Action plan to help patients with lung disease cope with wildfire smoke

A multidisciplinary team of UC Davis Health experts are calling on health systems to create wildfire preparedness action plans to support patients with preexisting respiratory diseases. They are urging providers to proactively put in place interventions to mitigate the effects of poor air quality from smoke.

Their article, published in the Journal of the COPD Foundation, identifies the needs of high-risk populations when affected by wildfire smoke. It outlines an action plan for health systems to help these groups with the burdens of poor air quality from wildfires.

"Patients being treated for respiratory conditions are at high-risk of exacerbations of symptoms when they are exposed to wildfire smoke," said Reshma Gupta, chief of population health and accountable care at UC Davis Health and co-author of the article. "Unfortunately, wildfire frequency and severity are increasing in the United States and negatively affecting these clinically at-risk and underserved communities. So, there is a significant need for us to install interventions to mitigate the health threat posed by wildfires."

Health impacts of poor air quality

Many components of wildfire smoke can have adverse impacts on health, especially for those with preexisting respiratory diseases.

Currently more than 34 million people living in the United States live with a chronic lung disease like asthma, chronic obstructive pulmonary disease (COPD) or Alpha-1 antitrypsin deficiency (AATD) according to the American Lung Association.

Exposure to wildfire-related air pollutants has been shown to cause and exacerbate diseases of the lungs, heart, brain and nervous system, skin and other major organs.

For patients being treated for preexisting respiratory conditions, poor air quality causes inflammation in the lungs. This can exacerbate symptoms and lead to emergency department visits and hospitalizations.

"Poor air quality can trigger exacerbations -- acute increase in shortness of breath, cough, dyspnea -- even leading to hospitalization," explained Brooks Kuhn, co-director of the Comprehensive COPD Clinic at UC Davis Health and co-author of the article. "The impact is not just transient: Respiratory exacerbations lead to persistent and accelerated worsening of lung function."

And adults are not the only ones at risk for these complications.

"Children also see these impacts when they are exposed to poor air quality from wildfires," said Kiran Nandalike, chief of pediatric pulmonology at UC Davis Children's Hospital. "As we see more wildfires impacting our communities each year, the urgency for health systems to outline a response to support patients is pressing."

Wildfire population health approach

The targeted wildfire preparedness action plan adopted by UC Davis Health uses a population health approach. This means care teams with providers from different specialties proactively work with patients who are at higher risk of developing symptoms from poor air quality.

"A population health approach zeroes in on targeted interventions tailored to specific communities or population groups," Gupta explained. "This approach considers a range of determinants, including social, economic, environmental and behavioral factors, which affect the health of these groups."

The team's wildfire preparedness action plan includes:

• Identifying clinically at-risk and underserved patient populations using well-validated, condition-targeted registries
• Assembling multidisciplinary care teams to understand the needs of these communities and patients
• Creating custom analytics and wildfire-risk stratification
• Developing care pathways based on wildfire-risk tiers by disease, risk of exposure and health care access
• Identifying outcome measures tailored to interventions with a commitment to continuous, iterative improvement efforts

"We have seen population health approaches be successfully implemented to support patients with dementia, chronic kidney disease, and cancer," Gupta said. "Using this model, we can adapt to the threat of poor air quality from wildfires and adopt a proactive approach to meet the needs of clinically at-risk and underserved patients."

UC Davis Health experience with wildfires

As the regional academic health system in Northern California, UC Davis Health has been at the epicenter of recent wildfires -- including the recent Park Fire, the fourth largest in California history. Because of this experience, the health system team has experience caring for patients in the most affected areas.

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Air pollution caused 2,780 deaths, illnesses, and IQ loss in children in Massachusetts in 2019

Air pollution remains a silent killer in Massachusetts, responsible for an estimated 2,780 deaths a year and for measurable cognitive loss in Bay State children exposed to fine particulate pollutants in the air they breathe, according to a new study by researchers at Boston College's Global Observatory on Planetary Health.

