Chronic Inflammatory Lung Diseases . Tissue remodelling . Cell differentiation. Inflammation
Pulmonary Cell Research
Tissue remodelling in different compartments of the lung is a pathology shared in all chronic inflammatory lung diseases including asthma, chronic obstructive inflammatory disease (COPD, smoker’s lung), and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Tissue remodelling occurs in a disease-specific pattern and a disease-specific compartment of the lung. The consequence of tissue remodelling is the loss of structure and function in a disease-specific pattern. Neither the origins nor the initiation of tissue remodelling is well-understood in any of the chronic inflammatory diseases. The long-held hypothesis that chronic inflammation causes remodelling is questioned by increasing number of studies showing that this pathology occurs often without preceding inflammation and the fact that anti-inflammatory drugs have no effect on tissue remodelling.
In asthma, the major structural change is an increase of bronchial smooth muscle cells and extracellular matrix deposition in the large and medium size airways. This increases the constriction of the airways during an asthma attack, thicken the airway wall, modifies tissue flexibility, and thereby reduces the breathing capacity. Neither anti-inflammatory drugs, nor muscle relaxing drugs, nor new biological drugs, have any effect on tissue remodelling in asthma. Therefore, the American Thoracic Society declared that the major focus on future studies should focus on the understanding of the origin of airway wall remodelling. In a series of studies, we provided evidence that remodelling in asthma results from epigenetic events that affect cell differentiation and mitochondrial activity, which increases proliferation and changes the composition of the extracellular matrix.
In COPD, tissue remodelling occurs in the medium and small airways, as well as in the peripheral lung. The structural changes similar to those described in asthma. The local composition of the extracellular matrix seems to play a more important role in the loss of tissue function than in asthma. Furthermore, the balance between de novo synthesis and degradation of collagens I, III, IV, V and VI, as well as the content of hyaluronic acid, heparan sulfate, and chondroitin sulfate play a role in the progression of the disease. The interaction of the different extracellular matrix components with each other and with embedded cells is further complicated by the fact that certain degradation products such as statins, results from collagen degradation inhibiting inflammation and proliferation, while others stimulates both events. These local changes of the extracellular matrix composition have a feedback mechanism on cell differentiation and function, especially on epithelial cells and bronchial smooth muscle cells. None of the available therapies has any proven effect on tissue remodelling in COPD. In two studies, we have shown that the serum levels of hyaluronic acid and collagen degradation products might be used as indicators for tissue remodelling and severity in COPD.
Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, and irreversible interstitial lung disease characterized by a progressive loss of lung function, limited therapeutic options and high mortality. The initial events leading to the development and progression of IPF are still not elucidated, however, evidence suggests that repeated injury to the alveolar epithelial cells and an expansion of stem-like cells within the alveolar region play a central role. Wedemonstrated the disease-enriched presence of stem-like cells in the peripheral lung parenchyma of patients with IPF and other interstitial lung diseases (ILD). Furthermore, we revealed a disease-specific transcriptomic difference in stem-like cells derived from IPF when compared to other ILD patients. The in vitro culture of disease-enriched primary stem-like cells from fibrotic lung tissue allows us to study their role and function in IPF, which will result in a better understanding of disease development and progression.
In summary, our studies highlighted new aspects that may lead to a better understanding of the origin of tissue remodelling in chronic inflammatory lung diseases. Our findings might provide a new basis for pharmaceutical industry to develop disease-specific anti-remodelling therapies.