Category: Lung

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Why Many Lung Diseases are Sex-biased

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Anatomical model of lungs
Photo by Robina Weermeijer on Unsplash

By studying sex differences in expression across more than 2500 genes in mouse lung cells, researchers may have found an explanation for sex biases in the prevalence and severity of lung diseases, such as the greater severity of COVID for males. In particular, very high numbers of X-linked genes escape transcriptional silencing in lung alveolar type 2 (AT2s) cells, according to their study published in Stem Cell Reports.

“Our study is the first to compare male and female AT2 cells for gene expression, and our findings suggest that there are likely sex differences in lung repair following viral-induced injury,” says co-senior author Montserrat Anguera, an associate professor at the University of Pennsylvania.

Sex differences exist for many lung diseases, but the mechanistic basis for this remains unclear. “We started this project during the beginning of the pandemic, because we were curious about the sex bias with COVID disease, where more older men have increased morbidity, and wondered whether X-chromosome inactivation (XCI) might contribute to this sex bias,” Anguera says. “We realised that the SARS-CoV2 virus first encounters AT2 cells in the lung, and that the virus enters cells through the angiotensin-converting enzyme 2 (Ace2) receptor, which is located on the X chromosome.”

XCI is a process by which one of the copies of the X chromosome is inactivated in female mammals. The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin. XCI prevents female mammals from having twice as many X-chromosome gene products as males, who only possess a single copy of the X chromosome.

In the new study, Anguera and co-senior author Andrew Vaughan, an assistant professor at the University of Pennsylvania, investigated XCI maintenance and sex-specific gene expression profiles using male and female AT2s. The results showed that approximately 68% of expressed X-linked genes in mouse AT2s escape XCI. These genes include Ace2, which serves as the entry point into cells for SARS-CoV-2, but is also involved in lung repair.

There were genome-wide expression differences between male and female AT2s, possibly contributing to sex differences in lung injury and repair in multiple settings. Taken together, the findings demonstrate that AT2 cells have the highest levels of XCI escape for mouse cells reported to date and support a renewed focus on AT2s as a potential contributor to sex-biased differences in lung disease.

In addition, the results showed that AT2 cells, similar to immune cells, do not strictly follow the classic rules of XCI. “We were surprised to find that female AT2 cells lack canonical epigenetic modifications that are typically enriched on the inactive X as a result of XCI. These include the long noncoding RNA Xist and heterochromatic histone modifications H3K27me3 and H2AK119-ubiquitin,” Anguera says. “Because the inactive X in female AT2 cells has fewer epigenetic marks, this enables more gene expression chromosome wide, including the Ace2 gene.”

For now, it remains an open question whether ACE2 escapes XCI in human AT2 cells. to The authors say this is a likely scenario because there are significantly higher numbers of XCI escape genes in human cells compared to mouse cells.

Moving forward, the authors plan to investigate how expression from the inactive X in AT2 cells is affected by SARS-CoV2 infections. They also will continue to study how expression from the X chromosome is regulated in other cell types that do not exhibit conventional XCI maintenance. “Our findings open the door to future work investigating the genetic and epigenetic basis, residing within the X chromosome, of sex differences in immune responses to inhaled viruses,” Anguera says.

Source: Science Daily

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A New Biomarker for Chronic Lung Diseases

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Scientists have discovered that people with asthma and chronic obstructive pulmonary disease (COPD) have a protein in their lungs that leaks a molecule into their bloodstream that leads to restricted breathing instead of relaxing their airways.

The findings of their study, appearing in the American Journal of Respiratory Cell and Molecular Biology, will help clinicians diagnose and determine the severity of chronic lung diseases and make bronchodilators more effective.

“This protein has been recognised as important in some diseases, but it has never been defined before in airway diseases, such as asthma and COPD, until now,” explained co-author Reynold Panettieri, vice chancellor of translational medicine at Rutgers. “In addition to identifying this protein, we demonstrated that if you decrease the leakage, the smooth muscles in the airways relax, which could be potentially very important in improving asthma and COPD management. In addition, the presence of too much cAMP in a patient’s blood is a new biomarker that can help characterize specific types of asthma and COPD.”