The study was supported by the Barr Foundation and is the first to examine far-reaching public health consequences of air pollution in the state on a town-by-town basis. The study found air-pollution-related disease, death and IQ loss occur in every city and town regardless of demographics or income level. Highest rates were in the most economically disadvantaged and socially underserved cities and towns.

The Boston College team estimates the cumulative impact on childhood cognitive development in Massachusetts in 2019 was a loss of almost 2 million Performance IQ points, or more than 2 IQ points for the average child, according to the report, published today in the journal Environmental Health. IQ loss impairs children's school performance and reduces graduation rates, the team noted.

"We are talking about the impacts of air pollution at a very local level in Massachusetts -- not just statewide," said lead author Boston College Professor of Biology Philip J. Landrigan, MD, director of the Observatory. "This report gives the people in every city and town the opportunity to see for themselves the quality of the air they and their families are breathing and the dangerous health implications for both adults and children as a consequence of air pollution."

"All of these health effects occurred at pollution levels below current EPA standards," Landrigan noted.

The average level of fine particulate pollution across Massachusetts in 2019 was 6.3 micrograms per cubic meter, and levels ranged from a low of 2.77 micrograms per cubic meter in Worcester County to a high of 8.26 in Suffolk County. The U.S. Environmental Protection Agency standard is 12 micrograms per cubic meter, and the World Health Organization's recommended guideline is 5.

"Clearly, current EPA air pollution standards are not adequately protecting public health," Landrigan said.

Town-by-town air pollution information is not typically available, given there are not enough air quality monitoring stations in the state. The team determined levels for all cities and towns using available data and computer modeling.

While Massachusetts meets federal clean air guidelines and air pollution in the U.S. has declined 70 percent since the passage of the Clean Air Act in the 1970s -- when Landrigan and other scientists successfully pushed for the removal of lead from gasoline -- unclean air at current levels still poses health hazards to both healthy individuals and those with other ailments or illnesses.

"We do not have the level of air pollution you see in China or India and because it is mostly invisible today people tend to forget about air pollution and we get complacent," Landrigan said. "We hope to break through this complacency and increase awareness. Air pollution is killing 2,780 people in Massachusetts each year, nearly 5 percent of all deaths in the state, and that is a big deal. Air pollution is something we can fix. We know the steps that need to be taken to reduce fatalities and the impact on our children and grandchildren. Now citizens in every city and town across the Commonwealth need to urge our elected officials to take those necessary steps."

Additional findings include:
 

• Of the 2,780 deaths attributable to air pollution in Massachusetts in 2019, at least 2,185 were due to lung cancer 1,677 to heart disease, 343 to chronic lung disease, and 200 to stroke.
• Air pollution was responsible for 15,386 cases of pediatric asthma and an estimated 308 low-birthweight babies (5.5 lbs. or less).

More than 95 percent of air pollution in Massachusetts results from the combustion of fossil fuels. Cars, trucks, buses, planes, trains and ships produced two-thirds of pollutant emissions-655,000 tons -- in 2017, the most recent year for which data were available. Power plants, industrial facilities, and home heating and cooking produced 283,000 tons. In all, these sources emitted 938,000 tons of pollutants.

Fossil fuel combustion is also the major source of the carbon dioxide and other greenhouse gases that drive global climate change, which the researchers said should further incentivize Massachusetts to reduce air pollution and greenhouse gas emissions by transitioning to cleaner fuels.

"Air pollution harms our environment and young people, and these burdens disproportionately impact environmental justice communities," said Kathryn Wright, the Barr Foundation's Senior Program Officer for Clean Energy. "Meaningful action on climate change requires us to swiftly address air pollution from transportation and our energy system and its many harmful effects."

