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, the devastating disorder that floods the lungs with fluid and has ushered countless millions to death after infection with pneumonia, sepsis, and COVID-19.
Two centuries after the lung damage caused by the disorder was first described in medicine, it’s now clear that ARDS is an autoimmune condition spurred by the body’s overactive defenses. There’s interest in disrupting “crosstalk” between cells, and rise of a new form of genetic analysis is allowing researchers to test their hypotheses more effectively than ever before. And, perhaps most importantly, recent findings reveal how stem cells in the epithelial lining of the lungs get stalled in an intermediate stage before regenerating into new cells. Reversing this process could trigger repair and recovery.
There’s still a ways to go before clinical trials can test therapies to turn things around at the epithelial level, acknowledged University of Michigan, Ann Arbor, professor of internal medicine Rachel L. Zemans, MD, in an interview. Still, “it’s a pretty exciting time,” said Dr Zemans, who manages a lab that explores how the lung epithelium responds to injury.
A lung disorder’s deep roots in human history
A British doctor first described the traits of ARDS in 1821, although this form of pulmonary edema had been described in “ancient writings,” according to a 2005 report by Gordon Bernard, MD, of Vanderbilt University Medical Center, Nashville, Tennessee. Sometimes called “double pneumonia,” ARDS was almost always fatal until the last few decades of the 20th century. “The advent of well-equipped ICUs, well-trained staff, and the availability of reliable positive pressure ventilators has allowed patients to be kept alive much longer and thus have the opportunity to heal the pulmonary injury and survive,” Dr Bernard wrote.
According to the Mayo Clinic, there are many causes of ARDS. Sepsis is the most common, and others include severe pneumonia, head/chest injuries, massive blood transfusions, pancreatitis, burns, and inhalation of harmful substances. Since 2020, ARDS has been a hallmark of COVID-19.
In an interview, University of Washington, Seattle, emeritus professor of medicine Thomas R. Martin MD, explained that ARDS occurs when the epithelium barrier in the lungs breaks down. Unlike the permeable endothelial barrier, the alveolar epithelium is “like a brick wall or a big dam, keeping red cells and plasma out of the airspace.”
In cases of pulmonary edema due to heart failure, fluid can back up into the lungs, said Dr Martin, who studies ARDS. However, pumps in the epithelium can clear that excess fluid pretty quickly because the epithelium remains in a normal state, he said. “Given enough time and enough medical support, people with heart failure and pulmonary edema can get better without lung injury.”
In ARDS, however, “the epithelium is damaged. Cells die in the alveolar wall, the scaffolding is exposed, and the fluid in the alveoli cannot be cleared out. You’ve got a disaster on your hands because all of the fluid and red blood cells and inflammatory products in the blood are going right into the airspace. The patient gets extremely short of breath because their oxygen level falls.”
COVID-19 virus finds a weak spot in the lungs
COVID-19 is “a classic example of an attack on the alveolar epithelium,” Dr Martin said.
By chance, the virus evolved to recognize receptors in the epithelium, allowing it to enter and propagate. “To make matters worse, defense mechanisms in the body attack those dying epithelial cells because the virus is visible on the surface cells. So lymphocytes from the immune system and macrophages attack the outer walls and cause further damage.”
Other scientists agree about this general picture of ARDS. “Studies of human lung tissue support the notion that failure of alveolar repair and regeneration mechanisms underlie the chronic lung dysfunction that can result from ARD,” wrote researchers from Cedars-Sinai Medical Center, Los Angeles, California, and Icahn School of Medicine at Mount Sinai, New York, NY, in a 2022 report.
According to Dr Martin, researchers and clinicians have discovered a pair of strategies to help vanquish COVID-19: Control viral entry through antiviral medication and dampen the body’s inflammatory response via steroids.
Still, “although we’ve learned lessons from COVID-19, we’re not good at all at promoting repair,” Dr Martin said. While new drugs have dramatically improved treatment for lung diseases such as cystic fibrosis, he said, “we don’t have good examples of new therapies that promote repair in ARDS.”
Looking for a way to turn the tide of fluid buildup
Dr Zemans and colleagues have uncovered a crucial obstacle to repair: the failure of stem cells to fully differentiate and become functional alveolar epithelial cells.
Researchers only began to understand a few years ago that the stem cells go through a transitional stage from type 2 to type 1, which make up 98% of cells in the epithelial surface, Dr Zemans said. In patients with ARDS who don’t get better quickly, “it looks like the cells get hung up in this intermediate state. They can’t finish that regeneration.”