The researchers found that a protein in smooth muscle cell membranes in the lungs of patients with chronic airway disease can leak cyclic adenosine monophosphate (cAMP), which signals to help relax muscles in the lungs and widen the airways. The leakage causes the airways to become constricted and cAMP can be found in the bloodstream, which can improve diagnosis of chronic airway diseases.

Researchers working together discovered the leak of cAMP from human airway smooth muscle cells from patients with and without asthma.  These cells control airway constriction in asthma, and by losing cAMP, the cells are more apt to constrict and worsen asthma. By analysing blood samples from a well-defined cohort of asthma patients, they defined cAMP in the bloodstream as a biomarker.

“We determined that cAMP blood levels are higher in asthma patients,” Panettieri said. “This knowledge allows for better diagnostics of the illness and forms the basis for new therapeutics that will plug the leak of cAMP in the protein.”

Source: Rutgers University

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Vaping Raises Oxidative Stress Levels Even in Nonsmokers

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Photo by Toan Nguyen on Unsplash
Photo by Toan Nguyen on Unsplash

In addition to the well-documented risks of smoking and vaping, a new UCLA study has revealed that a short vaping session can affect the cells of even healthy younger nonsmokers.

According to their study, published in JAMA Pediatrics, a single 30-minute vaping session can significantly increase cellular oxidative stress, which occurs when the body has an imbalance between free radicals, and the antioxidants which neutralise them.

“Over time, this imbalance can play a significant role in causing certain illnesses, including cardiovascular, pulmonary and neurological diseases, as well as cancer,” said the study’s senior author, Dr Holly Middlekauff, a professor of cardiology and physiology at the David Geffen School of Medicine at UCLA.

E-cigarettes, devices that deliver nicotine with flavouring and other chemicals in a vapour rather than smoke, are popularly seen as a safer cigarette alternative, but research by Prof Middlekauff and others has demonstrated that vaping is associated with a number of adverse changes in the body that can presage future health problems.

For the present study, 32 male and female study participants, aged 21 to 33, were split into three groups: 11 nonsmokers, nine regular tobacco cigarette smokers and 12 regular e-cigarette smokers. The researchers collected immune cells from each individual before and after a 30-minute vaping session to measure and compare changes in oxidative stress among the groups.

The researchers repeated this with a control session where participants spent 30 minutes “sham-vaping,” or puffing on an empty straw.

In nonsmokers, oxidative stress levels were found to be two to four times higher after the vaping session than before. Among the regular cigarette and e-cigarette smokers, the same 30-minute exposure did not lead to an increase in oxidative stress, the researchers noted, most likely because their baseline levels of oxidative stress were already increased.
“We were surprised by the gravity of the effect that one vaping session can have on healthy young people,” Prof Middlekauff said. “This brief vaping session was not dissimilar to what they may experience at a party, yet the effects were dramatic.”

The researchers noted that these results are especially troubling due to the increasing popularity of vaping, particularly among the youth. In a 2020 study, nearly a third of high school students reported e-cigarette use during the previous month.

There is still more to be understood about what exactly causes the changes in oxidative stress levels, whether it is caused by the nicotine or non-nicotine elements in e-cigarettes, which will be the subject of future research.

“While there’s a perception that e-cigarettes are safer than tobacco cigarettes, these findings show clearly and definitively that there is no safe level of vaping,” Prof Middlekauff said. “The results are clear, unambiguous and concerning.”

Source: UCLA

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Protein’s Involvement in Emphysema Could Yield a Treatment Target

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Researchers from Japan have found a protein that promotes the development of the early stages of emphysema, which could prove to be a target for treatment of the serious disease.

