Inhaled nitric oxide treats multidrug-resistant Pseudomonas pneumonia

Good news!

From the editor's summary and abstract:

"Editor’s summary

The global crisis of antimicrobial resistance urgently requires new therapeutic approaches.

Inhaled high-dose nitric oxide (NO) has potential antimicrobial activity against bacteria, viruses, and fungi.

In this study, Yu et al. first developed a swine model of Pseudomonas aeruginosa pneumonia and demonstrated that inhalation of 300 ppm of NO effectively reduced bacterial burden and improved lung function. The authors then showed that this inhaled high-dose NO was safe both in healthy individuals and in two patients in the intensive care unit with P. aeruginosa pneumonia. There were no adverse outcomes during 6 years of follow-up in another group of patients who received high-dose NO. ...

Abstract

Antibiotic resistance in respiratory infections is an escalating global concern that requires innovative antimicrobial approaches.

Pseudomonas aeruginosa is a common multidrug-resistant pathogen and a major cause of hospital-acquired pneumonia. Accumulating evidence suggests that, at high doses, inhaled nitric oxide (iNO) acts as a potent antimicrobial agent. This study evaluated the efficacy and safety of iNO at 300 parts per million (iNO300) as a treatment for P. aeruginosa infection.

In vitro, P. aeruginosa exhibited a dose-dependent reduction when exposed to an NO donor. In a mechanically ventilated swine model of P. aeruginosa pneumonia, intermittent iNO300 therapy resulted in a two-log reduction in bacterial burden, improved oxygenation and lung compliance, and reduced histopathological lung injury.

A phase 1 clinical trial in 10 healthy individuals confirmed the safety of intermittent iNO300 therapy with no adverse events.

In two critically ill patients with multidrug-resistant bacteria, who were in the intensive care unit, iNO300 was well tolerated, demonstrating clinical feasibility. Long-term follow-up of patients exposed to high-dose iNO for more than 6 years revealed no adverse outcomes.

Our findings establish iNO300 as a promising antimicrobial agent against P. aeruginosa pneumonia, warranting further clinical evaluation."

Inhaled nitric oxide at 300 ppm treats multidrug-resistant Pseudomonas pneumonia in swine and is safe in humans | Science Translational Medicine

Poland’s Transformed Tuberculosis Response following the influx of 1.5 million war refugees from the Ukraine in 2022

Good news! Bravo Poland for taking in so many war refugees!

"When Poland saw a rapid influx of 1.5 million Ukrainian refugees in 2022, health officials were on high alert for drug-resistant tuberculosis, as Ukraine has one of the highest TB burdens in the world. 

 

But the crisis laid bare Poland’s own outdated tuberculosis response system, which involved long, isolated hospital stays and multiyear, often toxic, drug regimens.  

 

Rapid revitalization: Poland swiftly overhauled its care model, implementing a pilot program that included a six‑month course of an oral drug combination known as BPaL/M, which has far higher cure rates than Poland’s previous standard protocol of various drugs. ..."

How Concerning Are Microplastics? The Jury Is Still Out.

How a refugee crisis revitalised Poland's tuberculosis care (no public access)

First breathing lung-on-chip developed using genetically identical cells

Amazing stuff!

"Researchers at the Francis Crick Institute and AlveoliX have developed the first human lung-on-chip model using stem cells taken from only one person. These chips simulate breathing motions and lung disease in an individual, holding promise for testing treatments for infections like tuberculosis (TB) and delivering personalized medicine. ...

Until now, these lung-on-chip devices have been made of a mixture of patient-derived and commercially available cells, meaning they can't fully replicate the lung function or disease progression of a single individual.

In the study, the team ... developed a new lung-on-chip model that contains only genetically identical cells derived from stem cells from a single donor. ...

To further simulate the human lung, AlveoliX has designed specialized machines to impose rhythmic three-dimensional stretching forces on the recreated air sac barrier, mimicking the motion of breathing. This stimulates the formation of microvilli, a key feature of alveolar epithelial cells, to increase surface area for lung functions ..."

