Observatory and Fast Facts

March 23, 2022
A disruption in lung cell repair probable cause of acute respiratory distress syndrome in COVID-19

Investigators studying lung cells have discovered that the normal repair process that occurs after lung disease or injury appears to be incomplete but still ongoing in patients who died of COVID-19 and non-COVID acute respiratory distress syndrome, according to the University of Michigan.

In patients who survive but develop scarring in the lungs, it appears that the repair process is permanently arrested, leading to chronic fibrotic lung disease. These findings may lead to novel therapies to promote healthy regeneration to increase survival and prevent fibrosis, they report in The American Journal of Pathology.

The alveolar epithelium in the lungs is made up of two types of cells. Type 1 alveolar epithelial cells (AEC1) are flat and broad and cover most of the alveolar surface. They play a critical role in barrier integrity and facilitate efficient oxygen absorption. Type 2 alveolar endothelial cells (AEC2) are small cuboidal cells that cover the rest of the surface. They produce a pulmonary surfactant to inflate the lungs and remove the fluid. AEC1 and AEC2 are damaged in ARDS due to COVID-19 or other causes. It is known that during lung injury in mice, AEC2 proliferate, exit the cell cycle, and enter a transitional state before changing into AEC1 to repair the alveolar epithelium. In humans with idiopathic pulmonary fibrosis (IPF), AEC2 never leave the transitional state, and change into AEC1, leading to the development of scar tissue known as fibrosis. The state of epithelial injury and regeneration in COVID-19 and non-COVID-19 ARDS without fibrosis had not been well characterized.

The investigators recovered lung tissue from the autopsies of patients who died of COVID-19 or non-COVID-19 ARDS within two weeks of hospitalization. They were compared with patients with IPF. The tissue was examined for evidence of AEC2 proliferation, transitional cells, AEC1 differentiation, indications of the loss of the ability to divide (senescence), and fibrosis. Investigators also compared the gene expression profiles of transitional cells in two mouse models of physiological regeneration without fibrosis, early human COVID-19 and non-COVID-19 ARDS, and human IPF.

The early ARDS lungs had extensive epithelial damage and a regenerative response in which ACE2 proliferated and entered the transitional state. The transitional cells occasionally assumed a flat AEC1 morphology but rarely expressed AEC1 markers. In contrast to patients with IPF, these lungs had not yet developed fibrosis.

The investigators propose that in COVID-19 survivors who recover normal lungs, the transitional cells ultimately regenerate the damaged cells. However, in survivors who develop scarred lungs, AEC1 are never regenerated; cells are stuck in the transitional state which can lead to scarring and lifelong respiratory impairment.

Alternative approach for the treatment of prostate cancer uses sound waves

UC San Diego Health is first in San Diego County to employ high-intensity, focused ultrasound for minimally invasive prostate cancer treatment, according to University of California San Diego Health.

High-intensity focused ultrasound (HIFU) is a minimally invasive, outpatient treatment for localized prostate cancer. The technology uses high-frequency sound waves directed at the cancerous tissue through an ultrasound probe inserted into the rectum.

The sound waves target and heat the cancerous tissue to temperatures high enough to cause cell death.

HIFU provides an alternative to surgery or radiation for eligible patients. UC San Diego Health is the only hospital system in San Diego County to offer HIFU to prostate cancer patients.

Ideal candidates for HIFU are those who have early-stage, low- to intermediate-grade cancer that is confined to the prostate. HIFU is used to treat a single tumor containing part of the prostate, half, or in all the gland.

Through the advanced HIFU system, high-resolution images are combined with biopsy data and real-time ultrasound imaging to provide urologists with a 3D view of cancerous tissues. Physicians can then draw precise contours around the diseased tissue, ablate only that portion of the affected organ and minimize damage to surrounding structures, which include nerves important for erectile function, blood vessels and muscle tissue. For the patient, the approach minimizes the risk of urinary incontinence and erectile dysfunction.

Researchers’ findings could help improve bone marrow and stem cell transplantation

A recent study led by researchers at Massachusetts General Hospital (MGH) and Boston University School of Medicine has revealed the unique signature of genes, hematopoietic stem cells (HSC) have the capacity to both self-renew and differentiate into all mature blood cell types, indicating promising treatments for a variety of diseases.

The findings, which are published in Nature Communications, could enable scientists to expand these cells outside of the body or to convert other types of stem cells into cells that can repopulate the blood system. However, the mechanisms involved in engraftment—when the cells start to grow and make healthy blood cells after being transplanted into a patient—are poorly understood.