Chronic obstructive pulmonary disease (COPD) causes illness and death worldwide, and is characterised by destruction of the alveolar walls in the lungs, known as emphysema, resulting in lung function declining and to date little is known about how it develops. The Global Initiative for chronic obstructive lung disease (GOLD) has defined COPD as “a common, preventable, and treatable disease that is characterised by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.”

It is known that COPD can be triggered by certain environmental factors, such as cigarette smoking, which result in lung inflammation. The development of inflammation involves the movement of molecules inside cells, and this “intracellular trafficking” is known to play a part in some diseases. The team searched for COPD-related proteins that are involved in trafficking and identified a protein called FCHSD1, which not known to have any lung function but is associated with some diseases.

The researchers deleted the FCHSD1 protein in mice and studied these mice against normal mice when emphysema was induced. In normal mice, a large increase was seen in FCHSD1 after treatment, while mice lacking FCHSD1 were protected from the development of emphysema. These mice showed less airspace expansion from damaged air sacs, and had less inflammation and reduced apoptosis.

The researchers went on to investigate the molecular mechanism by which FCHSD1 acts. In response to stress, a protein called NRF2 moves into the nucleus to protect it. However, FCHSD1 binds to NRF2, stopping it from moving to the nucleus. “Mice with a FCHSD1 deficiency showed enhanced nuclear translocation of NRF2 and a smaller reduction in SIRT1 levels, which is seen to occur as emphysema develops,” explained lead author Takahiro Kawasaki, “and this reduced inflammation and apoptosis of lung cells.”

Increasing the activity of NRF2 to counteract FCHSD1 could therefore be a potential therapy for COPD. Treatments are currently available that target NRF2, and inhibiting FCHSD1 while targeting NRF2 could enhance these treatments and prevent systemic complications. “Our findings may also lead to a specific therapeutic strategy to ameliorate, or even halt, the progression of emphysema by inhibiting FCHSD1,” said Takashi Satoh, senior author of the paper.

Source: EurekAlert!

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Dual Drug Therapy a First for Sleep Apnoea

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In a first, researchers have hit upon a combo of two existing medications to reduce the severity of sleep apnoea in people by at least 30 percent.

Millions of people around the world are affected by sleep apnoea, a condition where the upper airway from the back of the nose to the throat closes repetitively during sleep, restricting oxygen intake and causing people to wake as often as 100 times or more per hour.

Those with untreated sleep apnoea have a higher risk of developing cardiovascular disease, dementia and depression, and are two to four times more likely to crash a car than the general population. There are no approved drug therapies to treat the condition despite nearly three decades of research, and until now, the main therapy for sleep apnoea involves wearing a mask to bed, or Continuous Positive Airway Pressure Therapy (CPAP). However, many people find it uncomfortable and half the people that try it find it hard to tolerate. Second line therapies, such as mouthguards fitted by dentists, can be unpredictable and expensive.

Prior studies had shown that two classes of medication, reboxetine and butylbromide, were able to keep muscles active during sleep in people without sleep apnoea, and assist breathing ability.

Researchers used a multitude of recording instruments to measure whether reboxetine and butylbromide could successfully target the main causes of sleep apnoea.

This included balancing the electrical activity of muscles around the airway, preventing the throat from collapsing during sleep, and improving the regulation of carbon dioxide and breathing.

Results from the study, published in the Journal of Physiology, showed these medications did in fact increase the muscle activity around participants’ airways, with the drugs reducing the severity of participants’ sleep apnoea by up to one third.

Almost everyone studied had some improvement in sleep apnoea. People’s oxygen intake improved, their number of breathing stoppages was a third or more less. These new findings allow researchers to further refine these types of medications so that they have even greater benefit than what has currently been found.

Senior author Professor Danny Eckert, Director of Adelaide Institute for Sleep Health at Flinders University commented: “We were thrilled because the current treatment options for people with sleep apnoea are limited and can be a painful journey for many.

“Next, we will look at the effects of these and similar medications over the longer term. We will assess whether we can harness the benefits of one drug without needing to use them both.

“Equally, we will test whether these treatments can be combined with other existing medications to see if we can improve their efficacy even more,” he says.