"... Tuberculosis (TB) is a very slow-progressing disease in humans, taking months for a person to develop symptoms after being infected with the bacteria Mycobacterium tuberculosis. ... this highlights an increasing need to understand what’s happening in the early stages, when TB bacteria first encounter the body’s defences in the air sacs in the lungs. ..."

From the abstract (emphasis added):

"Immunocompetent and experimentally accessible alveolar systems to study human respiratory diseases are lacking.

Here, we developed a single-donor human induced pluripotent stem cell-derived lung-on-chip (iLoC) containing type II and I alveolar epithelial cells, vascular endothelial cells, and macrophages in a microfluidic device that mimic lung three-dimensional mechanical stretching and air-liquid interface.

Imaging and single-cell RNA sequencing analysis revealed that the iLoC recapitulated cellular profiles present in the human distal lung.
Infection of the iLoC with the human pathogen Mycobacterium tuberculosis (Mtb) showed that both macrophages and epithelial cells were infected but not permissive to bacterial replication. Stochastically, large macrophage clusters containing necrotic macrophages supporting Mtb replication were observed. A genetically engineered autophagy-deficient iLoC revealed that after Mtb infection, macrophage necrosis was higher upon ATG14 deficiency without bacterial replication. Together, we report an autologous, genetically tractable human alveolar model to study lung diseases and therapies."

First breathing 'lung-on-chip' developed using genetically identical cells

Built to breathe: mini ‘lungs’ recreate individual response to infection (original news release) "Lung-on-chip device exposes earliest stages of tuberculosis infection, and opens doors to investigate diversity in disease progression and personalised treatment. "

Autologous human iPSC–derived alveolus-on-chip reveals early pathological events of Mycobacterium tuberculosis infection (open access)

Image of the lung-on-chip, with cell nuclei in blue, macrophage in magenta, endothelial cells in yellow and tight junctions between epithelial and endothelial cells in white.

Image of a lung-on-chip infected by Mycobacterium tuberculosis, with cell nuclei in blue, dead macrophage in magenta, tight junctions between epithelial and endothelial cells in yellow and TB bacteria in white.

Fig. 1. iPSC-derived iAT2 and iAT1s are differentiated in a lung-on-chip microfluidic device.

Fig. 5. The iLoC mimic early stages of infection with Mtb.

How a newly examined gut microbe drives the gut-lung axis

Amazing stuff!

"Their findings highlight how a little-known member of the gut microbiome reshapes the lung immune environment to have both beneficial and detrimental effects on respiratory health. ...

For their study, the researchers looked at a protozoan called Tritrichomonas musculis, or T. mu, that resides harmlessly in the gut of mice.

They found that mice colonized with T. mu had unexpectedly high levels of specific immune cells in their lungs. Importantly, the researchers showed that some of these immune cells originated from the gut and moved to the lungs, where they fine-tuned the local immune environment and changed outcomes related to respiratory illnesses and infections.

By triggering the production and migration of these immune cells from the gut to the lung, T. mu functions as "a conductor in the intestine that orchestrates the immune system to populate other regions of the body," ...

One of the study's key findings was that T. mu-driven immune changes in the lung worsened airway inflammation caused by allergic asthma but appeared to have a protective effect against respiratory infections. ..."

From the highlights and abstract:

"Highlights

• Tritrichomonas musculis (T.mu) drives trafficking of gut-derived ILC2s to the lung

• T.mu instills an ILC2, B cell, and T cell tripartite network via ICOS-OX40-IL-2

• A T.mu-triggered lung immune network promotes steady-state eosinophilia

• T.mu exacerbates asthma and boosts shielding against Mycobacterium tuberculosis (M.tb)