Fine particulate air pollution is linked to multiple non-communicable diseases in adults, including cardiovascular disease, stroke, lung cancer and diabetes. Among infants and children air pollution increases risk for premature birth, low birthweight, stillbirth, impaired lung development, and asthma.

"All of these adverse health effects occur at fine particulate matter pollution levels below the U.S. Environmental Protection Agency's current annual standard of 12 micrograms per cubic meter," said Landrigan. "So even for a state like Massachusetts, which registered below that standard, air pollution is a formidable public health threat that needs urgently to be addressed."

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Decades after toxic exposure, 9/11 first responders may still lower their risk of lung injury

Losing weight and treating excess levels of fat in the blood may help prevent lung disease in firefighters exposed to dangerous levels of fine particles from fire, smoke, and toxic chemicals on Sept. 11, 2001, a new study shows. Experts have long feared that this exposure would later lead to lung disease in first responders. High body mass index (BMI), an indicator of obesity, and exposure to the highest levels of toxins from the attack on the World Trade Center were the two greatest risk factors for lowered lung function, according to the study authors.

After two decades of research analyzing thousands of first responders, a new investigation led by researchers at NYU Grossman School of Medicine identified a cluster of five factors that predicted lung disease in these patients. Along with excess body fat, the combination of insulin resistance, high blood pressure, and increased levels of sugar and cholesterol in the blood are components of so-called metabolic syndrome, a group of medical issues known to raise the risk of heart disease, stroke, and diabetes.

Adjusting at least one of these factors, the study investigators found, can greatly lower the risk of firefighters' developing lung disease within five years, even 20 years after toxic exposures at Ground Zero. For example, for a male firefighter of average height, a 7-pound weight loss could decrease his risk for lung injury by 20 percent.

"Our findings should reassure World Trade Center first responders that there are steps they can take to protect their lungs even decades after exposure," says study co-lead author Sophia Kwon, DO, MPH. Kwon is a fellow in the Division of Pulmonary, Critical Care, and Sleep at NYU Langone Health.

In work presented earlier this year on 100 overweight 9/11 firefighters, the team found that placing patients on a calorie-restricted Mediterranean diet featuring unrefined grains, olive oil, fruits, and fish reduced their risk of lung disease. Those following the regimen for six months lost nearly 2 BMI points (from an average BMI of about 33 to an average of 31) and had fewer signs of lung disease than they had reported before the study period.

"These results offer firefighters a concrete way to lose weight and achieve the lung-health benefits predicted by our risk model," says study co-lead author George Crowley, BA, a predoctoral fellow at NYU Langone.

Experts had previously understood that first responders who developed metabolic syndrome shortly after 9/11 were more likely to have higher rates of asthma. However, lung injury risks for a firefighter whose metabolic syndrome instead appeared later in life remained unclear until now.

The new study, publishing Sept. 2 in the American Journal of Respiratory and Critical Care Medicine, is part of what is likely the longest-running and most thorough exploration of the impact of metabolic syndrome on lung injury in 9/11 firefighters, according to the study authors. In addition, the investigation is the first to date to quantify how adjusting one or more of these risk factors changes lung disease risk.

For the investigation, the research team analyzed 20 years of data from more than 5,700 firefighters active on 9/11, of whom 1,475 later developed lung disease. Along with BMI, the data collected included smoking history, and whether they had served at the World Trade Center in early morning when pollutant exposure was at its peak.

"The lessons from our investigation can be applied not only to firefighters but to the millions of city dwellers exposed to air pollution on a daily basis," says study senior author and pulmonologist Anna Nolan, MD. "They should be aware that while their environment poses real health risks, they may still minimize their risk of lung disease even if they cannot change their exposure."

Nolan, a professor in the Departments of Medicine and Environmental Health at NYU Langone, cautions that while promising, the Mediterranean diet investigation only examined a small, specific group.

As a result, the research team next plans to expand the study to determine whether the diet could benefit a more diverse population who have been similarly exposed to urban pollutants. They also plan to explore how metabolic syndrome may affect other measures of lung function like asthma, says Nolan.