Source: University of Flinders

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A Step Towards an Asthma Vaccine

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Researchers have tested a newly developed vaccine that could confer long-term protection against allergic asthma, reducing the severity of its symptoms. 

Their research in animals has been published in the journal Nature Communications.

Asthma affects 340 million worldwide. It is a chronic disease of the air passages characterised by inflammation and narrowing of the airways in response to allergens such as dust mites. Symptoms of asthma include shortness of breath, cough, and wheezing. 

Exposure to dust mites and other allergens leads to the production of antibodies called immunoglobulin E (IgE) and type 2 cytokines (such as interleukin-4 (IL-4) and IL-13) in the airways. This leads to a cascade of reactions resulting in hyperresponsiveness of the respiratory tract, excessive mucus production, and eosinophilia (when there are too many eosinophils, a type of white blood cell, in the airways).

Currently, inhaled corticosteroids are the gold standard for controlling asthma — but in the case of severe asthma, this treatment is not enough. Then, it is necessary to use therapeutic monoclonal antibodies that target IgE or the IL-4 and IL-13 pathways. These are costly treatments, however, requiring long-term or even lifelong administration of injections.

To solve this, the researchers developed a conjugate vaccine, called a kinoid, by coupling the recombinant cytokines IL-4 and IL-13 with a carrier protein called CRM197 (a non-pathogenic mutated form of the diphtheria toxin, used in many conjugate vaccines).

The preclinical results from animal models demonstrate that this vaccine induces the sustained production of antibodies specifically directed against IL-4 and IL-13. The vaccine was so effective that six weeks after the first injection of the conjugate vaccine, 90% of the mice presented high levels of antibodies. Over one year after primary immunisation, 60% of them still had antibodies capable of neutralising IL-4 and IL-13 activity.

The vaccine was also shown to strongly reduce levels of IgE, eosinophilia, mucus production and airway hyperresponsiveness in a model of dust mite allergic asthma. This study therefore suggests both the prophylactic and therapeutic efficacy of the vaccine in this model of asthma and no adverse effects were observed in the animals. The next step for the researchers will be to test these findings in a clinical trial setting.

Source: Medical Xpress

Journal information: Eva Conde et al, Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice, Nature Communications (2021). DOI: 10.1038/s41467-021-22834-5

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Sleep Doctors are Concerned Over CPAP Negative Evaluation

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Sleep doctors are concerned about a draft report casting doubt on the clinical benefits of continuous positive airway pressure (CPAP), the clinical gold standard for sleep apnoea.

Reviewers from the Agency for Healthcare Research and Quality (AHRQ) found that studies of continuous positive airway pressure (CPAP) have consistently failed to show improvements in non-sleep-related outcomes linked to obstructive sleep apnea (OSA), such as stroke, heart attack, diabetes, and depression.

The report concluded that the published evidence “mostly does not support that CPAP prescription affects long-term, clinically important outcomes,” and it highlighted research gaps and methodological weaknesses in the available studies, along with significant CPAP compliance issues, which have all contributed to the failure to show long-term benefits for the treatment.

OSA specialists who spoke to MedPage Today about AHRQ’s research review agreed that CPAP remains by far the most effective treatment for sleep-related symptoms of OSA. They worried that the report could be misinterpreted as meaning that the treatment has no value. 
The US offers coverage for CPAP therapy under Medicare for patients with OSA, amounting to hundreds of millions of dollars per annum.. One recent study of Medicare recipients 56% were at high risk for OSA and possible candidates for treatment.

“The big fear that I have, and many of my colleagues have, is that the way this report is worded could easily be misinterpreted as saying that prescribing CPAP doesn’t improve these (long-term) outcomes, so we shouldn’t be paying for it,” said David Rapoport, MD, who directs the sleep medicine research program at the Icahn School of Medicine at Mount Sinai in New York City.

He said that it is widely recognised that CPAP is the most effective treatment for improving OSA symptoms, such as snoring and daytime sleepiness.