As a 2022 study by Dr Zemans and colleagues put it, this process can lead to “ongoing barrier permeability, noncardiogenic pulmonary edema, and ventilator dependence, and mortality.” In fact, she said, “when we look at the lungs of people who died of ARDS, their cells were all in that intermediate stage.”
The discovery of the intermediate state only came about because of new technology called single-cell RNA sequencing, she said. “Now, these transitional cells are being found in other organs.”
Why do the epithelial cells get only part way through the regeneration process? It’s not entirely clear, Dr Zemans said, but researcher are intrigued by the idea that “cross-talk” between cells is playing a role.
“When the cells are in that stage, they also activate neighboring cells, including inflammatory cells, like macrophages, and fibroblasts,” she said. “And once those cells become activated, they become pathologic. What we think is that those cells then can talk back to the epithelial cells and prevent the epithelial cells from finishing that differentiation. It’s really hard to snap out of that positive feedback loop.”
This interaction probably evolved “for a good reason,” she said, “but it also became pathologic.” If the cells stay in the intermediate stage too long, she said, fibrosis develops. “They have scar tissue that never goes away. It takes a lot of work to expand the lungs when they’re so stiff when they should be stretchy like a rubber band. Scar tissue also gets in the way of the oxygen absorption, so some people have low oxygen levels.”
Future directions: Teaching cells to get “unstuck”
What’s next for research? One direction is exploring the variety of types of cells in the epithelium. Recent finding are revealing “new cell subpopulations that maintain alveolar homeostasis, communicate injury signals, and participate in normal and maladaptive repair. Emerging data illuminate the complexity of alveolar physiology and pathology to provide a more complete picture of how alveoli maintain health and respond to injurious stimuli,” write the researchers from Cedars-Sinai Medical Center and Icahn School of Medicine at Mount Sinai in their 2022 report.
Meanwhile, “we’re trying to look at the signaling pathways, the proteins or molecules, to understand the signals that tell a cell how to get unstuck,” Dr Zemans said. And researchers are exploring whether knocking out certain genes expressed by transitional cells in mice will lead to better outcomes, she said.
The 2022 study by Dr Zeman and colleagues described the potential ramifications of better understanding of the entire process: “Ultimately, investigation of the cellular and molecular mechanisms underlying ineffectual alveolar regeneration in ARDS and fibrosis may lead to novel therapies to promote physiological regeneration, thus accelerating restoration of barrier integrity, resolution of edema, liberation from the ventilator and survival in ARDS, and preventing fibrosis in fibroproliferative ARDS and [idiopathic pulmonary fibrosis].”
To put it more simply, “if you can seal the barrier, you can get the fluid out of the lungs, and you can get the patients off the ventilator, get out of the ICU, and go home,” Dr Zemans said.
Dr Zemans and Dr Martin have no disclosures.
, the devastating disorder that floods the lungs with fluid and has ushered countless millions to death after infection with pneumonia, sepsis, and COVID-19.
Two centuries after the lung damage caused by the disorder was first described in medicine, it’s now clear that ARDS is an autoimmune condition spurred by the body’s overactive defenses. There’s interest in disrupting “crosstalk” between cells, and rise of a new form of genetic analysis is allowing researchers to test their hypotheses more effectively than ever before. And, perhaps most importantly, recent findings reveal how stem cells in the epithelial lining of the lungs get stalled in an intermediate stage before regenerating into new cells. Reversing this process could trigger repair and recovery.
There’s still a ways to go before clinical trials can test therapies to turn things around at the epithelial level, acknowledged University of Michigan, Ann Arbor, professor of internal medicine Rachel L. Zemans, MD, in an interview. Still, “it’s a pretty exciting time,” said Dr Zemans, who manages a lab that explores how the lung epithelium responds to injury.
A lung disorder’s deep roots in human history
A British doctor first described the traits of ARDS in 1821, although this form of pulmonary edema had been described in “ancient writings,” according to a 2005 report by Gordon Bernard, MD, of Vanderbilt University Medical Center, Nashville, Tennessee. Sometimes called “double pneumonia,” ARDS was almost always fatal until the last few decades of the 20th century. “The advent of well-equipped ICUs, well-trained staff, and the availability of reliable positive pressure ventilators has allowed patients to be kept alive much longer and thus have the opportunity to heal the pulmonary injury and survive,” Dr Bernard wrote.
