeneration through possible encouragement of proliferation and tissue remodeling.”

Injection of healthy lung endothelial cells (right) reverses the destruction of lung tissue seen in mice with emphysema (left). [©2021 Hisata et al. Originally published in Journal of Experimental Medicine.]
Choi and colleagues then investigated the role of leucine-rich alpha-2-glycoprotein-1 (LRG1), a cell signaling protein linked to diabetic nephropathy and various forms of cancer, which the researchers found to be elevated in the lung endothelial cells of patients with COPD.

Removing LRG1 from endothelial cells protected mice from the tissue destruction associated with emphysema, the researchers discovered. “Hence, EC LRG1 is a critical factor involved in promoting the development of the maladaptive lung vasculature in promoting the development of the maladaptive lung vasculature observed in our murine elastase model of COPD,” the team concluded. “ … targeting endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent strategies of immense potential for the treatment of COPD/emphysema.”

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