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Why do short-lived lung infections lead to long-lasting lung damage?

The deadliest time in a viral respiratory illness sometimes is actually after the virus is cleared from the body. Destructive processes that are set in motion during an infection crest in the weeks after the virus is defeated, leading to organ damage that can cause chronic illness or even death. After an initial bout of COVID-19, for example, some people struggle with persistent cough, difficulty breathing and shortness of breath -- signs of ongoing lung disease.

Researchers at Washington University School of Medicine in St. Louis have found clues to just how lung damage develops in the aftermath of a respiratory infection. Studying mice, they found that infection triggers the expression of a protein called IL-33, which is needed for stem cells in the lung to overgrow into air spaces, and increases mucus production and inflammation in the lung. The findings, published Aug. 24 in the Journal of Clinical Investigation, reveal potential points of intervention to prevent chronic lung damage caused by viral infections.

"Vaccines, antivirals, antibody therapies are all helpful, but they are not a solution for people who are already on the road to progressive disease," said senior author Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine and a professor of cell biology & physiology. "We've gotten better at taking care of the acute illness due to COVID-19, but what happens after that initial injury phase is still a major obstacle to a better outcome. At this point, we are also faced with tens of millions of people who already had infection, and a high percentage of them are having long-term disease, especially with respiratory symptoms. We don't have a treatment that can correct the problem."

It's long been recognized that acute respiratory infections can lead to chronic lung disease. Children hospitalized with respiratory syncytial virus, for example, are two to four times more likely to develop asthma that persists for long periods, maybe even for a lifetime. How exactly an acute respiratory infection triggers chronic disease, however, is not fully understood, making it difficult to develop therapies to prevent or treat it.

As part of this study, Holtzman and colleagues, including first author Kangyun Wu, PhD, an instructor in medicine, studied mice infected with Sendai virus. Sendai doesn't cause serious disease in people, but it naturally infects other animals including mice and causes respiratory infections that develop much like respiratory infections in people.

The researchers examined lung tissues from mice 12 and 21 days after infection with Sendai virus, and compared the samples to lung tissues of uninfected mice. They found that two populations of stem cells help maintain the barrier between the lung and the outside world in uninfected mice. After infection with Sendai virus, however, these two populations separately begin to multiply and spread into air spaces. Basal cells take over small airways and air sacs while AT2 cells remain confined to air sacs. Some of the new basal cells become mucus-producing cells while others release molecules that recruit immune cells to the lungs. Altogether, the process results in lungs with less air space, more mucus and ongoing inflammation that together interfere with breathing.

Further experiments showed that this process hinges on the protein IL-33. Under normal conditions, IL-33 increases in the nuclei of lung stem cells in response to stress or injury and helps the lung repair damaged barriers. During and after infection, though, IL-33 can take on a more detrimental role.

To assess the role of IL-33 in post-viral lung damage, the researchers genetically modified mice to lack IL-33 in the basal set of lung stem cells. The scientists then infected those mice -- and a separate group of unmodified mice -- with Sendai virus. The two groups of mice were equally effective at fighting off an initial Sendai virus infection. But three weeks after infection, the lungs of the mice that lacked IL-33 exhibited less cellular overgrowth, mucus and inflammation, indicating that they had fewer signs of harmful lung changes. At seven weeks after infection, the mice without IL-33 in basal cells also had higher oxygen levels in their blood and less airway hyperresponsiveness, both of which are signs of improvement in their chronic lung disease.

"These results were really nice to see because getting rid of IL-33 and in turn losing basal stem cells could have made things worse," Holtzman said. "The engineered mice could have died because they were no longer able to perform the normal repair of the viral damage to the lung barrier. But that's not the case. The mice lacking this population of basal cells instead had much better outcomes. That's what we're excited about. These findings put us on firm ground to find therapies that correct the bad behavior of basal stem cells."

