Damage to lungs may start with early immune cells in childhood CF: Study
Findings could help researchers develop therapies to slow disease progression
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The lungs of infants and children with cystic fibrosis (CF) show an early, overactive immune response driven by neutrophils — a type of immune cell — even in a patient receiving CFTR modulator therapy, a small study suggests.
The findings suggest that inflammatory processes that damage the lungs may begin very early in life and persist despite treatments targeting the underlying cause of CF. Understanding these immune changes may help researchers develop new therapies that could slow disease progression.
The study, “The single-cell transcriptional landscape of the pediatric cystic fibrosis lung from minimally invasive respiratory specimens,” was published in the journal Scientific Reports.
Not all CF patients benefit from CFTR modulators
In CF, a defective CFTR protein results in the production of abnormally thick, sticky mucus that builds up in the lungs and other organs. In the lungs, this mucus creates an environment that promotes persistent infections, leading to chronic inflammation that gradually damages the airways and reduces lung function.
Research has shown that these lung changes can start very early in life. In fact, signs such as mucus buildup and inflammation are detected in most infants in the first few months of life, while bacterial infections, airway changes, and decreased lung function have been described within the first year of life.
Newer treatments known as CFTR modulators help restore the activity of the defective CFTR protein and can significantly improve outcomes for many patients, particularly when started soon after newborn screening. However, some people with CF cannot take these therapies or do not benefit from them, making it important to better understand how lung disease begins and progresses early in life.
Recent studies have started to map the different immune and airway cells present in CF lungs. However, results have sometimes differed regarding which immune cells are most prominent. Additionally, there’s still limited information on how immune and airway cells interact.
Macrophages in CF lungs appeared more inflammatory
In this study, researchers at the Icahn School of Medicine at Mount Sinai in New York analyzed individual lung cells from children with and without CF using a technique called single-cell RNA sequencing. This approach looks at each cell’s genetic activity to know which genes are turned on or off at that exact moment.
The goal was to clarify the early cellular changes that occur in CF lungs and uncover potential targets for new therapies that could be used alongside or instead of CFTR modulators.
The researchers analyzed cells from two pediatric patients with CF — a 10-month-old boy and a 16-year-old girl — and three children without CF.
Samples were collected using minimally invasive procedures. Cells lining the airways, called epithelial cells, were collected by gently rotating a small brush over the tracheal and bronchial surfaces. Immune cells from the lower airways were collected using bronchoalveolar lavage, a procedure in which fluid is introduced into the lungs and then retrieved for analysis.
Overall, the researchers analyzed more than 20,000 individual cells, which were grouped into major immune cell types, including neutrophils, macrophages, T-cells, and B-cells, as well as basal, ciliated, and secretory epithelial cells.
Results showed that in samples from children without CF, macrophages — immune cells that help maintain lung health and remove debris — were the most abundant immune cell type. In contrast, neutrophils, which serve as the first line of defense against infection, were the most common immune cells in samples from the CF lungs.
Macrophages in CF lungs also appeared more inflammatory. In particular, the researchers found a higher proportion of macrophages producing CCL18, a signaling molecule linked to immune activation, while non-CF samples contained more of the more common lung macrophages.
Epithelial cells may actively shape neutrophil-driven inflammation
T-cells were detected in both groups, but they were relatively less abundant in CF samples. This finding is consistent with previous research suggesting that intense neutrophil activity in CF airways may suppress T-cell responses and limit their presence in airway spaces.
The researchers also examined epithelial cells collected from tracheal and bronchial brushings. While the overall proportions of basal, ciliated, and secretory cells were similar between CF and control samples, epithelial cells in CF lungs showed signs of immune and inflammatory activation.
When the researchers examined how airway epithelial cells and neutrophils “talk” to each other, they found that epithelial cells in CF lungs frequently initiated interactions with neutrophils, sending both pro-inflammatory and anti-inflammatory signals.
This suggests that airway epithelial cells may actively shape or regulate neutrophil-driven inflammation rather than simply being passive victims of inflammation.
Overall, the results point to a “dysregulated, neutrophil-dominant inflammation and an accompanying pro-inflammatory airway epithelium in the pediatric CF lung,” the researchers wrote.
They noted that larger studies will be needed to determine how early these inflammatory patterns arise and whether they contribute to the progression of lung disease in CF.
A better understanding of these early cellular interactions could help guide the development of new anti-inflammatory therapies to complement existing CFTR-targeting treatments, they said.