Summary

The underlying mechanisms used by the intestinal microbiota to shape disease outcomes of the host are poorly understood. Here, we show that the gut commensal protozoan, Tritrichomonas musculis (T.mu), remotely shapes the lung immune landscape to facilitate perivascular shielding of the airways by eosinophils. Lung-specific eosinophilia requires a tripartite immune network between gut-derived inflammatory group 2 innate lymphoid cells and lung-resident T cells and B cells. This network exacerbates the severity of allergic airway inflammation while hindering the systemic dissemination of pulmonary Mycobacterium tuberculosis. The identification of protozoan DNA sequences in the sputum of patients with severe allergic asthma further emphasizes the relevance of commensal protozoa in human disease. Collectively, these findings demonstrate that a commensal protozoan tunes pulmonary immunity via a gut-operated lung immune network, promoting both beneficial and detrimental disease outcomes in response to environmental airway allergens and pulmonary infections."

How a newly examined gut microbe drives the gut-lung axis "A team led by University of Toronto researchers has discovered a new communication pathway between the gut and lung."

U of T study uncovers how a new gut microbe drives the gut-lung axis (original news release)

A gut commensal protozoan determines respiratory disease outcomes by shaping pulmonary immunity

Graphical abstract

New asthma cause identified – and a new angle for treatment

Good news! This seems to be a breakthrough!

"... But the new study points to a different root cause, of which inflammation is itself a symptom. When the airway muscles contract – known as bronchoconstriction – the epithelial cells that line the airways are 'squeezed out' and later die. With fewer of these cells acting as a barrier, the chances for future asthma attacks increase. ...
“Without this barrier, asthma sufferers are far more likely to get long-term inflammation, wound healing, and infections that cause more attacks." ...
“Current therapies do not prevent this destruction – an inhaler such as Albuterol opens the airways, which is critical to breathing but, dishearteningly, we found it does not prevent the damage and the symptoms that follow an attack,” ... “Fortunately, we found that we can use an inexpensive compound, gadolinium which is frequently used for MRI imaging, to stop the airway damage in mice models as well as the ensuing inflammation and mucus secretion. Preventing this damage could then prevent the build-up of musculature that cause future attacks.”"

"Most current asthma treatments stem from the idea that it is an inflammatory disease. Yet, the life-threatening feature of asthma is the attack or the constriction of airways, making breathing difficult. The new study, published today in Science, shows for the first time that many features of an asthma attack—inflammation, mucus secretion, and damage to the airway barrier that prevents infections - result from this mechanical constriction in a mouse model. ..."

From the perspectives abstract:

"Reports of what were known at that time as “asthmatic fits” can be traced back millennia, but a mechanistic understanding of the basis for what are now called asthma exacerbations remains incomplete. Over the past 100 years, multiple mechanisms have been proposed, including constriction of the smooth muscle that encircles the airways (bronchoconstriction), persistent airway inflammation, and disruption of the epithelial layer that lines the airways. Yet how these processes interconnect and contribute to asthma exacerbations has been debated.  ... show that bronchoconstriction results in pathological overcrowding of cells in the airway epithelium, squeezing out (extruding) epithelial cells and thus damaging the epithelial layer enough to trigger inflammation. They also show that drugs that block the extrusion pathway, and thereby prevent mechanical damage to the epithelium during acute airway narrowing, may have the capacity to break the inflammatory cycle and potentially revolutionize how asthma is treated."

From the editor's summary and abstract:

"Editor’s summary

Asthma, a very common airway disorder, is generally understood to be a condition of excessive inflammation in which environmental triggers stimulate immune responses in the lungs, resulting in bronchoconstriction. The mainstays of asthma therapy are albuterol, which is a short-acting bronchodilator for immediate relief of symptoms, and corticosteroids to treat the underlying inflammation. Unfortunately, this approach is not always effective even in combination. ... have demonstrated that bronchoconstriction-induced mechanical damage to the airways and extrusion of epithelial cells also contribute to asthma pathology and may interfere with healing ... By contrast, compounds that counteracted this mechanical damage showed beneficial effects in mouse models, either alone or combined with albuterol, although their safety in humans remains to be assessed. ...