Targeting steps on the pathway between IL-33 and basal cell activation could form the basis of broadly effective therapies to prevent or treat lung disease caused by a variety of viruses and perhaps other forms of injury in the lung and other sites where the body meets the outside world, Holtzman said.

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Firefighters found to have persistent lung damage from Fort McMurray wildfire

Firefighters at the centre of the battle against the massive Fort McMurray wildfire in 2016 have persistent lung damage, according to new findings published by a University of Alberta occupational health research team.

"Those who were dealing with burning organic matter were exposed to a barrage of small particles in the smoke, and the ones with the highest exposure have long-term consequences," said principal investigator Nicola Cherry, an occupational epidemiologist, professor of medicine and Tripartite Chair of Occupational Health in the Faculty of Medicine & Dentistry.

The firefighters had more than double the risk of developing asthma compared with the general population. They also exhibited a number of changes in lung function tests supportive of an effect on the lungs, including greater lung hyperreactivity and increased thickening of the bronchial wall.

"The impact was correlated to exposure -- those who had more exposure had more effects," said Cherry.

For three years after the fire, Cherry's team followed 1,234 Alberta firefighters.The firefighters' exposure to fire-related particles was estimated based on the hours they worked on the blaze, the dates they were there, the firefighting tasks they were performing, and Alberta Environment estimates of particulate matter at different locations.

The Fort McMurray fire broke out in May 2016 and was under control by the fall, but it was not officially declared out until the following year. The highest exposure to particulate matter happened during the first week, Cherry said. Firefighters were deployed from across Alberta from crews that specialize in structural fires (i.e., buildings), oil and gas industry fires and wildland fires.

Many did not have sufficient supplies of specialized lung protection equipment or were not able to wear it while fighting the Fort McMurray fire, Cherry said.

"It was an extraordinarily violent fire," she said. "It's very difficult to rush uphill pulling equipment behind you if you have a heavy mask on that doesn't let you breathe."

Cherry modelled her study, which was funded by the Canadian Institutes for Health Research and the Government of Alberta, on studies that examined the respiratory health of first responders following the World Trade Center collapse in New York City in September 2001.

"It's not easy to do this kind of study during a catastrophe," said Cherry, who had serendipitously taken delivery of a mobile lung assessment lab the week before the Fort McMurray fire broke out.

"At the World Trade Center, the exposure was mainly to inorganic dust, whereas in Fort McMurray it was burning vegetation, as well as buildings," Cherry said. "It's interesting that we saw similar results from very different exposure."

Cherry's research team looked at three main sources of evidence about the lung health of the firefighters before and after the fire. First, they asked for permission to link to their administrative health record, which showed doctor's visits and diagnoses. The records for each firefighter were matched with five patients from the general population of similar age, sex, geographic location and health status as a control group for comparison.

The team also measured the firefighters' lung function, which shows how much air goes in and out of the lungs. Finally, some of the firefighters with no history of chronic respiratory disease or smoking were randomly selected for clinical followup, including CT scans of their lungs and methacholine challenge testing, used to check for asthma.

This is one of several papers Cherry has published on the mental and physical health of the Fort McMurray firefighters.

"They take enormous risks," she said. "This study shows clearly that it is possible for exposures to cause changes in the lung that don't get better over time."

Cherry said she will continue to study the occupational health of firefighters -- including crews currently fighting wildfires in the interior of British Columbia and Alberta -- in hopes of recommending ways to make the work safer. She is studying whether wearing a mask or washing skin more often could reduce exposure to chemicals from smoke. Putting more crews through shorter rotations at fire scenes might also help to lessen health impacts, she said.

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Scientists scour genes of 53,000+ people to better battle dangerous diseases

A new analysis of the entire genetic makeup of more than 53,000 people offers a bonanza of valuable insights into heart, lung, blood and sleep disorders, paving the way for new and better ways to treat and prevent some of the most common causes of disability and death.