According to the Mayo Clinic, there are many causes of ARDS. Sepsis is the most common, and others include severe pneumonia, head/chest injuries, massive blood transfusions, pancreatitis, burns, and inhalation of harmful substances. Since 2020, ARDS has been a hallmark of COVID-19.
In an interview, University of Washington, Seattle, emeritus professor of medicine Thomas R. Martin MD, explained that ARDS occurs when the epithelium barrier in the lungs breaks down. Unlike the permeable endothelial barrier, the alveolar epithelium is “like a brick wall or a big dam, keeping red cells and plasma out of the airspace.”
In cases of pulmonary edema due to heart failure, fluid can back up into the lungs, said Dr Martin, who studies ARDS. However, pumps in the epithelium can clear that excess fluid pretty quickly because the epithelium remains in a normal state, he said. “Given enough time and enough medical support, people with heart failure and pulmonary edema can get better without lung injury.”
In ARDS, however, “the epithelium is damaged. Cells die in the alveolar wall, the scaffolding is exposed, and the fluid in the alveoli cannot be cleared out. You’ve got a disaster on your hands because all of the fluid and red blood cells and inflammatory products in the blood are going right into the airspace. The patient gets extremely short of breath because their oxygen level falls.”
COVID-19 virus finds a weak spot in the lungs
COVID-19 is “a classic example of an attack on the alveolar epithelium,” Dr Martin said.
By chance, the virus evolved to recognize receptors in the epithelium, allowing it to enter and propagate. “To make matters worse, defense mechanisms in the body attack those dying epithelial cells because the virus is visible on the surface cells. So lymphocytes from the immune system and macrophages attack the outer walls and cause further damage.”
Other scientists agree about this general picture of ARDS. “Studies of human lung tissue support the notion that failure of alveolar repair and regeneration mechanisms underlie the chronic lung dysfunction that can result from ARD,” wrote researchers from Cedars-Sinai Medical Center, Los Angeles, California, and Icahn School of Medicine at Mount Sinai, New York, NY, in a 2022 report.
According to Dr Martin, researchers and clinicians have discovered a pair of strategies to help vanquish COVID-19: Control viral entry through antiviral medication and dampen the body’s inflammatory response via steroids.
Still, “although we’ve learned lessons from COVID-19, we’re not good at all at promoting repair,” Dr Martin said. While new drugs have dramatically improved treatment for lung diseases such as cystic fibrosis, he said, “we don’t have good examples of new therapies that promote repair in ARDS.”
Looking for a way to turn the tide of fluid buildup
Dr Zemans and colleagues have uncovered a crucial obstacle to repair: the failure of stem cells to fully differentiate and become functional alveolar epithelial cells.
Researchers only began to understand a few years ago that the stem cells go through a transitional stage from type 2 to type 1, which make up 98% of cells in the epithelial surface, Dr Zemans said. In patients with ARDS who don’t get better quickly, “it looks like the cells get hung up in this intermediate state. They can’t finish that regeneration.”
As a 2022 study by Dr Zemans and colleagues put it, this process can lead to “ongoing barrier permeability, noncardiogenic pulmonary edema, and ventilator dependence, and mortality.” In fact, she said, “when we look at the lungs of people who died of ARDS, their cells were all in that intermediate stage.”
The discovery of the intermediate state only came about because of new technology called single-cell RNA sequencing, she said. “Now, these transitional cells are being found in other organs.”
Why do the epithelial cells get only part way through the regeneration process? It’s not entirely clear, Dr Zemans said, but researcher are intrigued by the idea that “cross-talk” between cells is playing a role.
“When the cells are in that stage, they also activate neighboring cells, including inflammatory cells, like macrophages, and fibroblasts,” she said. “And once those cells become activated, they become pathologic. What we think is that those cells then can talk back to the epithelial cells and prevent the epithelial cells from finishing that differentiation. It’s really hard to snap out of that positive feedback loop.”
This interaction probably evolved “for a good reason,” she said, “but it also became pathologic.” If the cells stay in the intermediate stage too long, she said, fibrosis develops. “They have scar tissue that never goes away. It takes a lot of work to expand the lungs when they’re so stiff when they should be stretchy like a rubber band. Scar tissue also gets in the way of the oxygen absorption, so some people have low oxygen levels.”
