Emphysema is a condition that causes damage to the alveoli, the air sacs in your lungs. The walls of the damaged air sacs become stretched out and cause your lungs to get bigger. This makes it harder to move your air in and out. It is the most common form of the condition known as chronic obstructive pulmonary disease (COPD) and is typically triggered by long-term cigarette smoking. Estimates show that approximately 200 million people around the world are affected. Unfortunately, there is no cure for this disease of the lungs.
A study conducted by researchers at Weill Cornell Medicine and NewYork-Presbyterian found that specialized endothelial cells may hold the key to treating emphysema. Endothelial cells line the inner surface of blood vessels and have been shown to play an important role in protecting and restoring the health of key organs. Specifically, lung endothelial cells line the inner surface of the lung’s network of blood vessels.
As part of their research, the team studied lung tissue from human emphysema patients while also looking at lung issue from mice with an induced form of the disease. What they found that was that changes in the activity of certain genes in lung endothelial cells and the loss of those cells was associated with decreased lung function and other indicators of emphysema progression.
The researchers then infused mice with induced emphysema with healthy lung endothelial cells from genetically identical mice and the results were astounding. The team showed that they could prevent and/or reverse most of the lung damage that was seen in untreated mice. By contrast, injecting other cell types, including endothelial cells from other tissues, did not have the same effect.
The team believes that this treatment effect might have to do with differences in the molecules secreted by diseased versus healthy lung endothelial cells. To back up this claim, they found that lung endothelial cells in both humans and mice with emphysema showed sharp increases in production of LRG1, a molecule that promotes new blood vessel growth that has been linked to retinal and kidney diseases as well as some cancers. Additionally, when the researchers deleted the gene for LRG1 from lung endothelial cells in mice, the lungs were largely protected from the lung damage of induced emphysema, much as they had been by the endothelial cell therapy.
In a news release from Cornell, Dr. Alexandra Racanelli, a co-first author on this study and an instructor of medicine in the Division of Pulmonary and Critical Care Medicine at Weill Cornell Medicine and a pulmonologist at NewYork-Presbyterian/Weill Cornell Medical Center, had this to say about the results.
“Taken together, our data strongly suggest the critical role of endothelial cell function in mediating the pathogenesis of COPD/emphysema. 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.”
The full study was published in the Journal of Experimental Medicine.
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The increased of serum LRG1 levels are associated with various diseases, including different types of cancer, inflammatory bowel disease, joint disorders and cardiovascular diseases. Bone marrow derived cells serves as a major source of LRG1. The LRG1 is markedly induced in inflammatory stage of wound healing. The deletion of LRG1 causes impaired of immune cells infiltration, reepithelialization and angiogenesis resulting in substantial delay in wound closure. Therefore, LRG1 is required for normal wound healing but the excessive of LRG1 expression in diabetics is pathogenic and contributing to chronic wound formation. Thus, serum of patients with high levels of LRG1 is closely related to inflammatory, autoimmune and cardiovascular diseases.
Endothelial cell line is an inner part of vessel has important roles to maintain vascular homeostasis and regulate vascular tone, vessel permeability and leukocytes adhesion. The vascular homeostasis becoming breakdown, when endothelium cells (ECs) are activated by factors such as proinflammatory cytokines, hyperglycemia and pro-anthrogenic shear stress. However, dysfunctional of ECs is associated with development of atherosclerosis, a chronic inflammatory disease involves excessive net uptaktof low density lipoprotein(LDL). LRG1 is intimately linked to tissues inflammation. An increase of LRG1 expression is induced in activated ECs and endothelium of stenosed coronary arteries. The elevated uniaxial shear stress is relevant to arteries are already in stenotic. The different levels of LRG1expression in stenotic coronary arteries suggest a potential role of LRG1 evolved in vascular homeostasis and arterial disease. Therefore, shear stress has ability to regulate LRG1 expression in the condition of normal and pathologically. The LRG1 is stored in secretory vesicles of ECs and released quickly upon activation by external stimuli. The activated ECs also express high levels of adhesion molecules (VCAM-1 & ICAM-1) to enable monocytes capture adhesion and subsequent transendothelial migration before initiation of atherogenesis. The upregulation of LRG1 in human diseases could potentially prevent monocytes -endothelial interaction and monocytes infiltration into subendothelia space. Therefore, LRG1 plays an important regulatory role in ECs activation and endothelial-monocytes interaction.
Airspace diseases or COPD showed significant endothelial cell loss, apoptotic, angiogenic and inflammatory state of lung . Although alveolar destruction can be rescued by intravenous delivery of healthy lung ECs. However, LRG1 is a potential activator of emphysema in lung. The deletion of LRG1 from ECs was able to rescue vascular rarefaction and alveolar regression.
To note that the deletion of LRG1from ECs provides an efficiency tool for tissue therapy in patient with lung disease but the treatment is only supported short-term benefits of health. LRG1 is a key player for endothelial homeostasis and arterial disease. Thus, LRG1 is critical to support long-term health of lung tissue development and functioning.