The analysis from the Trans-Omics for Precision Medicine (TOPMed) program examines the complete genomes of 53,831 people of diverse backgrounds on different continents. Most are from minority groups, which have been historically underrepresented in genetic studies. The increased representation should translate into better understanding of how heart, lung, blood and sleep disorders affect minorities and should help reduce longstanding health disparities.

"The Human Genome Project has generated a lot of promises and opportunities for applying genomics to precision medicine, and the TOPMed program is a major step in this direction," said Stephen S. Rich, PhD, a genetics researcher at the University of Virginia School of Medicine who helped lead the project. "An important feature of TOPMed is not only publishing the genomic data on 53,000 people with massive amounts of data related to heart, lung, blood and sleep disorders but also the great diversity of the participants who donated their blood and data."

Historic Genome Analysis

The groundbreaking work identified 400 million genetic variants, of which more than 78% had never been described. Nearly 97% were extremely rare, occurring in less than 1% of people. This sheds light on both how genes mutate and on human evolution itself, the researchers say.

Of the groups studied, people of African descent had the greatest genetic variability, the researchers found. The resulting data is the best ever produced on people of African ancestry, the scientists report in the journal Nature.

The work also offers important new insights into certain gene variants that can reduce people's ability to benefit from prescription drugs. This can vary by race and ethnic group.

"TOPMed is an important and historic effort to include under-represented minority participants in genetic studies," said Rich, who served on the project's Executive Committee and chaired the Steering Committee. "The work of TOPMed should translate not only into better scientific knowledge but increase diversity at all levels -- scientists, trainees, participants -- in work to extend personalized medicine for everyone."

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Cooking with wood may cause lung damage

 Advanced imaging with CT shows that people who cook with biomass fuels like wood are at risk of suffering considerable damage to their lungs from breathing in dangerous concentrations of pollutants and bacterial toxins, according to a study being presented at the annual meeting of the Radiological Society of North America (RSNA).

Approximately 3 billion people around the world cook with biomass, such as wood or dried brush. Pollutants from cooking with biomass are a major contributor to the estimated 4 million deaths a year from household air pollution-related illness.

While public health initiatives have tried to provide support to transition from biomass fuels to cleaner-burning liquefied petroleum gas as a fuel source, a significant number of homes continue to use biomass fuels. Financial constraints and a reluctance to change established habits are factors, combined with a lack of information on the impact of biomass smoke on lung health.

"It is important to detect, understand and reverse the early alterations that develop in response to chronic exposures to biomass fuel emissions," said study co-author Abhilash Kizhakke Puliyakote, Ph.D., a postdoctoral researcher from the University of California San Diego School of Medicine.

A multidisciplinary team led by Eric A. Hoffman, Ph.D., at the University of Iowa, in collaboration with researchers from Periyar Maniammai Institute of Science and Technology, investigated the impact of cookstove pollutants in 23 people cooking with liquefied petroleum gas or wood biomass in Thanjavur, India.

The researchers measured the concentrations of pollutants in the homes and then studied the lung function of the individuals, using traditional tests such as spirometry. They also used advanced CT scanning to make quantitative measurements -- for instance, they acquired one scan when the person inhaled and another after they exhaled and measured the difference between the images to see how the lungs were functioning.

Analysis showed that the ones who cooked with wood biomass were exposed to greater concentrations of pollutants and bacterial endotoxins compared to liquefied petroleum gas users. They also had a significantly higher level of air trapping in their lungs, a condition associated with lung diseases.

"Air trapping happens when a part of the lung is unable to efficiently exchange air with the environment, so the next time you breathe in, you're not getting enough oxygen into that region and eliminating carbon dioxide," Dr. Kizhakke Puliyakote said. "That part of the lung has impaired gas exchange."