“Nothing else even comes close,” he said. “CPAP is really a remarkable treatment for addressing the breathing disorder associated with obstructive sleep apnea. But it has to be used, and compliance remains a big issue.”

The AHRQ review included data from 47 long term (≥6 or 12 months) randomised clinical trials for OSA.

Investigators noted that the studies used “highly inconsistent” definitions of measures such as respiratory events, as well as the Apnoea-Hypopnoea Index (AHI) metric.

“No standard definition of this measure exists and whether AHI (and associated measures) are valid surrogate measures of clinical outcomes is unknown,” the report states.

Elise Berliner, PhD, of AHRQ, told MedPage Today that addressing the inconsistencies and limitations of the existing studies should be a top priority of the sleep research community. She added that definitions should be standardised.

“I do think the community needs to get together and figure out how to do better studies,” she said. “We need larger and longer studies, and there is also the issue of compliance. In most of the studies, people were not using these devices all night long.”

The report found that the existing randomized controlled trials provide low strength of evidence that CPAP affects all-cause mortality, stroke and myocardial infarction risk, or other cardiovascular outcomes. Researchers also concluded that insufficient evidence exists showing an impact for CPAP on the risk for automobile accidents, depression, and anxiety and hypertension.

Sanjay Patel, MD, of the University of Pittsburgh, agreed inconsistency and poor CPAP compliance in sleep studies have made it difficult to assess its  impact on mortality and most other long-term outcomes.

But he, like Dr Rapoport, expressed concern that some will interpret the findings to mean that CPAP is ineffective.

“The thinking in the field has been that treatment may help prevent diseases like diabetes and heart disease that are related to sleep apnea,” he told MedPage Today. “This report says we don’t have good evidence on this, but it doesn’t really distinguish between outcomes where we do and do not have enough research to say definitively that treatment with CPAP isn’t beneficial.”

Dr Patel served on the writing committee for the American Academy of Sleep Medicine’s (AASM) latest clinical practice guidelines for OSA treatment with CPAP. He observed that the guidelines differ from the AHRQ findings, in that CPAP has been shown to lower blood pressure in hypertensive OSA patients.

The AHRQ analysis was also restricted to 6 month follow-ups or longer, while the AASM’s writing committee considered studies with shorter follow-up times.

“The effect [of CPAP] on blood pressure can be seen at 1 month,” he said. “Multiple studies with 3 months of follow-up show improvements in blood pressure, but AHRQ did not look at those studies.”

While CPAP is still considered the most effective treatment for OSA, Dr Rapoport said there is a growing recognition within the sleep medicine field that it’s not for everyone, given the ongoing issues with compliance.

“In the past, other treatments such as mandibular advancement devices have been marginalized,” he said. “These treatments don’t work nearly as well as CPAP in terms of lowering AHI, but they do work well for many patients, and people who are prescribed them actually use them. Until recently, there wasn’t much acceptance that this was good enough. But there is now greater recognition that we should maybe be prescribing treatments that aren’t perfect if people are more likely to use them.”

Source: MedPage Today

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Link Found Between Telomeres and COVID Lung Damage

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Researchers developing a therapy to regenerate lung tissue damaged by severe COVID have postulated that shortened telomeres are associated with the damage.

Telomeres are structures at the ends of chromosomes that maintain their integrity, and a small portion of them are lost with each cell division, such as when regenerating damaged tissue. As the telomere sections shorten, they eventually become unable to divide and are senescent. The team was already working on a way to regenerate lung tissue in pulmonary fibrosis, and adapted their research to the COVID pandemic. In pulmonary fibrosis, lung tissue becomes scarred and rigid, resulting in reduced lung capacity. In previous research, they had shown that telomere damage to the alveolar type II pneumocytes – which happen to be the same cells targeted by SARS-CoV-2.

Maria A Blasco, a researcher at CNIO said, “When I read that type II alveolar pneumocytes were involved in COVID-19, I immediately thought that telomeres might be involved.” The researchers believe short telomeres hinder tissue regeneration after severe COVID.

