Michael Roth, Research Group Leader at University Hospital Basel asks if disturbed cell-cell interaction causes asthma and provides a fascinating response
Asthma is the most prevalent lung chronic disease and despite decades of research, the available therapies allow only symptom control but do no cure. Asthma attacks can be caused by inhaled pollen, dust mite faeces, cockroach faeces, mould spores, flour dust, hay dust, and animal dander through an allergic reaction. Other asthma triggers not directly linked to allergies are: smoke from open fires, cigarettes, industry, cooking, gas/oil heaters, or chemical fumes, organic dust from farming or thunderstorms, air pollution, strong perfumes, odours, or medications that affect the cyclo-oxygenase metabolism. Non-allergic asthma causes are sportive activities, anger, pain, fear or sudden changes in air temperature or humidity.
All these asthma triggers rapidly induce: i) airway constriction by muscle contraction; ii) inflammation, iii) infiltration of immune cells (Th-2 type), and iv) mucus production. In addition, the airway’s epithelium is deranged, the basal membrane’s thickness increased, sub-epithelial fibroblast rich tissue shows increased vascularisation and the bundles of airway smooth muscle cells are increased by cell size and number.
Inflammation in asthma can be well controlled by inhaled steroids, theophylins and humanised antibodies to IgE or specific cytokines. Muscle constriction is relieved by short or long-acting β2-agonists. In contrast, the structural airway wall changes are not affected by these therapies. Only short-term heat application by radiofrequency (bronchial thermoplasty), used to treat patients with severe asthma, reduced smooth muscle hyperplasia and hypertrophy. Bronchial thermoplasty lasting reduced exacerbation rate and hospital admission over more than five years. Tissue analysis showed reduced smooth muscle cell bundles, and regain a normal epithelium structure. These observations support the idea that the interaction of the airway wall cell types is disturbed in asthma, and may cause inflammation.
The airway epithelium is the first cell layer exposed to inhaled factors (pollen, dust, smoke etc). Inhaled particles are removed by tiny hairs (cilia) that cover the epithelial cells and all dirt is transported towards the throat where it is swallowed and removed from the body. In asthma, this mechanism works, but the epithelium allows some particles to penetrate into the tissue below where it causes inflammation.
In addition, epithelial cells express so-called “pattern recognition receptors” which respond to inhaled factors. Thereby, they stimulate the epithelial cells to secrete “danger proteins”. This response sets cytokines free which activate dendritic and immune cells with the aim to remove the cause. In a healthy lung, this response may subside after the cause of inflammation has been removed, while in asthma it seems to continue for longer. Due to the lack of knowledge about these mechanisms in a healthy lung, we do not well understand what happens in asthma.
The importance of the epithelium for the proper function of our airway has been highlighted by the fact that pre-term born children show an immature lung structure at birth which is maintained for life if not treated with steroids. We know that the lung of a baby does not enter the last stage of development until the 36th week of pregnancy. Thus, the lungs are one of the organs that matures latest, moreover, its maturation continues through the first year of life. In the case of pre-term birth, the maturation of the lungs slows down or even stops. When untreated, this leads to asthma/COPD like symptoms in adolescence.
Lung maturation depends on the finely controlled interaction of epithelial cells with the underlying connective tissue fibroblasts, dendritic cells and smooth muscle cells. This interaction was termed the Epithelial-Mesenchymal-Unit (EMTU). In this concept, all tissue forming cells and immune cells act together to build and maintain the structure and function of the airways. Besides controlling the EMTU by secreted cytokines and growth factors, cells can exchange small molecules (peptides, microRNAs) through a “protein-tube” that links neighbouring cell to each other. If such mechanism(s) can be confirmed in asthma, they may present novel therapeutic targets and new therapeutic strategies.
Airway smooth muscle cells and fibroblast form the airway wall, control its constriction, elasticity, and stimulate or limit cell growth. These cells produce the extracellular matrix which clues the cells together. In asthma patients, these cells constitutively show increased secretion of pro-inflammatory proteins and, thereby, activated immune cells, as well as increased mitochondria activity and proliferation. These cell type-specific pathologies are maintained for weeks in the laboratory and can be studied, but not many laboratories have access to patient tissues. Genetic studies could not prove a single gene being responsible for asthma, and other mechanisms, for example, structure modification of the DNA, RNA or histones may explain the pathologies. In human asthma tissue, structural changes occur within less than one week in sensitive individuals, and it is unknown if these changes are repaired after the removal of the cause.
The fine-tuning of cell-cell interactions has to consider the extracellular matrix which glues the cells together. This cell-free component consists of collagens, fibres, sugars and growth factors. In a healthy lung, about 10% of it is remodelled every day. Some degradation products of collagens, statins, limit muscle cell growth and help re-epithelisation. In asthma, the metabolism of the extracellular matrix seems to be disturbed, but due to the complex interactions too little is known to understand the mechanism.
In the past, our research was focused on the effect of a specific drug, growth factor, or cytokine on the response of specific a cell type, without caring about what will happen in the neighbour cells. We know much about these specific responses, but we do not understand enough of the subsequent cell-cell interactions. Proteomic, transcriptomic and other –omics provide more information than we ever had before. However, like in earlier studies, this information only reflects the status of a cell or organ at this time point, it does not show – action et reaction.
In order to understand interactions and feedback mechanisms between cell types in health and disease expensive time consuming, more detailed studies are required to prove the claimed mechanisms are needed. Only then we will be able to progress and develop a cure for asthma and other diseases.
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Michael Roth
Research Group Leader
University Hospital Basel
Tel: +41 61 265 2337
https://biomedizin.unibas.ch/en/research/research-groups/roth-tamm-lab/