The researchers found a smaller subset of the biomass users who had very high levels of air trapping and abnormal tissue mechanics, even when compared to other biomass users. In about one-third of the group, more than 50% of the air they inhaled ended up trapped in their lungs.

"This increased sensitivity in a subgroup is also seen in other studies on tobacco smokers, and there may be a genetic basis that predisposes some individuals to be more susceptible to their environment," Dr. Kizhakke Puliyakote said.

CT added important information on smoke's effect on the lungs that was underestimated by conventional tests.

"The extent of damage from biomass fuels is not really well captured by traditional tests," Dr. Kizhakke Puliyakote said. "You need more advanced, sensitive techniques like CT imaging. The key advantage to using imaging is that it's so sensitive that you can detect subtle, regional changes before they progress to full blown disease, and you can follow disease progression over short periods of time."

The lack of emphysema in the study group suggests that exposure to biomass smoke is affecting the small airways in the lungs, Dr. Kizhakke Puliyakote said, although more research is needed to understand the disease process. Regardless, the study results underscore the importance of minimizing exposure to smoke. Even in the absence of overt symptoms or breathing difficulties, the lung may have injury and inflammation that can go undetected and potentially unresolved in some people.

"For people exposed to biomass smoke for any extended duration, it is critical to have a complete assessment of lung function by health care professionals to ensure that any potential injury can be resolved with appropriate interventions," Dr. Kizhakke Puliyakote said.

While the study focused on cooking with biomass, the findings have important implications for exposure to biomass smoke from other sources, including wildfires.

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New treatments for deadly lung disease could be revealed by 3D modeling

 A 3D bioengineered model of lung tissue built by University of Michigan researchers is poking holes in decades worth of flat, Petri dish observations into how the deadly disease pulmonary fibrosis progresses.

The causes of pulmonary fibrosis are not fully understood, but the condition is marked by scar tissue that forms inside the lungs. That scar tissue stiffens the walls of the lungs' air sacs, called alveoli, or, at advanced stages, can completely fill the alveolar spaces. Both scenarios make breathing difficult and decrease the amount of oxygen entering the bloodstream. Often the condition is irreversible, eventually causing lung failure and death.

Some clinicians are concerned that critically ill COVID-19 patients may develop a form of pulmonary fibrosis after a long stay in the ICU.

Researchers are searching for better treatments. While they've managed to find some drugs that relieve symptoms or slow the progression in practice, they haven't been able to reliably replicate those results in today's 2D lab models. So they don't understand how or why those drugs are working, and they can't always predict which compounds will make a difference. The new research from U-M takes a step in that direction, and it starkly demonstrates how prior approaches have been ineffective.

The team showed that in some 2D models, drugs that are already known to be effective in treatment do not produce test results that show efficacy. Their 3D tissue engineered model of fibrotic lung tissue, however, shows that those drugs work.

Before their tests on drugs, they first performed studies to understand how tissue stiffness drives the appearance of myofibroblasts -- cells that correlate with the progression of scarring.

"Even in cells from the same patient, we saw different outcomes," said Daniel Matera, a doctoral candidate and research team member. "When we introduced stiffness into the 2D testing environment, it activated myofibroblasts, essentially creating scar tissue. When we introduced that same kind of stiffness into our 3D testing environment, it prevented or slowed the activation of myofibroblasts, stopping or slowing the creation of scar tissue."

With the majority of pulmonary fibrosis research relying on 2D testing, he said, many have believed the high lung stiffness in patients is what should be targeted by treatments. U-M's research indicates that targeting stiffness alone may not hinder disease progression in patients, even if it works in a Petri dish.

To find effective treatments, researchers first screen libraries of pharmaceutical compounds. Today, they typically do that on cells cultured on flat plastic or hydrogel surfaces, but these settings often do a poor job of recreating what happens in the human body.