Abstract

Asthma is deemed an inflammatory disease, yet the defining diagnostic feature is mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial cell death when cells become too crowded. In this work, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion in both mice and humans. Although relaxing the airways with the rescue treatment albuterol did not affect these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these features. Our findings show that bronchoconstriction causes epithelial damage and inflammation by excess crowding-induced cell extrusion and suggest that blocking epithelial extrusion, instead of the ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle."

New asthma cause identified – and a new angle for treatment

Discovery of how limiting damage from an asthma attack could stop disease (original news release) Scientists at King’s have discovered a new cause for asthma that sparks hope for treatment that could prevent the life-threatening disease.

Epithelial cells crowded out in asthma (no public access) Bronchoconstriction causes epithelial cell extrusion that promotes airway inflammation

Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion (no public access)

Single-Cell Atlas of the Whole Human Lung from healthy and diseased cells

Good news! What a gigantic undertaking! A major milestone!

"... Now, a large team of researchers has successfully combined 49 lung datasets, from nearly 40 separate studies, into a single integrated Atlas, using advanced machine learning. By pooling and integrating datasets from every major single-cell RNA-sequencing lung study published to date, the team created the first integrated Human Lung Cell Atlas. This Atlas spans over 2.4 million cells from 486 individuals and gives new insights into lung biology that were not possible before. ...

While the core of the Human Lung Cell Atlas is data from healthy lungs, the team also took datasets from more than 10 different lung diseases and projected these onto the healthy data, to understand disease states. ..."

From the abstract:

"Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas."

Single-Cell Atlas of the Whole Human Lung | AZBio By combining data from nearly 40 studies, an international team of researchers ... created the first integrated single-cell atlas of the lung, revealing rare cell types and highlighting cellular differences between healthy people. In addition, the study found common cell states between lung fibrosis, cancer and COVID-19, offering new ways of understanding lung disease, which could help identify new therapeutic targets.

An integrated cell atlas of the lung in health and disease (open access)

Fig. 1: HLCA study overview.

Extended Data Fig. 10: Disease-specific cellular states and states shared across diseases in the extended HLCA.

New nanoparticles can perform gene editing in the lungs

Good news! After liver and muscles, the lungs are next!

"Engineers ... have designed a new type of nanoparticle that can be administered to the lungs, where it can deliver messenger RNA encoding useful proteins.

With further development, these particles could offer an inhalable treatment for cystic fibrosis and other diseases of the lung, the researchers say. ...

In a study of mice, Anderson and his colleagues used the particles to deliver mRNA encoding the machinery needed for CRISPR/Cas9 gene editing. That could open the door to designing therapeutic nanoparticles that can snip out and replace disease-causing genes. ...
Messenger RNA holds great potential as a therapeutic for treating a variety of diseases caused by faulty genes. One obstacle to its deployment thus far has been difficulty in delivering it to the right part of the body, without off-target effects. ..."

"The ability to create in vivo genomic medicines for tissues other than the liver has been impeded by difficulties in delivery. Using a high-throughput platform, we developed lipid nanoparticles that can effectively deliver mRNA and CRISPR–Cas9 gene editing tools to the lungs through intratracheal administration, expanding the potential clinical uses of gene editing and mRNA-based technologies."

From the abstract:

"The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for messenger RNA and CRISPR–Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases."

New nanoparticles can perform gene editing in the lungs | MIT News | Massachusetts Institute of Technology Using these RNA-delivery particles, researchers hope to develop new treatments for cystic fibrosis and other lung diseases.

Lipid nanoparticle-enabled gene editing in the lung via inhalation

Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing (no public access)

New treatment for a root cause of asthma proves promising in mice tests

Good news! However, it will take a while for medications to become available.

Again, those poor lab animals that have to suffer for us!