Future directions: Teaching cells to get “unstuck”
What’s next for research? One direction is exploring the variety of types of cells in the epithelium. Recent finding are revealing “new cell subpopulations that maintain alveolar homeostasis, communicate injury signals, and participate in normal and maladaptive repair. Emerging data illuminate the complexity of alveolar physiology and pathology to provide a more complete picture of how alveoli maintain health and respond to injurious stimuli,” write the researchers from Cedars-Sinai Medical Center and Icahn School of Medicine at Mount Sinai in their 2022 report.
Meanwhile, “we’re trying to look at the signaling pathways, the proteins or molecules, to understand the signals that tell a cell how to get unstuck,” Dr Zemans said. And researchers are exploring whether knocking out certain genes expressed by transitional cells in mice will lead to better outcomes, she said.
The 2022 study by Dr Zeman and colleagues described the potential ramifications of better understanding of the entire process: “Ultimately, investigation of the cellular and molecular mechanisms underlying ineffectual alveolar regeneration in ARDS and fibrosis may lead to novel therapies to promote physiological regeneration, thus accelerating restoration of barrier integrity, resolution of edema, liberation from the ventilator and survival in ARDS, and preventing fibrosis in fibroproliferative ARDS and [idiopathic pulmonary fibrosis].”
To put it more simply, “if you can seal the barrier, you can get the fluid out of the lungs, and you can get the patients off the ventilator, get out of the ICU, and go home,” Dr Zemans said.
Dr Zemans and Dr Martin have no disclosures.
, the devastating disorder that floods the lungs with fluid and has ushered countless millions to death after infection with pneumonia, sepsis, and COVID-19.
Two centuries after the lung damage caused by the disorder was first described in medicine, it’s now clear that ARDS is an autoimmune condition spurred by the body’s overactive defenses. There’s interest in disrupting “crosstalk” between cells, and rise of a new form of genetic analysis is allowing researchers to test their hypotheses more effectively than ever before. And, perhaps most importantly, recent findings reveal how stem cells in the epithelial lining of the lungs get stalled in an intermediate stage before regenerating into new cells. Reversing this process could trigger repair and recovery.
There’s still a ways to go before clinical trials can test therapies to turn things around at the epithelial level, acknowledged University of Michigan, Ann Arbor, professor of internal medicine Rachel L. Zemans, MD, in an interview. Still, “it’s a pretty exciting time,” said Dr Zemans, who manages a lab that explores how the lung epithelium responds to injury.
A lung disorder’s deep roots in human history
A British doctor first described the traits of ARDS in 1821, although this form of pulmonary edema had been described in “ancient writings,” according to a 2005 report by Gordon Bernard, MD, of Vanderbilt University Medical Center, Nashville, Tennessee. Sometimes called “double pneumonia,” ARDS was almost always fatal until the last few decades of the 20th century. “The advent of well-equipped ICUs, well-trained staff, and the availability of reliable positive pressure ventilators has allowed patients to be kept alive much longer and thus have the opportunity to heal the pulmonary injury and survive,” Dr Bernard wrote.
According to the Mayo Clinic, there are many causes of ARDS. Sepsis is the most common, and others include severe pneumonia, head/chest injuries, massive blood transfusions, pancreatitis, burns, and inhalation of harmful substances. Since 2020, ARDS has been a hallmark of COVID-19.
In an interview, University of Washington, Seattle, emeritus professor of medicine Thomas R. Martin MD, explained that ARDS occurs when the epithelium barrier in the lungs breaks down. Unlike the permeable endothelial barrier, the alveolar epithelium is “like a brick wall or a big dam, keeping red cells and plasma out of the airspace.”
In cases of pulmonary edema due to heart failure, fluid can back up into the lungs, said Dr Martin, who studies ARDS. However, pumps in the epithelium can clear that excess fluid pretty quickly because the epithelium remains in a normal state, he said. “Given enough time and enough medical support, people with heart failure and pulmonary edema can get better without lung injury.”
In ARDS, however, “the epithelium is damaged. Cells die in the alveolar wall, the scaffolding is exposed, and the fluid in the alveoli cannot be cleared out. You’ve got a disaster on your hands because all of the fluid and red blood cells and inflammatory products in the blood are going right into the airspace. The patient gets extremely short of breath because their oxygen level falls.”
COVID-19 virus finds a weak spot in the lungs
COVID-19 is “a classic example of an attack on the alveolar epithelium,” Dr Martin said.
