Millions of people around the globe are affected by chronic lung diseases, for which only symptomatic treatments exist. As life expectancy increases, the prevalence of age-related lung diseases is also rising swiftly. These conditions impose a significant social and economic burden, yet there remains a limited understanding of the underlying mechanisms.
Asthma and Chronic Obstructive Pulmonary Disease (COPD)
Allergic asthma and Chronic Obstructive Pulmonary Disease (COPD) are truly debilitating respiratory conditions and literally breath-taking diseases. They are marked by persistent airway inflammation, hyperreactivity, and structural changes of the lungs resulting from abnormal responses to inhaled allergens, pathogens and harmful substances, including cigarette smoke. Unfortunately, current therapeutic approaches cannot reverse these structural alterations. The pathophysiological differences between allergic asthma and COPD are not fully understood, highlighting the need for new insights into the molecular and cellular mechanisms that drive these diseases.
We propose that the airway epithelium plays a critical role in the onset of these airway diseases, serving as the first line of defense against environmental threats. Moreover, the epithelium is not only a physical barrier, it also plays a vital role in initiating and regulating immune and inflammatory responses, as well as in tissue repair and remodeling processes in response to these environmental insults. Notably, not everyone develops asthma or COPD after exposure, indicating a potential genetic factor at play. Interestingly, many susceptibility genes linked to asthma and COPD are found to be expressed in the airway epithelium.
Consequently, a significant focus of our research is on how allergens and cigarette smoke affect airway epithelial cells, their interactions with immune cells like Th2 lymphocytes, and other structural cells involved in tissue repair, along with the implications for disease development. Mouse models and human clinical studies are used to translate these in vitro findings to the real life situation.
Fibrotic lung diseases
Idiopathic pulmonary fibrosis (IPF) is a major progressive and debilitating lung disease with poor prognosis and limited treatment options. It is characterised by chronic inflammation, lung remodelling and fibrosis where normal lung tissue is replaced by excessive proteins that fill the spaces where gas exchange usually happens, resulting in severe breathing difficulties. It is ultimately fatal with a mean survival after diagnosis of ~2-5 years. The changes in the lung tissue in fibrosis are complex and thought to result from failed attempts by the body to repair the damaged tissue. As a result, the lung tissue integrity is lost and replaced by disorganised structural cells and abnormal deposition of proteins.
Many of these lung diseases are characterised by changes in the structure of the three-dimensional (3D) mesh of proteins and other molecules that surrounds all lung cells. This flexible mesh of proteins is called the extracellular matrix (ECM). A major research line in our lab focuses on the role of the disease altered ECM as an active contributor, and not just an end-stage of the disease. Recent evidence suggests that the modified ECM interacts with cells affecting their functions. Our research team is one of the few who consider the role of both the embedded, deposited ECM and the soluble, either precursor forms or cleaved fragments released during tissue repair or injury in driving cellular responses within this tissue environment. We are developing advanced 3D models of the the lung to facilitate greater examination of the interaction of cells with the 3D microenvironment that is created by the ECM in their local environment. We are bringing together advanced microscopic examination of the 3D space and cellular monitoring to address important research questions.
Our laboratory is part of the Groningen Research Institute for Asthma and COPD ( www.griac.nl ), in which different basic and clinical disciplines work closely together in a scientifically stimulating environment to translate research findings from bedside to bench and back.