The lungs are always under assault by harmful environmental factors, but they endure because they embody processes that are alert to tissue damage—and poised to implement hasty repairs. And since the lungs’ barricades are made neither of paving stones, nor of timbers, nor of iron, but of cells and proteins, any understanding of the lungs’ regenerative processes must come from this level, along the microscopic and submicroscopic battlefront, taking in the trafficking of molecules, the cellular secretions, the activating factors, and the contents of the extracellular matrix.
A particularly detailed look at how the lungs sustain the extracellular matrix (ECM) during injury and repair was undertaken by scientists at the Helmholtz Zentrum München and the Max Plank Institute of Biochemistry. These scientists used mass spectrometry techniques to quantify and profile dynamic change in the composition of the lung tissue through the different phases of lung regeneration.
The scientists presented their results July 14 in the journal EMBO Molecular Systems Biology, in an article entitled, “Time- and compartment-resolved proteome profiling of the extracellular niche in lung injury and repair.” The article detailed how the scientists monitored remodeling of the extracellular niche in a mouse model of lung injury.
“Mass spectrometry quantified 8,366 proteins from total tissue and bronchoalveolar lavage fluid (BALF) over the course of 8 weeks, surveying tissue composition from the onset of inflammation and fibrosis to its full recovery,” wrote the authors. “Combined analysis of proteome, secretome, and transcriptome highlighted post-transcriptional events during tissue fibrogenesis and defined the composition of airway epithelial lining fluid.”
Of particular interest were the proteins that are deemed crucial for tissue healing, such as proteins involved in activating specific stem cell populations. For example, the study noted that the ECM proteome contains potential factors in stem cell mobilization and fibrosis resolution.
“We directly measured the interactions of morphogens and other secreted proteins with the ECM in an unbiased way, revealing those that are bound to the matrix, signaling from that location or awaiting release by specific activating events,” explained the authors. “The time-resolved proteomic signatures revealed candidate molecular players for both the mobilization of multipotent epithelial progenitor cells early after injury and the resolution of fibrosis later in regeneration.”
“The information we have gained about the dynamic changes in ECM composition and its interactions with various secreted growth factor proteins enables us to develop new hypotheses for the activation of stem cells in the lung,” added Dr. Herbert Schiller, a researcher at the Max Planck Institute of Biochemistry and first author of the study.
According to the World Health Organization (WHO), lung diseases are the third most common cause of death worldwide: toxic particles, infections, and chronic inflammatory responses pose a permanent threat to our lungs. To date, the regenerative mechanisms leading to healing of lung injury remain incompletely understood. Since few to no causal therapies are in place for most lung diseases, it is important to understand how these healing processes, which involve initial inflammation, fibrosis, and then resolution thereof, occur in the lung.
The current study, which was led by Prof. Matthias Mann, director at the MPI of Biochemistry, and Prof. Oliver Eickelberg, chairman of the Comprehensive Pneumology Center (CPC) at the Helmholtz Zentrum München and University Hospital of the Ludwig-Maximilians-Universität, may help guide further translational research on the development of pulmonary fibrosis and chronic lung diseases in general. “These novel mass spectrometry techniques enable us to analyze variations in the type and abundance of proteins in patients with lung fibrosis and healthy individuals and will therefore likely lead to new approaches for the treatment of chronic lung diseases in general and lung fibrosis in particular,” predicted Prof. Eickelberg.