Lung map uncovers insights into asthma
UK and European researchers have mapped the building blocks of the human lungs and airways in asthma patients, creating the first draft human cell atlas of the lung. Reported in the journal Nature Medicine, the maps reveal the differences between asthmatic and normal airways and identify how cells in the lung communicate with each other.
The job of the human immune system is to read our environment and react to potentially harmful substances. In asthma, the immune system is overactive, causing inflammation in the lungs and symptoms such as coughing, wheezing and shortness of breath — and while it is often manageable with medication, the disease can cause ongoing problems and there is the risk of severe, life-threatening asthma attacks. A better understanding of healthy lung cells and the differences with asthmatic lungs is thus required to develop new effective medications.
To explore cell types within normal lungs and upper airways, researchers used single-cell technology to study samples from 17 people. They analysed more than 36,000 individual cells from the nasal area and from three different areas of the lung. This allowed them to see exactly which genes were active in each cell and identify the specific cell type.
The researchers then detected the different cell types and activities in lung samples from six asthma patients, comparing them to normal lungs. They discovered there were clear differences between the cells in normal and asthmatic lungs. For example, the researchers discovered a new mucus-creating cell state — the muco-ciliated state — in asthmatic lungs, which had not been seen before.
The study revealed large differences between normal and asthmatic lungs in the cells and how they communicated with each other. The asthmatic lungs had many more inflammatory Th2 immune cells, which sent the vast majority of cellular signals in asthma, compared with a broad range of cell communications in normal lungs.
“We already knew that inflammatory Th2 cells played a role in asthma, but only now do we see how great that influence is,” said senior author Dr Martijn Nawijn, from University Medical Center Groningen. “In normal people, all kinds of cells communicate with each other in order to keep the airways functioning well. But in asthma patients, almost all of those interactions are lost. Instead of a network of interactions, in asthma the inflammatory cells seem to completely dominate the communication in the airways.”
Knowing the types of cells in asthmatic lungs and how they communicate could help researchers seek new drug targets that could prevent the cells from responding to the inflammatory signals and help restore normal lung function. The study also showed that cells in different areas of the lung had very different cellular activities, which has further implications for studying drug targets and designing drug trials.
“Our large-scale, open access data reveals the activity of different cells, their communication pathways and locations,” said senior author Dr Sarah Teichmann, co-chair of the Human Cell Atlas Organising Committee. “The lung cell atlas will provide a great resource for further lung research and we hope that it will enable the identification of potential new therapeutic targets for asthma relief.”
Researchers from Sweden’s Karolinska Institutet have meanwhile released their own study of asthma development, seeking to assess the role of Th2 immune cells in asthma-related inflammation. The rarity of these cells and a lack of sensitivity technology has previously made it difficult to study them in any detail, but the researchers have now used a highly sensitive technique called single-cell RNA sequencing to analyse which genes are active in individual immune cells.
For the study, the team exposed mice to house dust mites, a common allergen to which most asthmatics are sensitive and which induces asthma-like lung inflammation. They then monitored gene expression in T cells before and after exposure to the allergens in the lymph glands to the point of inflammation in the lungs. The results were published in the journal Immunity.
The team found that in the mouse lung, the T cells express a unique profile of hundreds of genes, many of which are linked to how the cells make and break down fat. When they then gave mice a drug to block fat metabolism, the lung inflammation decreased relative to controls.
“Our results suggest that fats can help to aggravate the T cell-activated inflammation in the lungs that is seen in asthma,” said corresponding author Jonathan Coquet. “We now plan to systematically test the importance of the hundreds of uniquely expressed genes in order to find those that can trigger or prevent the development of the disease.”
Another feature of the study was that when T cells reached the lungs from the lymph glands, they received signals that switched on the production of two powerful inflammatory substances: the cytokines interleukin 5 and 13. These cytokines are responsible for many of our normal asthma symptoms, such as respiratory tract inflammation, muscle contraction and mucus discharge.
“Our observation is that the T cells change a great deal over time and seem to undergo a kind of reprogramming in the lungs that makes them highly inflammatory,” Dr Coquet said.
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