By chance, the virus evolved to recognize receptors in the epithelium, allowing it to enter and propagate. “To make matters worse, defense mechanisms in the body attack those dying epithelial cells because the virus is visible on the surface cells. So lymphocytes from the immune system and macrophages attack the outer walls and cause further damage.”
Other scientists agree about this general picture of ARDS. “Studies of human lung tissue support the notion that failure of alveolar repair and regeneration mechanisms underlie the chronic lung dysfunction that can result from ARD,” wrote researchers from Cedars-Sinai Medical Center, Los Angeles, California, and Icahn School of Medicine at Mount Sinai, New York, NY, in a 2022 report.
According to Dr Martin, researchers and clinicians have discovered a pair of strategies to help vanquish COVID-19: Control viral entry through antiviral medication and dampen the body’s inflammatory response via steroids.
Still, “although we’ve learned lessons from COVID-19, we’re not good at all at promoting repair,” Dr Martin said. While new drugs have dramatically improved treatment for lung diseases such as cystic fibrosis, he said, “we don’t have good examples of new therapies that promote repair in ARDS.”
Looking for a way to turn the tide of fluid buildup
Dr Zemans and colleagues have uncovered a crucial obstacle to repair: the failure of stem cells to fully differentiate and become functional alveolar epithelial cells.
Researchers only began to understand a few years ago that the stem cells go through a transitional stage from type 2 to type 1, which make up 98% of cells in the epithelial surface, Dr Zemans said. In patients with ARDS who don’t get better quickly, “it looks like the cells get hung up in this intermediate state. They can’t finish that regeneration.”
As a 2022 study by Dr Zemans and colleagues put it, this process can lead to “ongoing barrier permeability, noncardiogenic pulmonary edema, and ventilator dependence, and mortality.” In fact, she said, “when we look at the lungs of people who died of ARDS, their cells were all in that intermediate stage.”
The discovery of the intermediate state only came about because of new technology called single-cell RNA sequencing, she said. “Now, these transitional cells are being found in other organs.”
Why do the epithelial cells get only part way through the regeneration process? It’s not entirely clear, Dr Zemans said, but researcher are intrigued by the idea that “cross-talk” between cells is playing a role.
“When the cells are in that stage, they also activate neighboring cells, including inflammatory cells, like macrophages, and fibroblasts,” she said. “And once those cells become activated, they become pathologic. What we think is that those cells then can talk back to the epithelial cells and prevent the epithelial cells from finishing that differentiation. It’s really hard to snap out of that positive feedback loop.”
This interaction probably evolved “for a good reason,” she said, “but it also became pathologic.” If the cells stay in the intermediate stage too long, she said, fibrosis develops. “They have scar tissue that never goes away. It takes a lot of work to expand the lungs when they’re so stiff when they should be stretchy like a rubber band. Scar tissue also gets in the way of the oxygen absorption, so some people have low oxygen levels.”
Future directions: Teaching cells to get “unstuck”
What’s next for research? One direction is exploring the variety of types of cells in the epithelium. Recent finding are revealing “new cell subpopulations that maintain alveolar homeostasis, communicate injury signals, and participate in normal and maladaptive repair. Emerging data illuminate the complexity of alveolar physiology and pathology to provide a more complete picture of how alveoli maintain health and respond to injurious stimuli,” write the researchers from Cedars-Sinai Medical Center and Icahn School of Medicine at Mount Sinai in their 2022 report.
Meanwhile, “we’re trying to look at the signaling pathways, the proteins or molecules, to understand the signals that tell a cell how to get unstuck,” Dr Zemans said. And researchers are exploring whether knocking out certain genes expressed by transitional cells in mice will lead to better outcomes, she said.
The 2022 study by Dr Zeman and colleagues described the potential ramifications of better understanding of the entire process: “Ultimately, investigation of the cellular and molecular mechanisms underlying ineffectual alveolar regeneration in ARDS and fibrosis may lead to novel therapies to promote physiological regeneration, thus accelerating restoration of barrier integrity, resolution of edema, liberation from the ventilator and survival in ARDS, and preventing fibrosis in fibroproliferative ARDS and [idiopathic pulmonary fibrosis].”
To put it more simply, “if you can seal the barrier, you can get the fluid out of the lungs, and you can get the patients off the ventilator, get out of the ICU, and go home,” Dr Zemans said.
Dr Zemans and Dr Martin have no disclosures.