Proteomic characterization of human alveolar epithelial cells during pathological remodeling in chronic obstructive pulmonary disease

Bakgrund:

Improving treatment of chronic obstructive pulmonary disease (COPD) is an essential task in medicine due to a huge socioeconomic impact with severe suffering and increasing prevalence. The pathological remodelling is dominated by fibrotic remodelling of small airways, resulting in airflow restriction and emphysematous remodelling of the alveolar tissue.

The extracellular matrix (ECM) is crucial for determining the structure of the alveoli and influence cellular function both through its composition and by conveying mechanical stimuli. There is a reciprocal connection between the ECM and cells, where the ECM supplies signals to the cells, and cells maintain the ECM by a continual turnover. Production of ECM by epithelial cells in bronchioles is known to be crucial for repair after epithelial damage but little is known regarding the capacity for ECM production by alveolar epithelium.

Målsättning:

This project aims to expand our knowledge of the role of the alveolar epithelium in preserving the structural integrity of the lung, by characterizing its proteomics and in the pursuit, identify new therapeutic avenues targeting emphysema in COPD. Arbetsplan:

We will study ECM turnover using a tissue culture system, i.e. acellular slices of human lung tissue. By a proteomics technique which makes us differentiate newly synthesized proteins from repopulating cell, from proteins of the lung tissue, we hope to identify specific patterns in the matrix production of alveolar epithelial cells form healthy individuals and COPD patients.

To capture the dynamics of protein production, samples for mass spectrometry and immunohistochemistry will be collected at different timepoints. Results will be confirmed in intact patient derived tissue with immunohistological stainings for specific proteins and in situ hybridization for verifying active gene expression. Tissue samples from >20 COPD patients and an equal number of healthy subjects are available for evaluation.

Betydelse:

This first mapping of the ECM production will provide knowledge of the role of alveolar epithelial cells structural tissue homeostasis in health and in COPD, which would be of value to find new biomarkers for disease activity and the development of therapeutic strategies targeting alveolar epithelial cells to stop the progression of emphysema, by promoting production of a healthy ECM.