Brendon Baker, assistant professor in the U-M Department of Biomedical Engineering, and his team took a tissue engineering approach. They reconstructed 3D lung interstitium, or connective tissue, the home of fibroblasts and location where fibrosis begins. Their goal was to understand how mechanical cues from lung tissue affect fibroblast behavior and disease progression.

"Recreating the 3D fibrous structure of the lung interstitium allowed us to confirm effective drugs that wouldn't be identified as hits in traditional screening settings," Baker said.

At the center of the pulmonary fibrosis mystery is the fibroblast, a cell found in the lung interstitium that is crucial to healing but, paradoxically, can also drive disease progression. When activated, after an injury or when disease is present, they become myofibroblasts. Regulated properly, they play an important role in wound healing, but when misregulated, they can drive chronic disease. In the case of pulmonary fibrosis, they cause the stiffening of lung tissue that hampers breathing.

"Our lung tissue model looks and behaves similarly to what we have observed when imaging real lung tissue," Baker said. "Patient cells within our model can actively stiffen, degrade or remodel their own environment just like they do in disease."

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COPD as a lung stem cell disease

Two stem cell experts have found an abundance of abnormal stem cells in the lungs of patients who suffer from Chronic Obstructive Pulmonary Disease (COPD), a leading cause of death worldwide. Frank McKeon, professor of biology and biochemistry and director of the Stem Cell Center, and Wa Xian, research associate professor at the center, used single cell cloning of lung stem cells to make their discovery. Now they are targeting the cells for new therapeutics.

"We actually found that three variant cells in all COPD patients drive all the key features of the disease. One produces tremendous amounts of mucins which block the small airways, while the other two drive fibrosis and inflammation which together degrade the function of the lung," Xian reports in the May 14 issue of the journal Cell. "These patients have normal stem cells, though not many of them, but they are dominated by the three variant cells that together make up the disease," she said.

COPD is a progressive inflammatory disease of the lungs marked by chronic bronchitis, small airway occlusion, inflammation, fibrosis and destruction of alveoli, tiny air sacs in the lungs which exchange oxygen and carbon dioxide molecules in the blood. The Global Burden of Disease Study reports 251 million cases of COPD globally in 2016.

"It's a frustrating disease to care for. We can try and improve the symptoms, but we don't have anything that can cure the disease or prevent death," said UConn Health pulmonologist and critical care doctor Mark Metersky, who gathered the stem cells from lung fluid while performing bronchoscopies.

Despite its accounting for more deaths than any single disease on the planet, relatively little has been written or understood about the root cause of COPD.

Over the past decade, Xian and McKeon developed technology for cloning stem cells of the lungs and airways and have been at it since, noting that different parts of the airways give different stem cells, related but distinguishable.

"It's quite remarkable," said McKeon. "In the deep lung, the distal airway stem cells gave rise to both the distal tubes and the alveoli and our research indicates those are the stem cells that make it possible for lungs to regenerate on their own." Xian and McKeon discovered lung regeneration in 2011 in their studies of subjects recovering from infections by an H1N1 influenza virus that was nearly identical to that which sparked the 1918 pandemic.

Xian and McKeon found that, in contrast to normal lungs, COPD lungs were inundated by three unusual variant lung stem cells that are committed to form metaplastic lesions known to inhabit COPD lungs, but seen by many as a secondary effect without a causal link to the pathology of COPD. After the team's postdoctoral fellow, Wei Rao, transplanted each of the COPD clones into immunodeficient subjects, the team found they not only gave rise to the distinct metaplastic lesions of COPD, but they separately triggered the triad of pathologies of COPD including mucus hypersecretion, fibrosis and chronic inflammation.

"The long-overlooked metaplastic lesions in COPD were, in fact, driving the disease rather than merely secondary consequences of the condition," said McKeon.

Now that the team knows the identity of the cells that cause inflammation, fibrosis and small airway obstruction, they are hard at work screening them against libraries of drug-like molecules to discover new therapeutics.

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