In a recent study on the damage of COVID-19, researchers examined the critical role of vascular endothelial cells in lung repair. Their work was led by Andrew Vaughan of the University of Pennsylvania School of Veterinary Medicine and shows that, using techniques that deliver vascular endothelial growth factor alpha (VEGFA) via lipid nanoparticles (LNPs), they were able to improve greatly how these damaged blood vessels are repaired, just as plumbers repair sections of broken pipes and add new ones.
The results of research were published in Science Translational Medicine.
Here's how to repair lung tissue after Covid19
In the human body, the lungs and their vascular system can be compared to a building with an intricate plumbing system. The blood vessels of the lungs are the essential tubes for transporting blood and nutrients to supply oxygen and remove carbon dioxide. Just as pipes can rust or clog, interrupting the normal flow of water, damage caused by respiratory viruses, such as Covid19 or influenza, can interfere with this “plumbing system”.
“While our lab and others have already shown that endothelial cells are among the unsung heroes in lung repair after viral infections like influenza, this tells us more about the story and sheds light on the molecular mechanisms at play,” he says Vaughan, assistant. professor of biomedical sciences at Penn Vet.
“Here we identified and isolated the pathways involved in the repair of this tissue, delivered the mRNA to the endothelial cells and consequently observed improved recovery of the damaged tissue. These findings suggest a more efficient way to promote lung recovery after diseases like Covid19. ”
They discovered the involvement of VEGFA in this recovery, building on work in which they used single-cell RNA sequencing to identify transforming growth factor beta receptor 2 (TGFBR2) as the major signaling pathway.
The researchers saw that the lack of TGFBR2 disrupted the activation of VEGFA. This lack of signaling made blood vessel cells less able to multiply and renew themselves, which is vital for the exchange of oxygen and carbon dioxide in the small air sacs of the lungs.
“We knew there was a link between these two pathways, but this motivated us to see whether VEGFA mRNA distribution in endothelial cells could improve lung recovery after disease-related injury,” says first author Gan Zhao, PhD, Ph.D. postdoctoral fellow at Vaughan University. Laboratory.
The Vaughan Lab then contacted Michael Mitchell of the School of Engineering and Applied Science, whose lab specializes in LNP, to see if delivery of this mRNA payload would be feasible.
LNPs have been great for vaccine delivery and have proven to be incredibly effective vehicles for delivering genetic information. But the challenge here was to get the LNPs into the bloodstream without them going to the liver, which is where they tend to congregate as its porous structure lends itself favorably to substances passing from the blood into the liver cells for filtration,” says Professor Mitchell bioengineering associate at Penn Engineering and co-author of the paper.
“So, we had to figure out a way to specifically target the endothelial cells in the lungs.”
Lulu Xue, a postdoctoral researcher at the Mitchell Lab and co-first author of the paper, explains that they designed the LNP to have an affinity for lung endothelial cells, this is known as extra-hepatic delivery, going beyond the liver .
“We've seen evidence in the literature that suggests it's feasible, but the systems we saw were made of positively charged lipids that were too toxic,” Xue says.
“This led me to develop an ionizable lipid that does not become positively charged when it enters the bloodstream, but becomes charged when it gets to the endothelial cells, thus releasing the mRNA.”
Their LNPs were effective in delivering VEGFA into endothelial cells and as a result the researchers observed a marked improvement in vascular recovery in their animal models.
In animal models, researchers saw improved oxygen levels, and in some the treatment helped them regain weight better than the control group. These treated mice also had less lung inflammation, demonstrated by lower levels of certain markers in the lung fluid, and their lungs showed less damage and scarring, with healthier blood vessels.
“Although we were hopeful for this outcome, it was a real thrill to see how effective, safe and efficient this all turned out to be, so we look forward to testing this delivery platform for other cell types in the lung, and it will be important evaluate whether TGFB signaling is important in other injury settings, including chronic conditions such as emphysema and COPD,” says Vaughan.
“Once we validate this proof of concept, we are confident that we will pave the way for new mRNA-based strategies for the treatment of lung lesions.”
Health care providers are learning crucial new information to help improve care for long COVID patients, thanks to a pair of recent studies from the Post-covid19 program at UT Health Austin, the clinical practice of Dell Medical School at the University of Texas to Austin. In recent months, UT researchers have gotten closer to defining the pattern of symptoms it generates and how it affects patients, as well as developing ways to differentiate long COVID patients from other conditions.
While consensus on the clinical definition is evolving, the National Institutes of Health (NIH) defines long COVID as Covid19 symptoms and conditions that persist for weeks, months, or even years after a person's initial infection. Even people who had no symptoms at the time of infection can develop them later.
“These research efforts are critical for both doctors and health systems in grasping the complexities of long-term Covid19 and as part of providing the best possible care to patients,” said W. Michael Brode, MD, medical editor of the Post -covid19 Program.
Brode stressed that long COVID, which occurs in about 10% of Covid19 cases, remains a challenge.
“Our research is not only refining t
he definition and long-term treatment needs of Covid19, but is also demonstrating the effectiveness of innovative testing methods,” said Brode, who is also an assistant professor in the Department of Internal Medicine at Dell Med. “These methods can identify and diagnose common Covid19 problems for a long time, even when traditional tests fail.”
Research published in Scientific Reports aims to understand the experiences of long-term Covid19 patients to improve services in specialist clinics post-covid19. The study of 252 patients found that they experienced complex and disabling symptoms regardless of the severity of the initial infection, their age, gender or whether they had pre-existing health problems.
Patients reported an average of 18 new symptoms after recovering from Covid19 disease. The most common were fatigue (89%), “brain fog” (89%) and difficulty concentrating (77%).
Nearly half showed mild cognitive dysfunction during testing, and 65% of patients rated their mental health and 73% their physical health as “fair” or “poor.” The disease significantly affected patients' ability to work, with a decrease in full-time employment and an increase in the unemployment rate.
Another study, conducted in collaboration with researchers at Ohio State University, introduces a blood test capable of distinguishing between fibromyalgia patients and long Covid19 patients with 100% accuracy.
Published in Biomedicines, the study presents a promising approach to differentiate between Covid19 and fibromyalgia. Fibromyalgia is a chronic disorder that causes pain and tenderness throughout the body, as well as fatigue and sleep disturbances, symptoms that tend to overlap with long COVID. Neither condition currently has a diagnostic test.
The study involved 100 adult patients, half diagnosed with long COVID and half with fibromyalgia. Researchers found a distinct chemical marker in the blood of fibromyalgia patients, which was absent in those with long-term Covid19. According to Brode, the blood test is quick and could easily be conducted in the clinic, potentially leading to quicker and more accurate diagnoses.
“We hope that the findings can not only improve our understanding of COVID in the long term, but also pave the way for targeted diagnoses and interventions,” Brode said. “Millions of Americans are still living with the scars of the pandemic, and we hope to translate these insights into tangible health solutions.”
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