In adults, HSCs are found in the bone marrow and bloodstream, but before birth, they can be found to a greater extent in the liver, where they multiply, or proliferate, into additional HSCs at a very high rate. Moreover, research in animals has shown that HSCs in the fetal liver are more capable of engraftment than HSCs from bone marrow.

To understand what allows fetal liver HSCs to have these superior proliferation and engraftment characteristics, investigators examined the gene expression patterns that are unique to these highly potent stem cells. They combined this examination with a variety of experimental methods to characterize the protein expression and functionality of those same cells.

The enhanced understanding of the genes involved will also help scientists propagate HSCs with high engraftment potential in the lab and manipulate them to fight blood cell–related diseases, such as sickle cell anemia, HIV, and certain types of cancer, more efficiently. “Altogether, this work has resulted in a detailed blueprint of the most potent blood stem cells and will lead to a better understanding of why these cells have such an extraordinary regenerative capacity. Such insights will allow us to create safer and more efficient therapies for patients suffering from blood disorders,” says lead author Kim Vanuytsel, PhD, a Research Assistant Professor of Medicine at Boston University School of Medicine.

Co–senior author George J. Murphy, PhD, an associate professor of medicine at Boston University School of Medicine and co-founder of the BU and BMC Center for Regenerative Medicine (CReM), adds that the team’s openly shared resource will enable new biological insights into engraftment potential and stimulate a broad range of future studies. “This important work would not have been possible without the potent, collegial collaborations that took place between Boston area institutions. This project is also a shining example of ‘open-source biology’ at work where the freely shared information and insights can be harnessed by all for future discovery,” he says.

Link found between cholesterol crystals and heart infections

A study by researchers from the Michigan State University College of Human Medicine is the first to establish a link between the formation of cholesterol crystals and bacterial infections in the heart, according to a news release from the university.

The bacteria attach and feed on the cholesterol crystals, the study found. The microscopic crystals, which are jagged, imbed in heart valves, allowing the bacteria to grow and causing endocarditis, a life-threatening inflammation of the heart valves.

A key event is when liquid cholesterol transition to crystals, which assume a greater volume in the arteries. Even a moderate drop in body temperature can trigger crystallization, which likely explains why many heart attacks occur early in the morning.

As the jagged crystals flow through the bloodstream, they scrape and damage blood vessel walls, causing them to spasm and constrict and possibly triggering a heart attack, he said.

The researchers found crystals protruding from heart valves, allowing bacteria to grow and infect the valves. An earlier study found that statins could prevent the valve damage, but only if given before the onset of the disease.

Future studies could lead to new treatments to prevent cholesterol crystals from forming. Abela referred to these as “sort of super statins,” something that has the capacity to dissolve crystals rapidly. 

MAIT cells may be key to the next wave of immunotherapy and vaccine development

Mucosal-associated invariant T (MAIT) cells, an unconventional form of immune cell, exercise several complex roles during healthy and disease states and may help to serve as a benchmark for future research on these cells as targets for immunotherapies and vaccines, according to new research as described in a news release from Stony Brook University.

The findings were published in the Journal of Immunology.

In recent years, MAIT cells have received increasing attention by researchers because of their abundance in the human body, the fact that they can be rapidly activated by non-peptide vitamin intermediates from microbes, and because of their involvement in both infectious and non-infectious disease processes. Despite emerging interest in MAIT cells, it is not fully understood how they are involved in fighting disease.

“We used single cell RNA sequencing technology and immunologic techniques to reveal that despite being ‘one cell type with a semi-invariant T cell receptor,’ MAIT cells demonstrate marked heterogeneity that recapitulates conventional T cell biology,” explains lead author Charles K. Vorkas, MD, Assistant Professor in the Departments of Medicine, Microbiology and Immunology at the Renaissance School of Medicine at Stony Brook University.

Vorkas and colleagues demonstrated in the laboratory that this marked heterogeneity includes distinct CD4+ and CD8+ lineages, as well as “killer,” “helper,” and “regulatory” cell phenotypes — an indication that MAIT cells exercise complex functions.

He emphasizes that in light of recent studies showing that MAIT cells respond to infectious diseases like COVID-19, as well as during inflammatory events of autoimmune disease such as in lupus, or during tumorigenesis, a better understanding of their roles will help us to develop new therapies.

Vorkas and colleagues are now trying to identify MAIT cell subpopulations responding to initial infection with Mycobacterium tuberculosis, the causative agent of TB disease, as well as to tick-borne infections endemic to Long Island. His lab hopes to harness MAIT cells and other innate lymphocyte populations to develop immunotherapeutic alternatives to antibiotic drugs and to design novel vaccines.