Blasco explained, “we know that the virus infects alveolar type II pneumocytes and that these cells are involved in lung regeneration; we also know that if they have telomeric damage they cannot regenerate, which induces fibrosis. This is what is seen in patients with lung lesions after COVID-19: we think they develop pulmonary fibrosis because they have shorter telomeres, which limits the regenerative capacity of their lungs.”

To support this, the team analysed the telomeres of 89 COVID patients. Although it might be expected that older patients had shorter telomeres, the researchers found that all of those with severe COVID had shorter telomeres – regardless of age.

The researchers wrote: “These findings demonstrate that molecular hallmarks of aging, such as the presence of short telomeres, can influence the severity of COVID-19 pathologies.”The involvement of shorter telomeres opens up the possibility of using telomerase to lengthen them again, as a potential treatment.The team will now move to an experimental mouse model, infecting mice with short telomeres and no telomerase with COVID, giving telomerase to some to see if the lung tissue can regenerate after severe COVID.

Source:News-Medical.Net

Journal information: Sanchez-Vazquez R, Guío-Carrión A, Zapatero-Gaviria A, Martínez P, Blasco M. Shorter telomere lengths in patients with severe COVID-19 disease. Aging (Albany NY). 2021. doi:10.18632/aging.202463

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MRI Scans Reveal Post-COVID Extent of Lung Damage

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A study of non-hospitalised individuals who had recovered from COVID but still experienced breathing difficulties had revealed lung damage where other tests were unable to.

To investigate post-COVID lung damage, Prof Fergus Gleeson led a study involving 10 participants aged 19 to 69, of whom eight had been experiencing breathing difficulties three months after a COVID infection. They had not been hospitalised for their COVID, and conventional scans had not been able to detect any abnormalities with their lungs.

The patients’ lungs were imaged using magnetic resonance imaging (MRI) scans with xenon present in the lungs. Xenon, a noble gas, is non-toxic Xenon has a long history of use as a contrast agent, and is soluble with pulmonary tissue, allowing for investigation of specific lung characteristics that are connected to gas exchange and alveolar oxygenation, at the level of small airways where pulmonary function tests (PFTs) cannot provide information.

The scans revealed that there was indeed lung damage preventing alveolar oxygenation – and it was unexpectedly severe.

Prof Gleeson said, “I was expecting some form of lung damage, but not to the degree that we have seen.”

The findings help to explain the phenomenon of “long COVID”, where patients who have recovered from COVID continue to experience fatigue and breathing difficulties months after the original infection has ended.Based on the findings, Prof Gleeson will undertake a study with a further 100 participants based on the same criteria.

Source: BBC News 

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Gut Microbiome is Linked to Pulmonary Disease

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A link has been shown between the gut microbiome and chronic obstructive pulmonary disease (COPD), a lung disease with an often poor prognosis.

Senior author Prof Phil Hansbro, Director of the Centenary University of Technology Sydney Centre for Inflammation, said, “It’s already known that the lung microbiome is a contributing factor in COPD. We wanted to see if the gut environment was also somehow involved–to determine whether the gut could act as a reliable indicator of COPD or if it was connected in some way to the development of the disease.”

Stool samples of COPD patients showed elevated levels of the bacteria Streptococcus and Lachnospiraceae. Additionally a unique metabolite signature was identified in individuals with COPD, created by the chemical by-products of the metabolic process.

First author Dr Kate Bowerman from the University of Queensland said, “Our research indicates that the gut of COPD patients is notably different from healthy individuals. This suggests that stool sampling and analysis could be used to non-invasively diagnose and monitor for COPD,” she said.
“The ‘gut-lung axis’ describes the common immune system of the lung and gastrointestinal tract. This means that activity in the gut can impact activity in the lung. Our COPD findings suggest that the gut microbiome should now also be considered when looking for new therapeutic targets to help treat lung disease,” Prof Hansbro said.

Source: Medical Xpress