"... In a new study, researchers ... have demonstrated a molecule that may prevent this airway remodeling. Known as LIT-927, the molecule works by blocking the signal from a protein called CXCL12, which is what triggers pericytes to migrate to the airway walls.
In tests in asthmatic mice, the researchers found that the animals’ symptoms essentially disappeared after two weeks of treatment with LIT-927. The walls of their airways were also much thinner than in untreated mice. ..."

From the abstract:

"Background

Airway remodeling is a significant contributor to impaired lung function in chronic allergic airway disease. Currently, no therapy exists that is capable of targeting these structural changes and the consequent loss of function. In the context of chronic allergic inflammation, pericytes have been shown to uncouple from the pulmonary microvasculature, migrate to areas of inflammation, and significantly contribute to airway wall remodeling and lung dysfunction. This study aimed to elucidate the mechanism by which pulmonary pericytes accumulate in the airway wall in a model of chronic allergic airway inflammation.

Methods

Mice were subjected to a protocol of chronic airway inflammation driven by the common environmental aeroallergen house dust mite. Phenotypic changes to lung pericytes were assessed by flow cytometry and immunostaining, and the functional capacity of these cells was evaluated using in vitro migration assays. The molecular mechanisms driving these processes were targeted pharmacologically in vivo and in vitro.

Results

Pericytes demonstrated increased CXCR4 expression in response to chronic allergic inflammation and migrated more readily to its cognate chemokine, CXCL12. This increase in migratory capacity was accompanied by pericyte accumulation in the airway wall, increased smooth muscle thickness, and symptoms of respiratory distress. Pericyte uncoupling from pulmonary vessels and subsequent migration to the airway wall were abrogated following topical treatment with the CXCL12 neutraligand LIT-927.

Conclusion

These results provide new insight into the role of the CXCL12/CXCR4 signaling axis in promoting pulmonary pericyte accumulation and airway remodeling and validate a novel target to address tissue remodeling associated with chronic inflammation."

New treatment for a root cause of asthma proves promising in mice tests

Chemokine CXCL12 drives pericyte accumulation and airway remodeling in allergic airway disease (open access)

Bacteria in the Lungs Can Regulate Autoimmunity in Rat Brains

Amazing stuff! More on the symbiosis between human and internal living bacteria (microbiome)!

"The community of microbes living on the folds of the lung’s alveoli doesn’t attract the same scientific fascination as its neighbor, the gut microbiome. But new research in rats suggests it exerts significant influence over the immune system, just like gut microbes can. ...
Scientists f... demonstrated that perturbing the rat lung microbiome—a bacterial community that was long thought to not exist—can regulate autoimmunity in the central nervous system. ... Specifically, the scientists found that certain microbial treatments could alter the behavior of microglial cells in the animals’ brains—cells that typically maintain the central nervous system by clearing dead or damaged cells—influencing the development of symptoms in a rat model of multiple sclerosis (MS). ..."

From the abstract:

"... Here we detected a tight interconnection between the lung microbiota and the immune reactivity of the brain. A dysregulation in the lung microbiome significantly influenced the susceptibility of rats to developing autoimmune disease of the central nervous system. Shifting the microbiota towards lipopolysaccharide-enriched phyla by local treatment with neomycin induced a type-I-interferon-primed state in brain-resident microglial cells. Their responsiveness towards autoimmune-dominated stimulation by type II interferons was impaired, which led to decreased proinflammatory response, immune cell recruitment and clinical signs. ... Our data demonstrate the existence of a lung–brain axis in which the pulmonary microbiome regulates the immune reactivity of the central nervous tissue and thereby influences its susceptibility to autoimmune disease development."

Bacteria in the Lungs Can Regulate Autoimmunity in Rat Brains | The Scientist Magazine® Making specific alterations to the bacterial population in a rat’s lungs either better protects the animals against multiple sclerosis–like symptoms or makes them more vulnerable, a study finds—the first demonstration of a lung-brain axis.

The lung microbiome regulates brain autoimmunity (no public access, but the above article contains a link to the PDF file)